Development of Photosensitive Doxorubicin-Fe3+-Gallic Acid Nanoparticle Structure for Targeted Cancer Therapy

Development of Photosensitive Doxorubicin-Fe3+-Gallic Acid Nanoparticle Structure for Targeted Cancer Therapy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Development of Photosensitive Doxorubicin-Fe3+-Gallic Acid Nanoparticle Structure for Targeted Cancer Therapy Özge Özten, Engin Deniz Parlar, Mustafa Zahid YILDIZ, Mustafa CAN This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7104368/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Photodynamic therapy (PDT) is a medically recognized method with selective cytotoxic activity against cancer cells. In PDT, photosensitizer (PS) drugs produce singlet oxygen ( 1 O 2 ) that causes cell death when activated by light. One of the drug groups that has recently become prominent in cancer therapy studies is coordination polymer-based nanoparticles (CPNs). Gallic acid (GA) has strong antioxidant, antimutagenic, anticancer and anti-inflammatory properties. In addition, it has very high biocompatibility and can be easily absorbed by the human body. For this reason, it is widely applied for antitumor or anticancer treatments. Therefore, gallic acid is a promising natural polyphenolic compound for PDT applications. In addition, iron (Fe 3+ ) element is a metal widely applied in cancer treatment. Accordingly, a nano-sized CPN structure to be formed with GA and Fe 3+ is expected to be an effective FS in cancer treatment applications with PDT. In this study, Fe 3+ -GA nanoparticle material synthesis was carried out as a CPN structure. GA and Fe + 3 were selected as organic ligands and inorganic crosslinkers, respectively. Here, Fe + 3 -GA nanoparticles were first synthesized and then doxorubicin (DOX) was attached to the structure to obtain Fe 3+ -GA-DOX nanoplatforms. This obtained nanoplatform was verified by UV-Vis, FT-IR and TEM measurements. UV spectrum result was taken for PDT studies and LED light source design was carried out. LED light source was designed as 455 ± 10 nm. After determining the toxicity of the obtained nanoparticle structure in healthy (HUVEC) and cancerous (MCF-7) cell lines, PDT studies were started and it was determined that the obtained nanoparticle structure reduced cell viability depending on the dose increase in the cancerous cell line without harming the healthy cell line (p < 0.01**). The effective GA-Fe 3+ -DOX doses were determined as 70, 75 and 80 µg/ml (p < 0.01**). At these determined doses, power densities of 2, 4, 6, 8, 10, 12, 14, 16, 18, 20 J/cm 2 were applied and the most effective dose and power densities were determined as 80 µg/ml and 20J/cm 2 , respectively, according to increasing power densities. Gallic acid İron Doxorubicin Photodynamic therapy Cancer Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Introduction Breast cancer represents a major global health problem as it is the most frequently diagnosed malignant tumor worldwide. Due to the multitude of causes of breast cancer, preventive measures are necessary to increase awareness of risk factors and early diagnosis. The size of the tumor depends on clinical and pathological features. Diagnostic tools are a helpful tool in finding the tumor. In a case where the tumor is in a difficult to access area, it may be difficult to accurately determine its size [ 1 ]. The scope of diagnosis and treatment of breast cancer is very wide, but it remains one of the most lethal neoplasms [ 2 ]. Surgery, radiotherapy, chemotherapy, immunotherapy and hormone therapy are the main methods of cancer treatment. These techniques are applied to the treatment of both early and advanced stages of the tumor [ 3 ]. Despite the many tools available, new technologies are still needed to treat all stages of breast cancer. A relatively new treatment method that may be the gold standard in the treatment of neoplastic changes compared to traditional methods is photodynamic therapy (PDT) [ 4 ]. Photodynamic therapy (PDT) is a medically recognized method with selective cytotoxic activity against cancer cells; the treatment involves PS localization irradiated with a specific wavelength of light compatible with the absorbance band of the photosensitizer [ 5 ]. Since the PDT method is based on the activation of PS specifically in cancer cells, it attracts attention in cancer treatment due to its advantages such as low cost, high localization, development of drugs suitable for a specific tumor type, low side effects and tissue damage. PDT has three main components. These are PS, light source and oxygen. None of them are toxic alone, but when they come together and interact, they produce ROS. ROS cause significant toxicity in the cell through apoptosis or necrosis [ 5 ]. In PDT, PSs, when activated by light, produce singlet oxygen ( 1 O 2 ), which causes cell death. After the energy from the light is absorbed by FS, it is transferred to oxygen atoms commonly found in the living microenvironment. Here, cell death occurs with two different reaction types, type 1 and type 2. In the type 1 mechanism, ROS formation is triggered by electron exchange between PS and different substrates. In the type 2 mechanism, ROS species are formed by the direct reaction of high-energy PS with molecular oxygen [ 6 ]. The main method for the production of singlet oxygen ( 1 O 2 ) is photosensitization reactions. Singlet oxygen interacts with molecules in excited states in the environment it is in and rapidly transforms these molecules. Generally, the effectiveness of PDT is related to the amount of singlet oxygen produced in the tumor tissue. In other words, PDT is related to the singlet oxygen formed in the cancer cell as a result of radiation and its effectiveness is evaluated depending on the concentration of molecular oxygen in the tissue [ 7 ]. A successful PDT procedure requires photoactivation of PS with light. The entry of light into the tissue to be treated, its reflection, distribution and absorbance involve a complex process. The required parameters in this process vary according to the tissue type and the wavelength of light. Biological tissue is heterogeneous and heterogeneity in the microscopic environment (macromolecules, cell organelles, organized cell structure, intermediate layers) can cause blurring. In a cloudy environment, multiple scattering can cause a light beam to spread and lose direction. While blue light penetrates the tissue with the least efficiency, red light and infrared radiation can penetrate more deeply [ 4 , 7 ]. Light up to approximately 800 nm in the region between 600 and 1200 nm, called the optical window of the tissue, can produce singlet oxygen ( 1 O 2 ). Many light source systems are used and developed within the scope of PDT. Halogen lamps, LED lights, laser light sources can be given as examples of these light sources. Laser light is one of the primary light sources for activation because it is monochromatic, very sensitive and very intense. Light emitting diodes (LEDs) are gaining more attention due to their convenience and longer treatment times compared to lasers. LEDs provide a wide range of wavelengths in the range of 350–1100 nm and can be designed in different configurations and sizes [ 4 ]. Since the function of the light source in PDT is to activate the PSs, the preferred PSs are as important as the light source. PDT drugs contain PS molecules that produce reactive oxygen species under near infrared light (NIR) for the removal of tumor tissue [ 8 ]. PS is usually an aromatic compound that can transfer energy from light to molecular oxygen and lead to the formation of toxic singlet oxygen that causes cell death [ 9 ]. The properties that an ideal PS should provide include chemical purity, selectivity for tumor cells, chemical and physical stability, short time interval between application and maximum accumulation in tumor tissue, and optimal tissue penetration [ 7 ]. Many PS substances such as phthalocyanines, boron dipyrromethene, porphyrins, chlorins, 5-aminolevulinic acid (5-ALA), nanoparticles, etc. have been used as drugs in cancer treatment studies with PDT, and efforts have been made to develop the most suitable and efficient PS substances for the method [ 10 , 11 , 12 , 13 ]. One of the drug groups that have recently come to the forefront in cancer therapy studies is coordination polymer-based nanoparticles (CPNs), and these materials are also known as nano-sized metal-organic frameworks (MOFs) [ 14 , 15 ]. They are a hybrid material class formed by the self-assembly of metal ions or clusters and organic polydentate bridging ligands. CPNs and MOFs are widely used in nanomedicine due to their advantages such as biodegradability, easy surface modification, and their capacity to load various imaging and therapeutic molecules. It is known that coordination polymer-based nanoparticles have natural biocompatibility, can be gradually degraded without causing concerns about long-term retention and toxicity [ 14 , 15 , 16 ]. Therefore, CPNs are prominent substances in PDT applications to be applied for cancer treatment, and developing new CPN materials in this direction is of interest. Gallic acid (GA) (3,4,5-trihydroxybenzoic acid) is a natural polyphenolic compound found in eucalyptus, cranberries and other plants. Gallic acid is a trihydroxy benzoic acid with a group attached at positions 3, 4 and 5. It is in yellowish-white crystalline form. It is an endogenous plant polyphenol found abundantly in tea, grapes, fleshy and rindless fruits. It is also found in plant species such as oak and chestnut. GA can be obtained by hydrolysis of tannic acids. GA has strong antioxidant, antimutagenic, anticancer and anti-inflammatory properties. In addition, it has very high biocompatibility and can be easily absorbed by the human body [ 18 , 19 , 20 ]. For this reason, it is widely applied for antitumor or anticancer treatments. Therefore, gallic acid is a promising natural polyphenolic compound for PDT applications. However, iron element is a metal widely used in cancer treatment [ 14 , 18 , 21 ]. Accordingly, a nano-sized CPN structure formed with gallic acid and iron is expected to be an effective PS in cancer treatment applications with PDT. In addition, studies have shown that the effect of GA and DOX in cancer treatment increases when GA is applied together with DOX [ 18 , 22 ]. DOX is an anthracycline-based antineoplastic agent. It is used in the treatment of different types of cancer such as breast cancer and bladder cancer [ 23 ]. The therapeutic performance of DOX includes poor aqueous files, tumor drug resistance and cumulative dose-dependent side effects such as cardiac cytotoxicity, hepatotoxicity. [ 18 ]. It has been reported that GA increases the treatment of leukemia when given together with DOX. [ 24 ]. The aim of this research paper is to design and evaluate targeted DOX loaded gallic acid-iron nanoparticles (GA-Fe + 3 -DOX). The effective cytotoxicity and in vitro evaluation of this nanoparticle structure was carried out. Ying et al. (2022) developed a new strategy using injectable agarose hydrogel (AG) to perform local chemodynamic (CDT)/photothermal therapy (PTT) with FeGA-DOX NPs to achieve osteosarcoma tumor suppression in in vivo studies. As a result of these applications, they obtained an integrable result for PTT in clinical studies [ 18 ]. Zeng et al. (2016) successfully developed a new type of PAI-PTT nanotheranostic agent based on pH-sensitive Fe 3+ -gallic acid complex. In their in vitro experiments, they stated that Fe (III)-gallic acid nanoparticles are an effective photothermal agent, exhibit low toxicity and excellent photothermal ablation of cancer cells [ 24 ]. Sharma et al. (2019) studied the gallic acid-copper nanostructure they synthesized both in vitro and in vivo. In their in vitro studies, they determined that both gallic acid and DOX triggered apoptosis against MCF-7 cancer cells. They also reached the same conclusion by supporting their in vitro studies with in vivo studies [ 25 ]. Ying et al. (2022) conducted a study on chemodynamic and sonodynamic therapy by synthesizing injectable agarose hydrogels and GA-Fe-DOX [ 18 ]. However, the PDT activity of GA-Fe-DOX nanoplatforms in cancer cells was not demonstrated. In this study, Fe-gallic acid nanoparticle material synthesis was carried out as a CPN structure. GA and Fe were selected as organic ligands and inorganic crosslinkers, respectively. Here, Fe-GA nanoparticles were first synthesized, and then doxorubicin (DOX) was added to the structure to obtain DOX-Fe-GA nanoplatforms. The toxicity of the obtained DOX-Fe-GA in MCF-7 cancer cells was investigated, and PDT studies were performed based on the obtained results. Materials and Methods 1.1. Chemical Materials Iron III chloride anhydrous (FeCl 3 ), Gallic acid (C 6 H 2 (OH) 3 COOH), Doxorubicin (C 27 H 29 NO 11 ), Dimethyl sulfoxide (DMSO) and trypan blue dye were purchased from Sigma (St. Louis, Mo, USA). Fetal bovine serum (FBS), Phosphate Buffered Saline (PBS), Dulbecco's Modified Eagle Medium F12 (DMEM F12), Dulbecco's Minimum Essential Medium (DMEM), 0.25% Trypsin-EDTA were purchased from Gibco, Thermo Fisher Scientific (Waltham, MA, USA). 1.2. Instruments In the synthesis of FeCl 3 -GA, a magnetic heating stirrer (Heidolph MR HEI, Heidolph Instruments GmbH Co. Germany) and a precision weighing device (WSA-24, Sentez Optik Elektronik ve Endüstriyel Cihazlar Müh. Tic. Ltd.., Istanbul, Turkey) were used. UV (Spectrostar nano, BMG Labtech, Germany) and FTIR (Perkin Elmer Inc., USA) analyses were performed for Fe-GA synthesis characterization. TEM images were taken with a FEI TALOS F200S 200 kV (Thermo Fisher Scientific, Waltham, Massachusetts, USA) microscope. Synthesis of Fe 3+ -Gallic Acid Nanoparticles and DOX-Fe-Gallic Acid Nanoparticles 100 mg of polyvinylpyrrolidone (PVP) was dissolved in 10 ml of water at room temperature under vigorous stirring. Then, a FeCl 3 aqueous solution (0.2 ml, 100 mg/mL) was added to the PVP aqueous solution. After 1 h of incubation, a GA aqueous solution (1 ml, 10 mg/mL) was added to the above reaction mixture and stirred overnight. PVP also acts as a protective polymer during the nucleation and growth processes of coordination polymer nanodots. The amide moieties of PVP are weakly coordinated to Fe 3+ ions. Therefore, PVP can sterically stabilize the nanodots. The resulting coordination polymer nanoparticles (CPN or MOF) were filtered through black fine filter paper and stored in a refrigerator for later use [ 14 , 17 , 18 ]. The prepared Fe 3+− GA (100µg in 1mL PBS) and DOX (100µg in 1mL PBS) were mixed [ 18 ]. The molecular structure of the synthesized Fe 3+ -GA-DOX nanoparticle structure is given in Fig. 1 . 1.3. Cell Culture For cell culture studies, HUVEC (CRL-1730), an endothelial cell line isolated from the umbilical cord vein, and MCF-7 breast cancer cell line were purchased from the American Type Culture Collection (ATCC). For HUVEC cell line, L-glutamine, non-essential amino acids, sodium pyruvate, 10% Fetal Bovine serum (FBS) (Gibco, Thermo Fisher Scientific, Waltham, MA, USA) supplemented with 100 µg/ml Penicillin (Gibco, Thermo Fisher Scientific, Waltham, MA, USA) and 100µg/ml Streptomycin (Gibco, Thermo Fisher Scientific, Waltham, MA, USA) were grown in DMEM-F12 (Dulbecco’s modified eagle medium F-12) medium (Gibco, Thermo Fisher Scientific (Waltham, MA, USA) and MCF-7 cell line L-glutamine, non-essential amino acids, sodium pyruvate, 10% Fetal Bovine serum (FBS) supplemented with 100µg/ml Penicillin and 100µg/ml Streptomycin were grown in DMEM (Dulbecco’s modified eagle medium) supplemented with 5% CO 2 in an incubator at 37˚C. 1.4. Cell Viability Studies Cell Counting Kit-8 (CCK-8) test is a reliable and easily applicable colorimetric cell viability determination method widely used in cell proliferation and cytotoxicity assessments. CCK-8 test contains WST-8 (2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium monosodium salt), a water-soluble tetrazolium salt. This compound is reduced to water-soluble orange formazan derivatives by mitochondrial dehydrogenase enzymes of living cells [ 26 ]. The amount of formazan product formed is directly proportional to the number of viable cells and is usually measured spectrophotometrically at a wavelength of 450 nm. Unlike other tetrazolium-based tests (e.g. MTT), the WST-8 reduced product is water soluble, so no dissolution step is required, making the test faster and non-toxic [ 28 ]. For cytotoxicity studies, HUVEC and MCF-7 cells were seeded in 96-well plates with the respective media at a density of 1×10 4 cells per well. Fe-GA and Fe-GA-DOX were incubated at different concentrations for 24 h. Cell viabilities were determined by CCK-8 assay. 1.5. Statistical analysis The GraphPad Prism 6.0 program was used for statistical analysis s. The differences between groups were assessed by One Way ANOVA (Post-hoc Tukey) analysis. p < 0.05 was considered statistically significant. Experiments were repeated three times. Results and Discussion 3.1. Characterization of GA-Fe 3+ -DOX Gallic acid is a type of polyphenol that can react with Fe 3+ to form a stable GA n -Fe 3+ complex via the formation of Fe 3+− phenolate carboxylate coordination bonds. PVP-Fe 3+ complexes are formed immediately upon mixing PVP and Fe 3+ in water at ambient temperature. The incorporation of GA into the aqueous dispersion of PVP-Fe 3+ complexes allows the formation of MOF nanodots in the reactive site of the complexes where GA comes into contact with Fe 3+ . PVP also acts as a protective polymer during the nucleation and growth processes of coordination polymer nanodots because the amide moieties of PVP are weakly coordinated to Fe 3+ ions. Therefore, PVP can sterically stabilize the nanodots. 3.1.1. GA-Fe 3+ -DOX FTIR Analysis Since GA is a polyphenolic compound, it shows characteristic peaks in the FTIR spectrum. The broad and intense peak intensity in the region between 3400 − 3200 cm⁻¹ indicates the presence of hydroxyl (-OH) groups. Since GA has three phenolic -OH groups and one carboxylic acid -OH group, a strong peak is observed in this region. In addition, the peak intensity in this range shows the density of hydrogen bonds. The sharp peaks in the 1700 − 1680 cm⁻¹ range belong to the carboxylic acid (C = O) group. Since GA is a benzoic acid derivative, it shows a characteristic carbonyl peak in this region. The peaks in 1300 − 1000 cm⁻¹ belong to the phenolic and carboxylic acid C-O stretching vibrations. The peaks in this region are due to the stretching and bending vibrations of the C-O bonds. The peaks located at 900 − 650 cm⁻¹ show the C-H bending vibrations of the aromatic ring [ 28 ]. In the FTIR spectrum for the GA-Fe 3+ nanoparticle structure, the peaks located at 3400 − 3200 cm⁻¹ are caused by the binding of the -OH groups of gallic acid to Fe 3+ ions, causing the peak in this region to widen and its intensity to decrease. This situation shows that the hydroxyl groups form coordination bonds. The peak observed at 1700 − 1680 cm⁻¹ is due to the binding of the carboxylic acid (C = O) group to Fe 3+ ions, causing changes in the frequency and intensity of this peak. Decreases can be observed in the frequency of the carbonyl peak due to the coordination that occurs with the binding of Fe 3+ ions. The peaks observed at 1600 − 1450 cm⁻¹ show that the Fe 3+ ions interact with the substituents on the benzene ring. Phenolic and carboxylic acid (C-O) stretching vibrations located at 1300 − 1000 cm⁻¹ change with Fe 3+ binding. In particular, the formation of Fe-O bonds causes the emergence of new peaks in this region or the shift of existing peaks. The presence of peaks located at 500–600 cm⁻¹ is due to the interaction between iron oxide and GA in the nanoparticle structure, and new peaks belonging to Fe-O vibrations are observed around 500–600 cm⁻¹. These peaks confirm that Fe 3+ ions form coordination bonds with GA (Fig. 2 ). 3.1.2. GA-Fe 3+ -DOX UV Analysis Ying, H. et al. (2022) studied “Injectable agar hydrogels and doxorubicin-encapsulated iron-gallic acid nanoparticles for chemodynamic-photothermal synergistic therapy against osteosarcoma”. According to the results obtained in the UV-vis absorption analysis of FeGA-DOX, they stated that FeGA-DOX has a broad absorption spectrum of 600–800 nm, indicating that FeGA-DOX has a high potential for photothermal conversion in the NIR-I region [ 18 ]. GA, as a phenolic compound, shows an absorption peak around 270 nm. The peak seen around 270 nm in the spectrum is consistent with the presence of GA. Since Fe 3+ ions form complexes with GA and DOX, they can cause changes in the location and intensity of the peaks in the spectrum. The presence of Fe ions can show changes in the spectrum depending on the structure and type of the complex. DOX characteristically shows a strong absorption peak in the range of 480–520 nm. This peak is due to the anthracycline structure of DOX. The peak in this range in the spectrum confirms the presence of DOX. Doxorubicin also shows an absorption peak in the range of 250–300 nm. This peak is due to the π-π* transitions of aromatic rings [ 18 ]. The peak in this range in the spectrum also supports the presence of DOX. The wavelength peak in the obtained UV spectrum was found to be 455 nm (Fig. 3 ). 3.1.3. GA-Fe + 3 and GA-Fe 3+ -DOX TEM İmages 3.1.3.1. GA-Fe + 3 TEM İmages The prepared Fe 3+ –GA nanoparticle structure was visualized by TEM and it was determined that it had a crystalline structure ( Fig. 4 ) . In the obtained images, it was determined that the Fe + 3 –GA nanoparticle structure was homogeneously distributed and had a diameter of approximately 5–7 nm. In the microscope image at 50 nm, a structure with distinct edges and a cubic morphology is seen. These crystalline structures show that the coordination bonds between Fe³⁺ ions and GA form a regular structure. In addition, the particles generally appear as compact structures. In the microscope image at 100 nm, larger structures are seen than in the image at 50 nm. This indicates that the particles tend to grow or coalesce. Thus, it shows that the GA-Fe 3+ nanoparticle structure is formed. 3.1.3.2. GA-Fe 3+ -DOX TEM İmages The image at 1 µm shows the general morphology and distribution of the nanoparticles. It shows that the nanoparticles are spherical and monodisperse [ 29 ]. This reveals that the structure formed by the coordination of gallic acid and Fe³⁺ ions is well dispersed but shows a tendency for partial agglomeration [ 30 ]. The image at 2 nm reveals the presence of crystal structures. The parallel lines represent crystal planes. This situation shows that the gallic acid complexes interacting with Fe³⁺ ions gain a certain crystallinity. This structure is a feature frequently encountered in metal-phenolic coordination complexes. At 10 nm, a core-shell-like structure can be observed in the image. The dense part in the middle is the coordination complex formed by Fe³⁺- GA, and the less dense layer in the outer part belongs to DOX. At 20 nm, the image shows that particles of different sizes and shapes coexist. Some of the interlocking structures are thought to be multinuclear systems. Such structures may indicate high drug loading capacity, and the more open structures seen on the outside may exhibit porous structure or hydrogel-like properties with a tendency to swell in biological media (Fig. 5 ) [ 31 ]. 3.2. Cell Viability Against Normal and Cancer Cell Lines Cell viability test was performed using HUVEC and MCF-7 cell lines. Each cell line was treated with different concentrations of GA, Fe + 3 -GA- and Fe + 3 -GA-DOX for 24 h, and 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, monosodium salt (CCK-8) test was used to determine cell viability. It was determined that GA and GA-Fe + 3 and Fe + 3 -GA-DOX had no toxicity against HUVEC and MCF-7 cell lines (Table 1 and Fig. 6 ). Table 1 Toxicity results of HUVEC and MCF-7 cell lines against GA, GA-Fe + 3 and GA-Fe + 3 -DOX in CCK-8 test (p < 0.01**). HUVEC GA GA-Fe GA-Fe-DOX MCF-7 GA GA-Fe GA-Fe-DOX Control 100 100 100 Control 100 100 100 5 100 100 100 5 100 100 99.17 ± 6.02 10 100 100 100 10 100 100 98.356 ± 5.45 15 100 100 100 15 100 100 97.84 ± 5.09 20 100 100 100 20 100 100 96.51 ± 4.15 25 100 100 100 25 100 100 95.11 ± 3.16 30 100 100 100 30 100 100 93.21 ± 1.81 35 100 100 100 35 100 100 90.63 ± 0.01 40 100 100 100 40 100 100 89.77 ± 0,75 45 100 100 100 45 100 100 88.61 ± 1.44 50 100 100 100 50 100 100 87.11 ± 1.76 55 100 100 98.73 ± 0.26 55 100 100 86.53 ± 2.90 60 100 100 97.10 ± 0.89 60 100 100 85.79 ± 3.43 65 100 100 96.06 ± 1.62 65 100 100 84.16 ± 4.58 70 100 100 94.11 ± 3.00 70 100 100 83.35 ± 5.15 75 100 100 93.46 ± 3.46 75 100 100 82.95 ± 5.44 80 100 100 92.77 ± 3.95 80 100 100 82.04 ± 6.08 3.3. PDT Studies in MCF-7 Cell Line 3.3.1. Light Source Design Depending on the UV spectrum of Fe 3+ -GA-DOX obtained in PDT studies, 455 ± 10 nm light source was designed and measured by compact spectrometer (Thorlabs (Type: CCS200/M), Germany) (Fig. 8 ). According to the obtained results, PDT studies were performed on the MCF-7 cell line. In all experiments, the wavelength of the LED light source was determined as 465 nm with ± 10 nm. Power densities of 2,4,6,8,10,12,14,16,18,20 J/cm 2 were determined for LED radiation (Fig. 7 ). The output power was measured with a power meter (PM100 Thorlabs Germany) before the experiment. The fluence rate was used to obtain different power densities at 30 mW/cm 2 (Table 2 ). Control cells were incubated with fresh medium in the same medium without radiation. Table 2 Radiation Parameters Wavelength (nm) 465 ± 10 nm Power Output 30 mW Energy Density (J/cm 2 ) 2,4,6,8,10,12,14,16,18,20 PS GA-Fe + 3 -DOX According to the results obtained, it was observed that cell viability decreased depending on the increasing dose (Fe-GA-DOX) and increasing energy density (p < 0.01**). Effective doses were determined as 80 µg/ml and effective energy densities were determined as 20J/cm 2 (p < 0.01**) (Table 3 and Fig. 8 ). Table 3 Toxicity results of CCK-8 application according to effective doses on MCF-7 cells after LED irradiation (p < 0.01**). 70 µg/ml 75µg/ml 80µg/ml 2 93.12 ± 2.70 91.63 ± 3.32 91.52 ± 3.28 4 91.11 ± 1.28 90.18 ± 2.29 90.24 ± 2.37 6 90.01 ± 0.50 89.01 ± 1.47 89.58 ± 1.91 8 89.25 ± 0.03 88.35 ± 1.00 88.74 ± 1.31 10 89.12 ± 0.12 87.85 ± 0.64 87.01 ± 0.09 12 88.22 ± 0.76 86.28 ± 0.45 86.14 ± 0,52 14 88.16 ± 0.80 85.18 ± 1.23 85.01 ± 1.32 16 88.01 ± 0.90 84.07 ± 2.02 84.01 ± 2.02 18 87.99 ± 0.92 83.54 ± 2.39 83.99 ± 2.04 20 87.98 ± 0.93 83.21 ± 2.63 82.54 ± 3.06 In this study, DOX-loaded Fe 3+ -Gallic acid nanoparticles (DOX-Fe 3+ -GA) were synthesized. After the synthesis, FTIR analysis and TEM images were taken to confirm the structure. UV spectrum result was taken for PDT studies and LED light source design was carried out. LED light source was designed as 455 ± 10 nm. Before the experiment, the output power was measured with a power meter (PM100 Thorlabs Germany). The fluence rate was used to obtain different power densities at 30 mW/cm 2 . After determining the toxicity of the obtained nanoparticle structure in healthy (HUVEC) and cancerous (MCF-7) cell lines, PDT studies were started and it was determined that the obtained nanoparticle structure reduced cell viability depending on the dose increase in the cancerous cell line without harming the healthy cell line (p < 0.01**) (Fig. 9 ). Experiments were repeated 3 times in terms of accuracy. Liu et al. (2022) studied pH-sensitive Fe-gallic acid coordination polymer for multimodal synergistic therapy and MRI in cancer treatment. Based on their results, they synthesized Fe–GA/BSA nanostructures combined with bovine serum albumin (BSA). While the Fe–GA/BSA@DOX structure, formed by loading doxorubicin (DOX), maintained 80‑90% viability in normal cells (293, HKC), viability decreased significantly ( 125 µg/mL), demonstrating effective antitumor activity. The gallic acid–Fe(III)–DOX complex exhibited similar or higher cytotoxicity than free DOX, indicating that the carrier is functional and provides effective passive targeting to the tumor [ 32 ]. When the cytotoxicity results of our PDT studies were evaluated, it was determined that the viability rate of PS generated from MCF cells was significantly reduced compared to the HUVEC cell line (p < 0.01**). It is thought that the presented studies can be improved by supporting the obtained in vitro data with in vivo experiments in future studies. Declarations Author Contribution Ö.Ö. proposed the project. Ö.Ö. E.D.P., M.Z.Y. and M.C. designed the experimental and laboratory studies. Ö.Ö., E.D.P, and M.C. carried out experimental and characterization studies. M.C., and Ö.Ö. assembled the data, and wrote the manuscript. Acknowledgment This research was supported by Sakarya University of Applied Sciences Scientific Research Projects Coordination Unit (Project Number: 152–2023). 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Eur J Med Chem 220:113438. 10.1016/j.ejmech.2021.113438 Huang L, Asghar S, Zhu T, Ye P, Hu Z, Chen Z, Xiao Y (2021) Advances in chlorin-based photodynamic therapy with nanoparticle delivery system for cancer treatment. Expert Opin Drug Deliv 18(10):1473–1500. 10.1080/17425247.2021.1950685 Gomes AT, Neves MG, Cavaleiro JA (2018) Cancer, photodynamic therapy and porphyrin-type derivatives. An Acad Bras Cienc 90:993–1026. 10.1590/0001-3765201820170811 Li R, Zhou Y, Liu Y, Jiang X, Zeng W, Gong Z, Dai Z (2022) Asymmetric, amphiphilic RGD conjugated phthalocyanine for targeted photodynamic therapy of triple negative breast cancer. Signal Transduct Target Therapy 7(1):64. 10.1038/s41392-022-00906-2 Jin Q, Zhu W, Jiang D, Zhang R, Kutyreff CJ, Engle JW, Cheng L (2017) Ultra-small iron-gallic acid coordination polymer nanoparticles for chelator-free labeling of 64 Cu and multimodal imaging-guided photothermal therapy. 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Front Chem 10:1045612. 10.3389/fchem.2022.1045612 Verma S, Singh A, Mishra A (2013) Gallic acid: Molecular rival of cancer. Environ Toxicol Pharmacol 35(3):473–485. 10.1016/j.etap.2013.02.011 Locatelli C, Filippin-Monteiro FB, Creczynski-Pasa TB (2013) Alkyl esters of gallic acid as anticancer agents: A review. Eur J Med Chem 60:233–239. 10.1016/j.ejmech.2012.10.056 Cheng J, Zhu Y, Xing X, Xiao J, Chen H, Zhang H, Liu Y (2021) Manganese-deposited iron oxide promotes tumor-responsive ferroptosis that synergizes the apoptosis of cisplatin. Theranostics 11(11):5418. 10.7150/thno.53346 Shao Y, Luo W, Guo Q, Li X, Zhang Q, Li J (2019) In vitro and in vivo effect of hyaluronic acid modified, doxorubicin and gallic acid co-delivered lipid-polymeric hybrid nano-system for leukemia therapy. Drug design, development and therapy , 2043–2055. 10.2147/DDDT.S202818 El-Ghareb WI, Swidan MM, Ibrahim IT, El-Bary A, Tadros A, Sakr MI, T. M (2020) 99mTc-Doxorubicin-loaded gallic acid-gold nanoparticles (99mTc-DOX-loaded GA-Au NPs) as a multifunctional theranostic agent. Int J Pharm 586:119514. 10.1016/j.ijpharm.2020.119514 Xiong XB, Ma Z, Lai R, Lavasanifar A (2010) The therapeutic response to multifunctional polymeric nano-conjugates in the targeted cellular and subcellular delivery of doxorubicin. Biomaterials 31(4):757–768. 10.1016/j.biomaterials.2009.09.080 Shao Y, Luo W, Guo Q, Li X, Zhang Q, Li J (2019) In vitro and in vivo effect of hyaluronic acid modified, doxorubicin and gallic acid co-delivered lipid-polymeric hybrid nano-system for leukemia therapy. Drug design, development and therapy , 2043–2055. 10.2147/DDDT.S202818 Stoddart MJ (2011) Cell viability assays: introduction. Mammalian cell viability: methods and protocols , 1–6. 10.1007/978-1-4939-6960-9 Tominaga H, Ishiyama M, Ohseto F, Sasamoto K, Hamamoto T, Suzuki K, Watanabe M (1999) A water-soluble tetrazolium salt useful for colorimetric cell viability assay. Anal Commun 36(2):47–50. 10.1039/A809656B Wang T, Sun Y, Li A, Ma Y, Feng D, Fang Y, Dai S (2017) A general synthesis of abundant metal nanoparticles functionalized mesoporous graphitized carbon. RSC Adv 7(80):50966–50972. 10.1039/C7RA09560K Zen Zeng J, Cheng M, Wang Y, Wen L, Chen L, Li Z, Chai Z (2016) pH-Responsive Fe (III)–Gallic Acid Nanoparticles for In Vivo Photoacoustic‐Imaging‐Guided Photothermal Therapy. Adv Healthc Mater 5(7):772–780. 10.1002/adhm.201500898 Sharma S, Mittal D, Verma AK, Roy I (2019) Copper-gallic acid nanoscale metal–organic framework for combined drug delivery and photodynamic therapy. ACS Appl Bio Mater 2(5):2092–2101. 10.1021/acsabm.9b00116 Liu Y, Ai K, Lu L (2014) Polydopamine and its derivative materials: synthesis and promising applications in energy, environmental, and biomedical fields. Chem Rev 114(9):5057–5115. 10.1021/cr400407a Liu C, Li C, Jiang S, Zhang C, Tian Y (2022) pH-responsive hollow Fe–gallic acid coordination polymer for multimodal synergistic-therapy and MRI of cancer. Nanoscale Adv 4(1):173–181. 10.1039/d1na00721a Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7104368","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":491504279,"identity":"62440cc5-dc10-43a3-b5f3-1cdebdce4960","order_by":0,"name":"Özge Özten","email":"","orcid":"","institution":"Sakarya University of Applied Sciences","correspondingAuthor":false,"prefix":"","firstName":"Özge","middleName":"","lastName":"Özten","suffix":""},{"id":491504280,"identity":"54b87ecd-2aeb-44f8-8cd2-f7e70c0e282b","order_by":1,"name":"Engin Deniz Parlar","email":"","orcid":"","institution":"Sakarya University of Applied Sciences","correspondingAuthor":false,"prefix":"","firstName":"Engin","middleName":"Deniz","lastName":"Parlar","suffix":""},{"id":491504281,"identity":"c2f98a5c-4bfa-4723-9510-75e0ada73efd","order_by":2,"name":"Mustafa Zahid YILDIZ","email":"","orcid":"","institution":"Sakarya University of Applied Sciences","correspondingAuthor":false,"prefix":"","firstName":"Mustafa","middleName":"Zahid","lastName":"YILDIZ","suffix":""},{"id":491504282,"identity":"98b8d3f1-d36d-4fa3-b164-785cc6acaa52","order_by":3,"name":"Mustafa CAN","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA50lEQVRIiWNgGAWjYNACGxDBfICBsQHESCCoHqguDUSzJSC0HCBOC48BcVp0Z6Q/f/AjwU6ef3bP58+8Ow4z8LPnGDB/3INbi9mNHMPGnoRkwxl3zm6T5j1zmEGy540Bw4FneLUwNvD+YE5guJG7jZm37TCDwY0coBY8LjO7kf6w8U9CfYL8jZzHn0Fa7AlrSTBs5kk4nAA0nEEabIsEIS1n3hjOlkk4brjxRpqZ5Nwz6TwSZ54VHDiDT8vx9Acf3yRUy8vdSH784e0Oazn+9uSNDyrwaMEAPCCCFA2jYBSMglEwCrAAAN6pWkwV8HmcAAAAAElFTkSuQmCC","orcid":"","institution":"Sakarya University of Applied Sciences","correspondingAuthor":true,"prefix":"","firstName":"Mustafa","middleName":"","lastName":"CAN","suffix":""}],"badges":[],"createdAt":"2025-07-11 20:23:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7104368/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7104368/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":87736091,"identity":"27395984-2d13-4849-b655-577ccff93366","added_by":"auto","created_at":"2025-07-28 12:32:52","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":40073,"visible":true,"origin":"","legend":"\u003cp\u003eSchematic representation of Fe\u003csup\u003e+3\u003c/sup\u003e-GA-DOX nanoparticle structure\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7104368/v1/f7eebc32cf9fb703d5c2fca5.png"},{"id":87736092,"identity":"ee84c8e7-405f-44e8-ac16-36d68217c92d","added_by":"auto","created_at":"2025-07-28 12:32:52","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":69362,"visible":true,"origin":"","legend":"\u003cp\u003eGA and Fe\u003csup\u003e3+\u003c/sup\u003e-GA FTIR analysis result\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7104368/v1/1ab56fedf6d645d9129da0d8.png"},{"id":87737132,"identity":"2ceaf097-d3d1-4da7-8e8b-26a8056d9114","added_by":"auto","created_at":"2025-07-28 12:40:52","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":34574,"visible":true,"origin":"","legend":"\u003cp\u003eGA and Fe\u003csup\u003e3+\u003c/sup\u003e-GA-DOX UV analysis result\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7104368/v1/4fa510eaf4b51f5c71e87612.png"},{"id":87736097,"identity":"965a3c6c-1fa6-4cc6-9c76-37d2cfd88725","added_by":"auto","created_at":"2025-07-28 12:32:52","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":527382,"visible":true,"origin":"","legend":"\u003cp\u003eFe\u003csup\u003e3+\u003c/sup\u003e-GA TEM image \u003cstrong\u003ea) \u003c/strong\u003e50 nm, \u003cstrong\u003eb)\u003c/strong\u003e 100 nm,\u003cstrong\u003e c) \u003c/strong\u003e200 nm\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-7104368/v1/74ad508c53eeb00714b16496.png"},{"id":87737133,"identity":"0262935b-62c8-4364-90c8-17bfd58caa7f","added_by":"auto","created_at":"2025-07-28 12:40:52","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":968228,"visible":true,"origin":"","legend":"\u003cp\u003eFe\u003csup\u003e3+\u003c/sup\u003e-GA-DOX TEM image \u003cstrong\u003ea) \u003c/strong\u003e1 µm, \u003cstrong\u003eb)\u003c/strong\u003e 2 nm,\u003cstrong\u003e c) \u003c/strong\u003e5nm \u003cstrong\u003ed)\u003c/strong\u003e 10 nm\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-7104368/v1/b62e1d452c73f66ded3ce55f.png"},{"id":87736096,"identity":"c0ce7aab-4714-4c66-99b1-a74b74f4dca5","added_by":"auto","created_at":"2025-07-28 12:32:52","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":73517,"visible":true,"origin":"","legend":"\u003cp\u003eResults of CCK-8 analysis of viability percentages of \u003cstrong\u003eA \u003c/strong\u003eHUVEC and \u003cstrong\u003eB \u003c/strong\u003eMCF-7cells for GA, GA-Fe and GA-Fe-DOX dose determination (p \u0026lt;0.01**).\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-7104368/v1/b8a533ba89ff03045731da59.png"},{"id":87736098,"identity":"ebca9f54-2460-4324-86c3-cf4804f92af6","added_by":"auto","created_at":"2025-07-28 12:32:53","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":89775,"visible":true,"origin":"","legend":"\u003cp\u003eWavelength spectrum of the light source used for PDT application of Fe\u003csup\u003e3+\u003c/sup\u003e-GA-DOX nanoparticles\u003c/p\u003e","description":"","filename":"7.png","url":"https://assets-eu.researchsquare.com/files/rs-7104368/v1/883a93742277fa55c198629e.png"},{"id":87736094,"identity":"88cbcd80-f2d9-408a-9a23-c6d987c691f2","added_by":"auto","created_at":"2025-07-28 12:32:52","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":20480,"visible":true,"origin":"","legend":"\u003cp\u003eResults of CCK-8 analysis of viability percentages of MCF-7 cells after LED irradiation at different power density (p \u0026lt;0.01**).\u003c/p\u003e","description":"","filename":"8.png","url":"https://assets-eu.researchsquare.com/files/rs-7104368/v1/501aa65f7ec5e581f9c0c173.png"},{"id":87736107,"identity":"a3e97231-ba66-4380-9542-a01cb0872156","added_by":"auto","created_at":"2025-07-28 12:32:53","extension":"png","order_by":9,"title":"Figure 9","display":"","copyAsset":false,"role":"figure","size":14575,"visible":true,"origin":"","legend":"\u003cp\u003eResults of CCK-8 application versus effective doses of MCF-7 cells after LED irradiation (p \u0026lt;0.01**).\u003c/p\u003e","description":"","filename":"9.png","url":"https://assets-eu.researchsquare.com/files/rs-7104368/v1/e765391f76b7d1e0f457f293.png"},{"id":97201769,"identity":"afec130b-7c61-433c-a654-3f55b8142fb3","added_by":"auto","created_at":"2025-12-02 01:08:49","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2776268,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7104368/v1/21dcef8f-b330-4106-b377-980b9738832e.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Development of Photosensitive Doxorubicin-Fe3+-Gallic Acid Nanoparticle Structure for Targeted Cancer Therapy","fulltext":[{"header":"Introduction","content":"\u003cp\u003eBreast cancer represents a major global health problem as it is the most frequently diagnosed malignant tumor worldwide. Due to the multitude of causes of breast cancer, preventive measures are necessary to increase awareness of risk factors and early diagnosis. The size of the tumor depends on clinical and pathological features. Diagnostic tools are a helpful tool in finding the tumor. In a case where the tumor is in a difficult to access area, it may be difficult to accurately determine its size [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The scope of diagnosis and treatment of breast cancer is very wide, but it remains one of the most lethal neoplasms [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Surgery, radiotherapy, chemotherapy, immunotherapy and hormone therapy are the main methods of cancer treatment. These techniques are applied to the treatment of both early and advanced stages of the tumor [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Despite the many tools available, new technologies are still needed to treat all stages of breast cancer. A relatively new treatment method that may be the gold standard in the treatment of neoplastic changes compared to traditional methods is photodynamic therapy (PDT) [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e\u003cp\u003ePhotodynamic therapy (PDT) is a medically recognized method with selective cytotoxic activity against cancer cells; the treatment involves PS localization irradiated with a specific wavelength of light compatible with the absorbance band of the photosensitizer [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Since the PDT method is based on the activation of PS specifically in cancer cells, it attracts attention in cancer treatment due to its advantages such as low cost, high localization, development of drugs suitable for a specific tumor type, low side effects and tissue damage. PDT has three main components. These are PS, light source and oxygen. None of them are toxic alone, but when they come together and interact, they produce ROS. ROS cause significant toxicity in the cell through apoptosis or necrosis [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In PDT, PSs, when activated by light, produce singlet oxygen (\u003csup\u003e1\u003c/sup\u003eO\u003csub\u003e2\u003c/sub\u003e), which causes cell death. After the energy from the light is absorbed by FS, it is transferred to oxygen atoms commonly found in the living microenvironment. Here, cell death occurs with two different reaction types, type 1 and type 2. In the type 1 mechanism, ROS formation is triggered by electron exchange between PS and different substrates. In the type 2 mechanism, ROS species are formed by the direct reaction of high-energy PS with molecular oxygen [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The main method for the production of singlet oxygen (\u003csup\u003e1\u003c/sup\u003eO\u003csub\u003e2\u003c/sub\u003e) is photosensitization reactions. Singlet oxygen interacts with molecules in excited states in the environment it is in and rapidly transforms these molecules. Generally, the effectiveness of PDT is related to the amount of singlet oxygen produced in the tumor tissue. In other words, PDT is related to the singlet oxygen formed in the cancer cell as a result of radiation and its effectiveness is evaluated depending on the concentration of molecular oxygen in the tissue [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eA successful PDT procedure requires photoactivation of PS with light. The entry of light into the tissue to be treated, its reflection, distribution and absorbance involve a complex process. The required parameters in this process vary according to the tissue type and the wavelength of light. Biological tissue is heterogeneous and heterogeneity in the microscopic environment (macromolecules, cell organelles, organized cell structure, intermediate layers) can cause blurring. In a cloudy environment, multiple scattering can cause a light beam to spread and lose direction. While blue light penetrates the tissue with the least efficiency, red light and infrared radiation can penetrate more deeply [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Light up to approximately 800 nm in the region between 600 and 1200 nm, called the optical window of the tissue, can produce singlet oxygen (\u003csup\u003e1\u003c/sup\u003eO\u003csub\u003e2\u003c/sub\u003e). Many light source systems are used and developed within the scope of PDT. Halogen lamps, LED lights, laser light sources can be given as examples of these light sources. Laser light is one of the primary light sources for activation because it is monochromatic, very sensitive and very intense. Light emitting diodes (LEDs) are gaining more attention due to their convenience and longer treatment times compared to lasers. LEDs provide a wide range of wavelengths in the range of 350\u0026ndash;1100 nm and can be designed in different configurations and sizes [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Since the function of the light source in PDT is to activate the PSs, the preferred PSs are as important as the light source.\u003c/p\u003e\u003cp\u003ePDT drugs contain PS molecules that produce reactive oxygen species under near infrared light (NIR) for the removal of tumor tissue [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. PS is usually an aromatic compound that can transfer energy from light to molecular oxygen and lead to the formation of toxic singlet oxygen that causes cell death [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The properties that an ideal PS should provide include chemical purity, selectivity for tumor cells, chemical and physical stability, short time interval between application and maximum accumulation in tumor tissue, and optimal tissue penetration [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Many PS substances such as phthalocyanines, boron dipyrromethene, porphyrins, chlorins, 5-aminolevulinic acid (5-ALA), nanoparticles, etc. have been used as drugs in cancer treatment studies with PDT, and efforts have been made to develop the most suitable and efficient PS substances for the method [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eOne of the drug groups that have recently come to the forefront in cancer therapy studies is coordination polymer-based nanoparticles (CPNs), and these materials are also known as nano-sized metal-organic frameworks (MOFs) [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. They are a hybrid material class formed by the self-assembly of metal ions or clusters and organic polydentate bridging ligands. CPNs and MOFs are widely used in nanomedicine due to their advantages such as biodegradability, easy surface modification, and their capacity to load various imaging and therapeutic molecules. It is known that coordination polymer-based nanoparticles have natural biocompatibility, can be gradually degraded without causing concerns about long-term retention and toxicity [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Therefore, CPNs are prominent substances in PDT applications to be applied for cancer treatment, and developing new CPN materials in this direction is of interest.\u003c/p\u003e\u003cp\u003eGallic acid (GA) (3,4,5-trihydroxybenzoic acid) is a natural polyphenolic compound found in eucalyptus, cranberries and other plants. Gallic acid is a trihydroxy benzoic acid with a group attached at positions 3, 4 and 5. It is in yellowish-white crystalline form. It is an endogenous plant polyphenol found abundantly in tea, grapes, fleshy and rindless fruits. It is also found in plant species such as oak and chestnut. GA can be obtained by hydrolysis of tannic acids. GA has strong antioxidant, antimutagenic, anticancer and anti-inflammatory properties. In addition, it has very high biocompatibility and can be easily absorbed by the human body [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. For this reason, it is widely applied for antitumor or anticancer treatments. Therefore, gallic acid is a promising natural polyphenolic compound for PDT applications. However, iron element is a metal widely used in cancer treatment [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Accordingly, a nano-sized CPN structure formed with gallic acid and iron is expected to be an effective PS in cancer treatment applications with PDT. In addition, studies have shown that the effect of GA and DOX in cancer treatment increases when GA is applied together with DOX [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. DOX is an anthracycline-based antineoplastic agent. It is used in the treatment of different types of cancer such as breast cancer and bladder cancer [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. The therapeutic performance of DOX includes poor aqueous files, tumor drug resistance and cumulative dose-dependent side effects such as cardiac cytotoxicity, hepatotoxicity. [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. It has been reported that GA increases the treatment of leukemia when given together with DOX. [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe aim of this research paper is to design and evaluate targeted DOX loaded gallic acid-iron nanoparticles (GA-Fe\u003csup\u003e+\u0026thinsp;3\u003c/sup\u003e-DOX). The effective cytotoxicity and in vitro evaluation of this nanoparticle structure was carried out. Ying et al. (2022) developed a new strategy using injectable agarose hydrogel (AG) to perform local chemodynamic (CDT)/photothermal therapy (PTT) with FeGA-DOX NPs to achieve osteosarcoma tumor suppression in in vivo studies. As a result of these applications, they obtained an integrable result for PTT in clinical studies [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Zeng et al. (2016) successfully developed a new type of PAI-PTT nanotheranostic agent based on pH-sensitive Fe\u003csup\u003e3+\u003c/sup\u003e-gallic acid complex. In their in vitro experiments, they stated that Fe (III)-gallic acid nanoparticles are an effective photothermal agent, exhibit low toxicity and excellent photothermal ablation of cancer cells [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Sharma et al. (2019) studied the gallic acid-copper nanostructure they synthesized both in vitro and in vivo. In their in vitro studies, they determined that both gallic acid and DOX triggered apoptosis against MCF-7 cancer cells. They also reached the same conclusion by supporting their in vitro studies with in vivo studies [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Ying et al. (2022) conducted a study on chemodynamic and sonodynamic therapy by synthesizing injectable agarose hydrogels and GA-Fe-DOX [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. However, the PDT activity of GA-Fe-DOX nanoplatforms in cancer cells was not demonstrated. In this study, Fe-gallic acid nanoparticle material synthesis was carried out as a CPN structure. GA and Fe were selected as organic ligands and inorganic crosslinkers, respectively. Here, Fe-GA nanoparticles were first synthesized, and then doxorubicin (DOX) was added to the structure to obtain DOX-Fe-GA nanoplatforms. The toxicity of the obtained DOX-Fe-GA in MCF-7 cancer cells was investigated, and PDT studies were performed based on the obtained results.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e1.1. Chemical Materials\u003c/h2\u003e\u003cp\u003eIron III chloride anhydrous (FeCl\u003csub\u003e3\u003c/sub\u003e), Gallic acid (C\u003csub\u003e6\u003c/sub\u003eH\u003csub\u003e2\u003c/sub\u003e(OH)\u003csub\u003e3\u003c/sub\u003eCOOH), Doxorubicin (C\u003csub\u003e27\u003c/sub\u003eH\u003csub\u003e29\u003c/sub\u003eNO\u003csub\u003e11\u003c/sub\u003e), Dimethyl sulfoxide (DMSO) and trypan blue dye were purchased from Sigma (St. Louis, Mo, USA). Fetal bovine serum (FBS), Phosphate Buffered Saline (PBS), Dulbecco's Modified Eagle Medium F12 (DMEM F12), Dulbecco's Minimum Essential Medium (DMEM), 0.25% Trypsin-EDTA were purchased from Gibco, Thermo Fisher Scientific (Waltham, MA, USA).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e1.2. Instruments\u003c/h2\u003e\u003cp\u003eIn the synthesis of FeCl\u003csub\u003e3\u003c/sub\u003e-GA, a magnetic heating stirrer (Heidolph MR HEI, Heidolph Instruments GmbH Co. Germany) and a precision weighing device (WSA-24, Sentez Optik Elektronik ve End\u0026uuml;striyel Cihazlar M\u0026uuml;h. Tic. Ltd.., Istanbul, Turkey) were used. UV (Spectrostar nano, BMG Labtech, Germany) and FTIR (Perkin Elmer Inc., USA) analyses were performed for Fe-GA synthesis characterization. TEM images were taken with a FEI TALOS F200S 200 kV (Thermo Fisher Scientific, Waltham, Massachusetts, USA) microscope.\u003c/p\u003e\u003cp\u003e\u003cb\u003eSynthesis of Fe\u003c/b\u003e\u003csup\u003e\u003cb\u003e3+\u003c/b\u003e\u003c/sup\u003e\u003cb\u003e-Gallic Acid Nanoparticles and DOX-Fe-Gallic Acid Nanoparticles\u003c/b\u003e\u003c/p\u003e\u003cp\u003e100 mg of polyvinylpyrrolidone (PVP) was dissolved in 10 ml of water at room temperature under vigorous stirring. Then, a FeCl\u003csub\u003e3\u003c/sub\u003e aqueous solution (0.2 ml, 100 mg/mL) was added to the PVP aqueous solution. After 1 h of incubation, a GA aqueous solution (1 ml, 10 mg/mL) was added to the above reaction mixture and stirred overnight. PVP also acts as a protective polymer during the nucleation and growth processes of coordination polymer nanodots. The amide moieties of PVP are weakly coordinated to Fe\u003csup\u003e3+\u003c/sup\u003e ions. Therefore, PVP can sterically stabilize the nanodots. The resulting coordination polymer nanoparticles (CPN or MOF) were filtered through black fine filter paper and stored in a refrigerator for later use [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. The prepared Fe\u003csup\u003e3+\u0026minus;\u003c/sup\u003eGA (100\u0026micro;g in 1mL PBS) and DOX (100\u0026micro;g in 1mL PBS) were mixed [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. The molecular structure of the synthesized Fe\u003csup\u003e3+\u003c/sup\u003e-GA-DOX nanoparticle structure is given in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e1.3. Cell Culture\u003c/h2\u003e\u003cp\u003eFor cell culture studies, HUVEC (CRL-1730), an endothelial cell line isolated from the umbilical cord vein, and MCF-7 breast cancer cell line were purchased from the American Type Culture Collection (ATCC). For HUVEC cell line, L-glutamine, non-essential amino acids, sodium pyruvate, 10% Fetal Bovine serum (FBS) (Gibco, Thermo Fisher Scientific, Waltham, MA, USA) supplemented with 100 \u0026micro;g/ml Penicillin (Gibco, Thermo Fisher Scientific, Waltham, MA, USA) and 100\u0026micro;g/ml Streptomycin (Gibco, Thermo Fisher Scientific, Waltham, MA, USA) were grown in DMEM-F12 (Dulbecco\u0026rsquo;s modified eagle medium F-12) medium (Gibco, Thermo Fisher Scientific (Waltham, MA, USA) and MCF-7 cell line L-glutamine, non-essential amino acids, sodium pyruvate, 10% Fetal Bovine serum (FBS) supplemented with 100\u0026micro;g/ml Penicillin and 100\u0026micro;g/ml Streptomycin were grown in DMEM (Dulbecco\u0026rsquo;s modified eagle medium) supplemented with 5% CO\u003csub\u003e2\u003c/sub\u003e in an incubator at 37˚C.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003e1.4. Cell Viability Studies\u003c/h2\u003e\u003cp\u003eCell Counting Kit-8 (CCK-8) test is a reliable and easily applicable colorimetric cell viability determination method widely used in cell proliferation and cytotoxicity assessments. CCK-8 test contains WST-8 (2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium monosodium salt), a water-soluble tetrazolium salt. This compound is reduced to water-soluble orange formazan derivatives by mitochondrial dehydrogenase enzymes of living cells [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. The amount of formazan product formed is directly proportional to the number of viable cells and is usually measured spectrophotometrically at a wavelength of 450 nm. Unlike other tetrazolium-based tests (e.g. MTT), the WST-8 reduced product is water soluble, so no dissolution step is required, making the test faster and non-toxic [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. For cytotoxicity studies, HUVEC and MCF-7 cells were seeded in 96-well plates with the respective media at a density of 1\u0026times;10\u003csup\u003e4\u003c/sup\u003e cells per well. Fe-GA and Fe-GA-DOX were incubated at different concentrations for 24 h. Cell viabilities were determined by CCK-8 assay.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003e1.5. Statistical analysis\u003c/h2\u003e\u003cp\u003eThe GraphPad Prism 6.0 program was used for statistical analysis s. The differences between groups were assessed by One Way ANOVA (Post-hoc Tukey) analysis. p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. Experiments were repeated three times.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results and Discussion","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003e3.1. Characterization of GA-Fe\u003csup\u003e3+\u003c/sup\u003e-DOX\u003c/h2\u003e\u003cp\u003eGallic acid is a type of polyphenol that can react with Fe\u003csup\u003e3+\u003c/sup\u003e to form a stable GA\u003csub\u003en\u003c/sub\u003e-Fe\u003csup\u003e3+\u003c/sup\u003e complex via the formation of Fe\u003csup\u003e3+\u0026minus;\u003c/sup\u003ephenolate carboxylate coordination bonds. PVP-Fe\u003csup\u003e3+\u003c/sup\u003e complexes are formed immediately upon mixing PVP and Fe\u003csup\u003e3+\u003c/sup\u003e in water at ambient temperature. The incorporation of GA into the aqueous dispersion of PVP-Fe\u003csup\u003e3+\u003c/sup\u003e complexes allows the formation of MOF nanodots in the reactive site of the complexes where GA comes into contact with Fe\u003csup\u003e3+\u003c/sup\u003e. PVP also acts as a protective polymer during the nucleation and growth processes of coordination polymer nanodots because the amide moieties of PVP are weakly coordinated to Fe\u003csup\u003e3+\u003c/sup\u003e ions. Therefore, PVP can sterically stabilize the nanodots.\u003c/p\u003e\u003cdiv id=\"Sec10\" class=\"Section3\"\u003e\u003ch2\u003e3.1.1. GA-Fe\u003csup\u003e3+\u003c/sup\u003e-DOX FTIR Analysis\u003c/h2\u003e\u003cp\u003eSince GA is a polyphenolic compound, it shows characteristic peaks in the FTIR spectrum. The broad and intense peak intensity in the region between 3400\u0026thinsp;\u0026minus;\u0026thinsp;3200 cm⁻\u0026sup1; indicates the presence of hydroxyl (-OH) groups. Since GA has three phenolic -OH groups and one carboxylic acid -OH group, a strong peak is observed in this region. In addition, the peak intensity in this range shows the density of hydrogen bonds. The sharp peaks in the 1700\u0026thinsp;\u0026minus;\u0026thinsp;1680 cm⁻\u0026sup1; range belong to the carboxylic acid (C\u0026thinsp;=\u0026thinsp;O) group. Since GA is a benzoic acid derivative, it shows a characteristic carbonyl peak in this region. The peaks in 1300\u0026thinsp;\u0026minus;\u0026thinsp;1000 cm⁻\u0026sup1; belong to the phenolic and carboxylic acid C-O stretching vibrations. The peaks in this region are due to the stretching and bending vibrations of the C-O bonds. The peaks located at 900\u0026thinsp;\u0026minus;\u0026thinsp;650 cm⁻\u0026sup1; show the C-H bending vibrations of the aromatic ring [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eIn the FTIR spectrum for the GA-Fe\u003csup\u003e3+\u003c/sup\u003e nanoparticle structure, the peaks located at 3400\u0026thinsp;\u0026minus;\u0026thinsp;3200 cm⁻\u0026sup1; are caused by the binding of the -OH groups of gallic acid to Fe\u003csup\u003e3+\u003c/sup\u003e ions, causing the peak in this region to widen and its intensity to decrease. This situation shows that the hydroxyl groups form coordination bonds. The peak observed at 1700\u0026thinsp;\u0026minus;\u0026thinsp;1680 cm⁻\u0026sup1; is due to the binding of the carboxylic acid (C\u0026thinsp;=\u0026thinsp;O) group to Fe\u003csup\u003e3+\u003c/sup\u003e ions, causing changes in the frequency and intensity of this peak. Decreases can be observed in the frequency of the carbonyl peak due to the coordination that occurs with the binding of Fe\u003csup\u003e3+\u003c/sup\u003e ions. The peaks observed at 1600\u0026thinsp;\u0026minus;\u0026thinsp;1450 cm⁻\u0026sup1; show that the Fe\u003csup\u003e3+\u003c/sup\u003e ions interact with the substituents on the benzene ring. Phenolic and carboxylic acid (C-O) stretching vibrations located at 1300\u0026thinsp;\u0026minus;\u0026thinsp;1000 cm⁻\u0026sup1; change with Fe\u003csup\u003e3+\u003c/sup\u003e binding. In particular, the formation of Fe-O bonds causes the emergence of new peaks in this region or the shift of existing peaks. The presence of peaks located at 500\u0026ndash;600 cm⁻\u0026sup1; is due to the interaction between iron oxide and GA in the nanoparticle structure, and new peaks belonging to Fe-O vibrations are observed around 500\u0026ndash;600 cm⁻\u0026sup1;. These peaks confirm that Fe\u003csup\u003e3+\u003c/sup\u003e ions form coordination bonds with GA (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec11\" class=\"Section3\"\u003e\u003ch2\u003e3.1.2. GA-Fe\u003csup\u003e3+\u003c/sup\u003e-DOX UV Analysis\u003c/h2\u003e\u003cp\u003eYing, H. et al. (2022) studied \u0026ldquo;Injectable agar hydrogels and doxorubicin-encapsulated iron-gallic acid nanoparticles for chemodynamic-photothermal synergistic therapy against osteosarcoma\u0026rdquo;. According to the results obtained in the UV-vis absorption analysis of FeGA-DOX, they stated that FeGA-DOX has a broad absorption spectrum of 600\u0026ndash;800 nm, indicating that FeGA-DOX has a high potential for photothermal conversion in the NIR-I region [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eGA, as a phenolic compound, shows an absorption peak around 270 nm. The peak seen around 270 nm in the spectrum is consistent with the presence of GA. Since Fe\u003csup\u003e3+\u003c/sup\u003e ions form complexes with GA and DOX, they can cause changes in the location and intensity of the peaks in the spectrum. The presence of Fe ions can show changes in the spectrum depending on the structure and type of the complex. DOX characteristically shows a strong absorption peak in the range of 480\u0026ndash;520 nm. This peak is due to the anthracycline structure of DOX. The peak in this range in the spectrum confirms the presence of DOX. Doxorubicin also shows an absorption peak in the range of 250\u0026ndash;300 nm. This peak is due to the π-π* transitions of aromatic rings [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. The peak in this range in the spectrum also supports the presence of DOX. The wavelength peak in the obtained UV spectrum was found to be 455 nm (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section3\"\u003e\u003ch2\u003e3.1.3. GA-Fe\u003csup\u003e+\u0026thinsp;3\u003c/sup\u003e and GA-Fe\u003csup\u003e3+\u003c/sup\u003e-DOX TEM İmages\u003c/h2\u003e\u003cdiv id=\"Sec13\" class=\"Section4\"\u003e\u003ch2\u003e3.1.3.1. GA-Fe\u003csup\u003e+\u0026thinsp;3\u003c/sup\u003e TEM İmages\u003c/h2\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe prepared Fe\u003csup\u003e3+\u003c/sup\u003e\u0026ndash;GA nanoparticle structure was visualized by TEM and it was determined that it had a crystalline structure \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e. In the obtained images, it was determined that the Fe\u003csup\u003e+\u0026thinsp;3\u003c/sup\u003e\u0026ndash;GA nanoparticle structure was homogeneously distributed and had a diameter of approximately 5\u0026ndash;7 nm. In the microscope image at 50 nm, a structure with distinct edges and a cubic morphology is seen. These crystalline structures show that the coordination bonds between Fe\u0026sup3;⁺ ions and GA form a regular structure. In addition, the particles generally appear as compact structures. In the microscope image at 100 nm, larger structures are seen than in the image at 50 nm. This indicates that the particles tend to grow or coalesce. Thus, it shows that the GA-Fe\u003csup\u003e3+\u003c/sup\u003e nanoparticle structure is formed.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section4\"\u003e\u003ch2\u003e3.1.3.2. GA-Fe\u003csup\u003e3+\u003c/sup\u003e-DOX TEM İmages\u003c/h2\u003e\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eThe image at 1 \u0026micro;m shows the general morphology and distribution of the nanoparticles. It shows that the nanoparticles are spherical and monodisperse [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. This reveals that the structure formed by the coordination of gallic acid and Fe\u0026sup3;⁺ ions is well dispersed but shows a tendency for partial agglomeration [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. The image at 2 nm reveals the presence of crystal structures. The parallel lines represent crystal planes. This situation shows that the gallic acid complexes interacting with Fe\u0026sup3;⁺ ions gain a certain crystallinity. This structure is a feature frequently encountered in metal-phenolic coordination complexes. At 10 nm, a core-shell-like structure can be observed in the image. The dense part in the middle is the coordination complex formed by Fe\u0026sup3;⁺- GA, and the less dense layer in the outer part belongs to DOX. At 20 nm, the image shows that particles of different sizes and shapes coexist. Some of the interlocking structures are thought to be multinuclear systems. Such structures may indicate high drug loading capacity, and the more open structures seen on the outside may exhibit porous structure or hydrogel-like properties with a tendency to swell in biological media (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003e3.2. Cell Viability Against Normal and Cancer Cell Lines\u003c/h2\u003e\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eCell viability test was performed using HUVEC and MCF-7 cell lines. Each cell line was treated with different concentrations of GA, Fe\u003csup\u003e+\u0026thinsp;3\u003c/sup\u003e-GA- and Fe\u003csup\u003e+\u0026thinsp;3\u003c/sup\u003e-GA-DOX for 24 h, and 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, monosodium salt (CCK-8) test was used to determine cell viability. It was determined that GA and GA-Fe\u003csup\u003e+\u0026thinsp;3\u003c/sup\u003e and Fe\u003csup\u003e+\u0026thinsp;3\u003c/sup\u003e-GA-DOX had no toxicity against HUVEC and MCF-7 cell lines (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eToxicity results of HUVEC and MCF-7 cell lines against GA, GA-Fe\u003csup\u003e+\u0026thinsp;3\u003c/sup\u003e and GA-Fe\u003csup\u003e+\u0026thinsp;3\u003c/sup\u003e-DOX in CCK-8 test (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01**).\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"8\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHUVEC\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGA\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eGA-Fe\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eGA-Fe-DOX\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMCF-7\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eGA\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eGA-Fe\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eGA-Fe-DOX\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eControl\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003eControl\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e5\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e5\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e99.17\u0026thinsp;\u0026plusmn;\u0026thinsp;6.02\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e10\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e10\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e98.356\u0026thinsp;\u0026plusmn;\u0026thinsp;5.45\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e15\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e15\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e97.84\u0026thinsp;\u0026plusmn;\u0026thinsp;5.09\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e20\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e20\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e96.51\u0026thinsp;\u0026plusmn;\u0026thinsp;4.15\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e25\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e25\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e95.11\u0026thinsp;\u0026plusmn;\u0026thinsp;3.16\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e30\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e30\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e93.21\u0026thinsp;\u0026plusmn;\u0026thinsp;1.81\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e35\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e35\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e90.63\u0026thinsp;\u0026plusmn;\u0026thinsp;0.01\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e40\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e40\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e89.77\u0026thinsp;\u0026plusmn;\u0026thinsp;0,75\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e45\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e45\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e88.61\u0026thinsp;\u0026plusmn;\u0026thinsp;1.44\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e50\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e50\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e87.11\u0026thinsp;\u0026plusmn;\u0026thinsp;1.76\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e55\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e98.73\u0026thinsp;\u0026plusmn;\u0026thinsp;0.26\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e55\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e86.53\u0026thinsp;\u0026plusmn;\u0026thinsp;2.90\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e60\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e97.10\u0026thinsp;\u0026plusmn;\u0026thinsp;0.89\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e60\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e85.79\u0026thinsp;\u0026plusmn;\u0026thinsp;3.43\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e65\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e96.06\u0026thinsp;\u0026plusmn;\u0026thinsp;1.62\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e65\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e84.16\u0026thinsp;\u0026plusmn;\u0026thinsp;4.58\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e70\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e94.11\u0026thinsp;\u0026plusmn;\u0026thinsp;3.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e70\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e83.35\u0026thinsp;\u0026plusmn;\u0026thinsp;5.15\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e75\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e93.46\u0026thinsp;\u0026plusmn;\u0026thinsp;3.46\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e75\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e82.95\u0026thinsp;\u0026plusmn;\u0026thinsp;5.44\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e80\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e92.77\u0026thinsp;\u0026plusmn;\u0026thinsp;3.95\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e80\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e82.04\u0026thinsp;\u0026plusmn;\u0026thinsp;6.08\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003e3.3. PDT Studies in MCF-7 Cell Line\u003c/h2\u003e\u003cdiv id=\"Sec17\" class=\"Section3\"\u003e\u003ch2\u003e3.3.1. Light Source Design\u003c/h2\u003e\u003cp\u003eDepending on the UV spectrum of Fe\u003csup\u003e3+\u003c/sup\u003e-GA-DOX obtained in PDT studies, 455\u0026thinsp;\u0026plusmn;\u0026thinsp;10 nm light source was designed and measured by compact spectrometer (Thorlabs (Type: CCS200/M), Germany) (Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eAccording to the obtained results, PDT studies were performed on the MCF-7 cell line. In all experiments, the wavelength of the LED light source was determined as 465 nm with \u0026plusmn;\u0026thinsp;10 nm. Power densities of 2,4,6,8,10,12,14,16,18,20 J/cm\u003csup\u003e2\u003c/sup\u003e were determined for LED radiation (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e). The output power was measured with a power meter (PM100 Thorlabs Germany) before the experiment. The fluence rate was used to obtain different power densities at 30 mW/cm\u003csup\u003e2\u003c/sup\u003e (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Control cells were incubated with fresh medium in the same medium without radiation.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eRadiation Parameters\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWavelength (nm)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e465\u0026thinsp;\u0026plusmn;\u0026thinsp;10 nm\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePower Output\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e30 mW\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eEnergy Density (J/cm\u003c/b\u003e\u003csup\u003e\u003cb\u003e2\u003c/b\u003e\u003c/sup\u003e\u003cb\u003e)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2,4,6,8,10,12,14,16,18,20\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePS\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGA-Fe\u003csup\u003e+\u0026thinsp;3\u003c/sup\u003e-DOX\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eAccording to the results obtained, it was observed that cell viability decreased depending on the increasing dose (Fe-GA-DOX) and increasing energy density (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01**). Effective doses were determined as 80 \u0026micro;g/ml and effective energy densities were determined as 20J/cm\u003csup\u003e2\u003c/sup\u003e (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01**) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eToxicity results of CCK-8 application according to effective doses on MCF-7 cells after LED irradiation (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01**).\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e70 \u0026micro;g/ml\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e75\u0026micro;g/ml\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e80\u0026micro;g/ml\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e2\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e93.12\u0026thinsp;\u0026plusmn;\u0026thinsp;2.70\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e91.63\u0026thinsp;\u0026plusmn;\u0026thinsp;3.32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e91.52\u0026thinsp;\u0026plusmn;\u0026thinsp;3.28\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e4\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e91.11\u0026thinsp;\u0026plusmn;\u0026thinsp;1.28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e90.18\u0026thinsp;\u0026plusmn;\u0026thinsp;2.29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e90.24\u0026thinsp;\u0026plusmn;\u0026thinsp;2.37\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e6\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e90.01\u0026thinsp;\u0026plusmn;\u0026thinsp;0.50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e89.01\u0026thinsp;\u0026plusmn;\u0026thinsp;1.47\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e89.58\u0026thinsp;\u0026plusmn;\u0026thinsp;1.91\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e8\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e89.25\u0026thinsp;\u0026plusmn;\u0026thinsp;0.03\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e88.35\u0026thinsp;\u0026plusmn;\u0026thinsp;1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e88.74\u0026thinsp;\u0026plusmn;\u0026thinsp;1.31\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e10\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e89.12\u0026thinsp;\u0026plusmn;\u0026thinsp;0.12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e87.85\u0026thinsp;\u0026plusmn;\u0026thinsp;0.64\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e87.01\u0026thinsp;\u0026plusmn;\u0026thinsp;0.09\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e12\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e88.22\u0026thinsp;\u0026plusmn;\u0026thinsp;0.76\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e86.28\u0026thinsp;\u0026plusmn;\u0026thinsp;0.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e86.14\u0026thinsp;\u0026plusmn;\u0026thinsp;0,52\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e14\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e88.16\u0026thinsp;\u0026plusmn;\u0026thinsp;0.80\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e85.18\u0026thinsp;\u0026plusmn;\u0026thinsp;1.23\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e85.01\u0026thinsp;\u0026plusmn;\u0026thinsp;1.32\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e16\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e88.01\u0026thinsp;\u0026plusmn;\u0026thinsp;0.90\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e84.07\u0026thinsp;\u0026plusmn;\u0026thinsp;2.02\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e84.01\u0026thinsp;\u0026plusmn;\u0026thinsp;2.02\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e18\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e87.99\u0026thinsp;\u0026plusmn;\u0026thinsp;0.92\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e83.54\u0026thinsp;\u0026plusmn;\u0026thinsp;2.39\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e83.99\u0026thinsp;\u0026plusmn;\u0026thinsp;2.04\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e20\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e87.98\u0026thinsp;\u0026plusmn;\u0026thinsp;0.93\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e83.21\u0026thinsp;\u0026plusmn;\u0026thinsp;2.63\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e82.54\u0026thinsp;\u0026plusmn;\u0026thinsp;3.06\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eIn this study, DOX-loaded Fe\u003csup\u003e3+\u003c/sup\u003e-Gallic acid nanoparticles (DOX-Fe\u003csup\u003e3+\u003c/sup\u003e-GA) were synthesized. After the synthesis, FTIR analysis and TEM images were taken to confirm the structure. UV spectrum result was taken for PDT studies and LED light source design was carried out. LED light source was designed as 455\u0026thinsp;\u0026plusmn;\u0026thinsp;10 nm. Before the experiment, the output power was measured with a power meter (PM100 Thorlabs Germany). The fluence rate was used to obtain different power densities at 30 mW/cm\u003csup\u003e2\u003c/sup\u003e. After determining the toxicity of the obtained nanoparticle structure in healthy (HUVEC) and cancerous (MCF-7) cell lines, PDT studies were started and it was determined that the obtained nanoparticle structure reduced cell viability depending on the dose increase in the cancerous cell line without harming the healthy cell line (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01**) (Fig.\u0026nbsp;\u003cspan refid=\"Fig9\" class=\"InternalRef\"\u003e9\u003c/span\u003e). Experiments were repeated 3 times in terms of accuracy.\u003c/p\u003e\u003cp\u003eLiu et al. (2022) studied pH-sensitive Fe-gallic acid coordination polymer for multimodal synergistic therapy and MRI in cancer treatment. Based on their results, they synthesized Fe\u0026ndash;GA/BSA nanostructures combined with bovine serum albumin (BSA). While the Fe\u0026ndash;GA/BSA@DOX structure, formed by loading doxorubicin (DOX), maintained 80‑90% viability in normal cells (293, HKC), viability decreased significantly (\u0026lt;\u0026thinsp;60%) in cancer cells (HeLa, C6, Pc‑12), especially in the C6 cell line, after 24 hours at high concentrations (\u0026gt;\u0026thinsp;125 \u0026micro;g/mL), demonstrating effective antitumor activity. The gallic acid\u0026ndash;Fe(III)\u0026ndash;DOX complex exhibited similar or higher cytotoxicity than free DOX, indicating that the carrier is functional and provides effective passive targeting to the tumor [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. When the cytotoxicity results of our PDT studies were evaluated, it was determined that the viability rate of PS generated from MCF cells was significantly reduced compared to the HUVEC cell line (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01**). It is thought that the presented studies can be improved by supporting the obtained in vitro data with in vivo experiments in future studies.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003e\u0026Ouml;.\u0026Ouml;. proposed the project. \u0026Ouml;.\u0026Ouml;. E.D.P., M.Z.Y. and M.C. designed the experimental and laboratory studies. \u0026Ouml;.\u0026Ouml;., E.D.P, and M.C. carried out experimental and characterization studies. M.C., and \u0026Ouml;.\u0026Ouml;. assembled the data, and wrote the manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgment\u003c/h2\u003e\u003cp\u003eThis research was supported by Sakarya University of Applied Sciences Scientific Research Projects Coordination Unit (Project Number: 152\u0026ndash;2023).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAdesoye T, Lucci A (2021) Current surgical management of inflammatory breast cancer. 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Nanoscale Adv 4(1):173\u0026ndash;181. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1039/d1na00721a\u003c/span\u003e\u003cspan address=\"10.1039/d1na00721a\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Gallic acid, İron, Doxorubicin, Photodynamic therapy, Cancer","lastPublishedDoi":"10.21203/rs.3.rs-7104368/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7104368/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePhotodynamic therapy (PDT) is a medically recognized method with selective cytotoxic activity against cancer cells. In PDT, photosensitizer (PS) drugs produce singlet oxygen (\u003csup\u003e1\u003c/sup\u003eO\u003csub\u003e2\u003c/sub\u003e) that causes cell death when activated by light. One of the drug groups that has recently become prominent in cancer therapy studies is coordination polymer-based nanoparticles (CPNs). Gallic acid (GA) has strong antioxidant, antimutagenic, anticancer and anti-inflammatory properties. In addition, it has very high biocompatibility and can be easily absorbed by the human body. For this reason, it is widely applied for antitumor or anticancer treatments. Therefore, gallic acid is a promising natural polyphenolic compound for PDT applications. In addition, iron (Fe\u003csup\u003e3+\u003c/sup\u003e) element is a metal widely applied in cancer treatment. Accordingly, a nano-sized CPN structure to be formed with GA and Fe\u003csup\u003e3+\u003c/sup\u003e is expected to be an effective FS in cancer treatment applications with PDT. In this study, Fe\u003csup\u003e3+\u003c/sup\u003e-GA nanoparticle material synthesis was carried out as a CPN structure. GA and Fe\u003csup\u003e+\u0026thinsp;3\u003c/sup\u003e were selected as organic ligands and inorganic crosslinkers, respectively. Here, Fe\u003csup\u003e+\u0026thinsp;3\u003c/sup\u003e-GA nanoparticles were first synthesized and then doxorubicin (DOX) was attached to the structure to obtain Fe\u003csup\u003e3+\u003c/sup\u003e-GA-DOX nanoplatforms. This obtained nanoplatform was verified by UV-Vis, FT-IR and TEM measurements. UV spectrum result was taken for PDT studies and LED light source design was carried out. LED light source was designed as 455\u0026thinsp;\u0026plusmn;\u0026thinsp;10 nm. After determining the toxicity of the obtained nanoparticle structure in healthy (HUVEC) and cancerous (MCF-7) cell lines, PDT studies were started and it was determined that the obtained nanoparticle structure reduced cell viability depending on the dose increase in the cancerous cell line without harming the healthy cell line (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01**). The effective GA-Fe\u003csup\u003e3+\u003c/sup\u003e-DOX doses were determined as 70, 75 and 80 \u0026micro;g/ml (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01**). At these determined doses, power densities of 2, 4, 6, 8, 10, 12, 14, 16, 18, 20 J/cm\u003csup\u003e2\u003c/sup\u003e were applied and the most effective dose and power densities were determined as 80 \u0026micro;g/ml and 20J/cm\u003csup\u003e2\u003c/sup\u003e, respectively, according to increasing power densities.\u003c/p\u003e","manuscriptTitle":"Development of Photosensitive Doxorubicin-Fe3+-Gallic Acid Nanoparticle Structure for Targeted Cancer Therapy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-28 12:32:48","doi":"10.21203/rs.3.rs-7104368/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a87ad0bc-53b2-447f-96c3-924f0ed56e31","owner":[],"postedDate":"July 28th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-12-02T01:08:15+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-28 12:32:48","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7104368","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7104368","identity":"rs-7104368","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}