{"paper_id":"2f6c97cb-de39-4563-88fc-384d7215082f","body_text":"PLA-HA/Fe3O4 magnetic nanoparticles loaded with Curcumin: Physicochemical characterization and toxicity evaluation in HCT116 Colorectal cancer cells | 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 PLA-HA/Fe3O4 magnetic nanoparticles loaded with Curcumin: Physicochemical characterization and toxicity evaluation in HCT116 Colorectal cancer cells Shima Bourang, Sina Asadian, Mehran Noruzpour, Atefeh Mansuryar, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3745071/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract Colorectal cancer (CRC) is the third most common, harmful, and universal cancer and the second lethal type. This paper discusses the therapeutic potential of curcumin, a major curcuminoid found in the substructure of plant Curcuma longa (turmeric), against CRC. Curcumin has the ability to disrupt a variety of cellular signaling pathways and has been validated in several preclinical and clinical studies, but suffers from low solubility and bioavailability. To address these issues, PLA-HA/Fe 3 O4 magnetic nanoparticles were synthesized and loaded with curcumin. The average size and zeta potential of the nanoparticles and the magnetic properties were measured. The drug encapsulation efficiency and cumulative release of curcumin from the nanoparticles under acidic and neutral pH values were evaluated, as well as the cytotoxic effect of the nanoparticles on HCT116 colorectal cancer cells. The results demonstrated that nanoparticles have a high degree of biocompatibility and the ability to carry Curcumin medications. HCT116 cells with 200 µg/ml PLA-HA/Fe 3 O 4 /Curcumin nanoparticles have 58.63 ± 3.7% percent cell viability. Ultimately, PLA-HA, Fe 3 O 4 , and Curcumin's physicochemical characteristics and impact on cell viability render them valuable instruments for precisely delivering drugs to colorectal cancer cells. The PLA-HA/Fe 3 O 4 -curcumin nanoparticles demonstrated a well-targeted drug delivery system for upcoming colorectal cancer treatments, as evidenced by their overall strong cytotoxic effects on colorectal cancer cells and negligible toxicity towards non-cancerous cells. Curcumin targeted drug delivery nanoparticles green synthesis metastatic disease CD44 Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Study Highlights What is the current knowledge? Investigating the characteristics of loading, release, drug transfer efficiency and toxicity of PLA-HA/Fe 3 O 4 nanoparticles loaded with curcumin. Determining the characteristics of a drug delivery system for effective cancer treatment without side effects on healthy tissues. What is new here? Using curcumin as drug to treat HCT116 colorectal cancer cells. Investigating the toxicity of PLA-HA/Fe 3 O 4 nanoparticles. Comparing the efficiency of nanocarrier in drug delivery to cancer tissue compared to free drug. PLA-HA/Fe 3 O 4 /curcumin nanoparticles can be a potential approach for targeted drug delivery due to the presence of physicochemical properties and release profile, appropriate toxicity and efficiency in the transfer of curcumin drug to colorectal cancer cells. Introduction Colorectal cancer (CRC) is the third most common, harmful, and universal cancer and the second lethal type. In 2020, an estimated 1,880,725 people were diagnosed with colon cancer. By 2035, there may be nearly 2.5 million new cases. [ 1 ] According to the pathological characteristics of the tumor, there are various therapeutic options for CRC. The principal therapeutic strategy for mCRC (Metastatic colorectal cancer) patients is palliative chemotherapy, while non-systematic therapy (such as surgery and optional radiation and ablative techniques) is optional for patients with respectable metastatic lesions to improve survival. The early-stage primary disease typically requires laparoscopic surgery; cases involving metastases necessitate open surgery for tumor resection, and nonresectable cases typically require adjuvant radiotherapy. Neoadjuvant and palliative chemotherapies, [ 2 ] immunotherapy, [ 3 ] and tyrosine kinase inhibitor (TKI) [ 4 ] therapy are additional CRC treatments. Currently, targeted drug delivery through nanoparticles has been an emerging approach for addressing various problems associated with chemotherapeutic agents. [ 5 – 7 ] Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)- 1,6-heptadiene-3,5-dione), likewise alluded to as diferuloylmethane, comprises one of the major curcuminoids existing in the substructure of plant Curcuma longa (turmeric). [ 8 ] Curcumin has been practically studied for the majority of human diseases and is highly adequate in treating a diversity of medical conditions, including, but not limited to, cancer, arthritis, major depression, liver disease, dyslipidemia, and chronic obstructive pulmonary disease. [ 8 – 12 ] Curcumin has the ability to encourage a wide range of chemical reactions in living things, such as hydrolysis, enzymatic reactions, reversible and irreversible nucleophilic addition (Michael reaction), and hydrogen donation leading to oxidation. [ 13 ] Evidence demonstrates that curcumin disrupts a variety of cellular signaling pathways by directly targeting bioactive proteins or epigenetically regulating gene expression in key disease-associated signaling pathways, according to mounting evidence. [ 14 , 15 ] Curcumin's therapeutic potential against CRC has been validated in a number of preclinical and clinical studies, and its effectiveness in suppressing various stages of CRC development is noteworthy. [ 16 , 17 ] In spite of these advantages, curcumin suffers from some limitations in drug administration. Low solubility and bioavailability are major problems of this drug. Also, the passive distribution of curcumin, as to other chemical entities, is another important obstacle to the effective anticancer properties of this drug. The incorporation of curcumin into nanocarriers is a promising strategy to solve the mentioned problems. Nanoparticles have many important potentials to overcome these obstacles. They could increase the solubility and dissolution profile of less soluble drugs. Also, the absorption pathway of drugs may be improved using nanocarriers. However, the most attractive capability of nanocarriers is the ability to modify drug distribution in the body. [ 18 ] Since the drug is entrapped inside the nanoparticles, they can release the drug actively, and also through interaction with different organs, and biological or cell components, the fate of the drug could be changed according to treatment goals. Numerous nanocarriers were used for this strategy and among them, the conjugation of polymeric nanoparticles with magnetic cores is very advantageous. Bioanalytical methods and biomedical applications completely rely on magnetic nanoparticles. With bio-type specimens, they encounter less background interference, making bio-type samples' magnetic susceptibilities nearly nonexistent. [ 19 ] As a result of this benefit, and biological samples can be easily accessed in the direction of the external magnetic field. Analytical tools, bioimaging, biosensors, contrast agents (CAs), hyperthermia, photoablation therapy, physical therapy applications, separation, signal markers, and targeted drug delivery (TDD) are just a few of the many biomedical applications that can now be designed into magnetic nanoparticles. [ 20 ] Iron oxide nanoparticles (IONPs) are used in most studies because of their biocompatibility, high saturation magnetization, high magnetic susceptibility, chemical stability, and innocuousness. Nickel and cobalt, two examples of IONPs with high magnetic properties, are toxic and easily oxidized. Magnetite (Fe 3 O 4 ) nanoparticles (MNPs) are by far the most commonly used IONPs in biomedical applications. [ 21 ] As a result of ion transfer from Fe2 + ions to Fe 3+ ions, magnetite nanoparticles have unique electrical and magnetic properties.[ 22 ] Most biomedical MNPs have superparamagnetism properties because they are smaller than 20 nm. [ 22 ] They are also widely used in this field due to their biocompatible surface chemistry, high magnetization saturation value, narrow particle size distribution (100 nm), and superparamagnetism property compared to other magnetic IONPs (M-IONPs). [ 19 – 21 ] In addition to targeting tumors using an external magnetic field, magnetite nanoparticles can also cause hyperthermia-induced apoptosis of cancer cells. [ 23 ] One of the most employed polymers for coating Fe 3 O 4 is PLA which is readily oxidized and agglomerated, they are often coated with natural or synthetic polymers. [ 24 ] Polylactic acid (PLA) is a flexible polymer that is fermented into a carboxylic acid from sustainable agricultural waste. [ 25 – 27 ] The lactic acid is then polymerized using a cyclic dilactone, lactide, and ring for product modification. [ 28 ] PLA and its copolymers have been utilized to encapsulate many classes of drugs, such as hormones, proteins, and chemotherapeutic agents. [ 29 – 31 ] Slow degradation rate and high hydrophobicity are some of the disadvantages that restrict the biomedical application of PLA. [ 32 ] On the other hand, nanoparticles can actively target tumor cells by recruiting targeting moieties that bind specifically to over-expressed receptors on cancerous cells. CD44, a transmembrane glycoprotein receptor, is abundantly expressed in tumor cells and plays an important role in tumor progression and metastasis. [ 33 ] Hyaluronic acid, a natural mucopolysaccharide found in the extracellular matrix, is a CD44 ligand that has been recently used in tumor-targeting nanoparticle formulations. The great biocompatibility, biodegradability, and hydrophilicity of hyaluronic acid make it a proper candidate for the targeted delivery of drugs and genes to tumor cells. [ 34 ] Literature Review Curcumin, a polyphenol derived from the turmeric plant, has shown potential in cancer treatment. It reduces inflammation, encourages cell apoptosis, and inhibits cell proliferation to demonstrate anticancer effects.[ 35 ] Nevertheless, curcumin's low bioavailability and poor water solubility restrict its efficacy. Curcumin's stability and cellular bioavailability have been enhanced through the use of nanotechnologies in order to overcome these obstacles.[ 36 ] To improve curcumin's absorption and delivery, nano-based formulations like cubosomes and nanocarriers have been created.[ 37 ] Curcumin's bioavailability, retention in target tissues, and cytotoxic effects against cancer cells have all improved with these formulations, which have demonstrated encouraging outcomes. Curcumin's anticancer properties have also been shown in clinical trials for a variety of cancers, including brain tumors, lung, breast, prostate, pancreatic, gastric, leukemia, and colorectal cancers.[ 38 ] It's common knowledge that curcumin inhibits the cell cycle and speeds up cell death in relation to colorectal cancer, two factors that can help prevent the disease from spreading. According to in vitro studies done on different cancer cell lines, curcumin stopped the growth of the cells by molecularly interacting with several targets, which in turn regulated a number of distinct signaling cascade series.[ 39 ] In line with He et al., curcumin stopped the cell cycle that was partially in the G1 phase and present in the cells, which inhibited their growth.[ 40 ] One key feature that makes PLA useful for drug carriers is its biodegradability. PLA readily dissolves in extracellular settings.[ 41 ] Aside from this capability, the rate of degradation can be changed to accomplish a particular result. Drug carrier systems might be able to sustain a continuous release of therapeutic agents by prolonging the kinetics of this breakdown.[ 42 ] This is crucial because metabolic processes could potentially reduce the effectiveness of this therapeutic approach. It also gives the medication enough time to take effect. Through better drug delivery and fewer side effects, PLA-HA has demonstrated promise in the treatment of cancer. They can reduce toxicity and increase the effectiveness of anticancer medications like arenobufagin (ArBu), tamoxifen, docetaxel, daunorubicin, and ibuprofen.[ 43 ] Exploring new avenues for targeted treatment and overcoming multidrug resistance, nanotechnology-based chemotherapy employing nanoparticles has opened up new possibilities. In vitro, cytotoxicity against breast cancer cells has been shown for polymeric nanoparticles of polylactic acid-poly (ethylene glycol) (PLA-PEG) copolymers encapsulating a novel biosurfactant. [ 44 ]Biosurfactant has been shown to release under controlled conditions via these nanoparticles, and they are capable of actively delivering anticancer cargo to the cancer site. Biological components attached to nanoparticles can also improve their targetability to the cancerous area. Superparamagnetic Fe 3 O 4 NPs have drawn interest due to their versatility in applications such as localized hyperthermia therapy, target-based carriage, stem cell labeling and tracking, and magnetic resonance imaging (MRI) contrast agents. When an external alternating magnetic field is applied, it can produce heat in tumor regions through hyperthermia therapy.[ 45 ] The material of choice for generating magnetism in these nanoparticles is iron oxide. The combination of magnetic hyperthermia and chemotherapeutic drug-loaded nanoparticles has shown remarkable antitumor effects. [ 46 ]By enhancing drug targeting, solubility, and bioavailability, nanoparticles can also enhance colorectal cancer diagnosis and treatment.[ 47 ] Specifically, nanomagnetic iron oxides have demonstrated potential as drug-delivery vehicles in the context of cancer treatment. Developing an intravenous injectable aqueous formulation of curcumin is an intriguing idea, as curcumin's bioavailability in vivo is significantly reduced when administered orally. Hydrophobic drugs' poor water solubility can be addressed with biodegradable nanodrug carriers, offering promise for future use.[ 48 ] There have been a lot of studies done on this subject to deliver curcumin conjugation with micelles, liposomes, polymeric nanoparticles, and lipid based nanoparticles. In a recent study, CUR and doxorubicin (DOX) co-encapsulated in long circulating liposomes (LCL) at a molar ratio of 1:167 significantly reduced C26 cell proliferation when compared to free DOX in vitro. It was also reported that the amount of CUR encapsulated determines the degree of the synergistic cytotoxic effects of DOX and CUR, with higher amounts of CUR resulting in greater cytotoxic effects. [ 49 ] Sesarman et al., revealed a similar result when employing the same liposomal formulation as Tefas et al. to co-deliver CUR and DOX. (LCL-CUR-DOX) in cells of C26. The increased cytotoxic activity of LCL-CUR-DOX in comparison to free CUR-DOX prompted the authors to look into the protumor mechanism causing the C26 cell cytotoxicity. In addition to slightly inhibiting NF-κB activation, LCL-CUR-DOX also inhibits most of the proteins involved in the development of tumors. In contrast to free CUR-DOX, it has less of an effect on oxidative stress reduction in vitro. This might be the result of liposomes' distinct uptake mechanism from that of free medications. The process of endocytosis allows liposomes to enter cells, facilitating a higher degree of CUR internalization. On the other hand, transmembrane diffusion is how free CUR enters the cells. [ 50 ] In an effort to enhance CUR encapsulation, Dash and Konkimalla have recently loaded CUR into hydroxypropyl-β-cyclodextrin (HP-β-CD) using polyvinyl alcohol (PVA) as a stabilizer. The solubility of CUR in water has been improved by this formulation of nano-curcumin. It was applied in combination therapy to address the issue of drug resistance resulting from overexpression of p-glycoprotein (P-gp) to DOX. Following prescreening, CUR was chosen as combinatorial agents in this study over other P-gp inhibitors because it sensitized DOX-resistant Colo205 cells at the lowest concentration of 40 µM. CUR-loaded HP-β-CD dramatically reversed DOX resistance, which was obtained by administering DOX liposomes at concentrations ranging from 0.1 to 10 µM, once it reached 40 µM.[ 51 ] Drug delivery systems containing folate can penetrate cells through receptor-mediated endocytosis, preventing non-specific attacks on healthy tissues. Additionally, the agents can enhance cellular uptake in target cells and deliver the therapeutic agents to tumor cells. [ 52 ]According to reports, the lower micelle concentration resulting from folate conjugation can enhance the stability of the FA-copolymer micelle when compared to copolymer (PLAMPEG) alone. [ 53 ]Baek and Cho. have demonstrated that Nutlin-3a's therapeutic potential can be enhanced by folate-decorated, curcumin-loaded nanoparticles, which reverse multidrug resistance. [ 54 ]As demonstrated by Kazemi et al. (2020) and Zhang et al. (2019), also demonstrated that folate-drug delivery systems can improve drug targeting and uptake to tumor cells while also extending the drug's half-life in the body.[ 55 , 56 ] Additionally, Phan et al. developed a folate-modified curcumin-loaded micelle delivery system (Cur/PLA-PEG-Fol) using poly(lactic acid)-poly(ethylene glycol) to improve curcumin's solubility in aqueous solution and increase its targeting ability. As per their research, Folate-modified micelles exhibit promise as a nanocarrier to enhance Cur's solubility, anticancer activity, and systemic targeting capabilities.[ 57 ] Therefore, we decided to use the nanotechnology-targeted drug delivery method using PLA-HA copolymer with Fe3O4 magnetic core to increase the efficiency of drug transfer and drug solubility to transfer curcumin drug and increase the efficiency of colorectal cancer treatment. Research gap Based on the aforementioned information, the prescribed treatment options demonstrate efficacy in the management of cancer. However, in contemporary times, with the advancement of integrated therapeutic sciences, the conventional and conventional approaches used in the past are of minimal utility in addressing critical disease, including cancer. Therefore, contemporary researchers primarily attribute to integrating diverse methodologies in order to enhance effectiveness and overcome the limitations imposed by different techniques. In recent times, several investigations have been conducted, focusing on the utilization of various chemotherapy medications in combination with different copolymers and nanoparticles. Despite the studies conducted, based on the investigations carried out by our team, until today there is no research on the simultaneous use of curcumin, PLA-HA copolymer, and Fe3O4 nanoparticles for colorectal cancer treatment, to enhance drug efficacy, biodegradability, water solubility, release kinetics, and targeted delivery. Objective and contributions The purpose of this work is to assess the physicochemical properties of curcumin-loaded PLA-HA/Fe 3 O 4 MNPs and determine their level of toxicity in HCT116 colorectal cancer cells. We predict that these nanoparticles will present with the right physicochemical characteristics to facilitate drug delivery and cause cytotoxicity in HCT116 cells. Materials and methods Materials Poly Vinyl Alcohol (PVA) were purchased from Merck (Germany). PLA, HA, FeCl 3 .6H 2 O, FeCl 2 .4H 2 O, RPMI 1640, penicillin/streptomycin, FBS, and DMSO were obtained from Sigma-Aldrich (USA). The MTT solution was purchased from Atocel (Hungary) and amphotericin B was obtained from Biowest (France). Other solutions, reagents, and solvents were at analytical grade and obtained domestically. Green synthesis of magnetite (Fe 3 O 4 ) nanoparticles using the hydroalcoholic extract of Silybum marianum Equal amounts of FeCl 3 and FeCl 2 (3.3 g) were dissolved separately in 50 ml of water. The reaction was initiated by mixing 15 ml of Silybum marianum methanolic extract, FeCl 3 , and FeCl 2 solution under nitrogen gas at 80 ° C for 30 minutes using a stirrer. Then, 60 ml of NaOH (1 mM) was added to the above solution and incubated for another 4 hours under similar conditions. The nanoparticles were centrifuged (10000 rpm for 10 minutes) and washed several times with phosphate buffer (PBS). The resulting iron oxide nanoparticles were then freeze-dried. Synthesis of PLA-HA copolymer To polymerize poly lactic acid-hyaluronic acid (PLA-HA), the NH 2 -Hyaluronic acid and Acrylate-PLA solutions in chloroform were mixed slowly by 24 hours of stirring at 50°C. To remove impurities, the resulting product was centrifuged for half an hour at 4°C (10000 rpm) using equal volumes of water and methanol. The copolymer was further purified using dialysis membranes (10000 MW) and then the PLA-HA polymer was centrifuged again under the above-mentioned conditions and freeze-dried. Characterization of PLA-HA copolymer H-NMR spectroscopy was carried out to investigate the structure of PLA-HA copolymer using CDCl 3 as the solvent (Varian Unityinova 500 NMR Spectrometer, USA). Additionally, the FTIR technique (1B-AR-010, Biotec, USA) was used for confirming the synthesis of PLA-HA synthesis. Also, the thermal stability of PLA and PLA-HA copolymer was evaluated by Thermogravimetric analysis (TGA, STA-PT1000, License, Germany) in a thermal range of 40 ºC to 700 ºC with a heating rate of 10 ºC/min. Synthesis of PLA-HA/Fe 3 O 4 /curcumin and PLA/Fe 3 O 4 nanoparticles A solvent diffusion technique was used to prepare PLA-HA/Fe 3 O 4 /curcumin and PLA/Fe 3 O 4 without drug nanoparticles. 5 mg of Fe 3 O 4 nanoparticles coated by Oleic Acid was added to PLA-HA solutions (30 mg in 1 ml chloroform). Then, 4 mg of curcumin and 1 ml of PVA solutions (1% w/v) were added to the mixture and sonicated for another 30 seconds, respectively. The resulting emulsions were then collected using a syringe and slowly injected into 25 ml of PVA solution (0.3% w/v) under stirring. The final emulsion was stirred at room temperature for 24 hours. The yielded nanoparticles were washed 3 times with centrifugation using deionized water (13000 rpm for 1 hour) and freeze-dried. In order to prepare drug-free nanoparticles (PLA-HA/Fe 3 O 4 ), the aforementioned procedure was used either. With the difference that curcumin was not added in the loading phase. Characterization of nanoparticles The average size and zeta potential of PLA-HA/Fe 3 O 4 /curcumin and PLA/Fe 3 O 4 nanoparticles were determined using dynamic light scattering (DLS, SZ100, Horiba, Japan) techniques. The morphology and size distribution of synthesized nanoparticles were investigated by TEM images (LEO906, Zeiss, Germany). The formation of magnetite nanoparticles was confirmed by FTIR and UV-Vis (Thermo Scientific, USA) spectroscopy. VSM (Vibrating Sample Magnetometer, MDKF-Co., Iran) technique was used to measure the magnetic properties of nanoparticles. Determination of drug encapsulation efficiency of synthesized nanoparticles To calculate the drug (curcumin) encapsulation efficiency, the supernatant of the nanoparticle’s mixture was centrifuged (13000 rpm for 1 hour) and the amount of free curcumin present in the supernatant was determined using spectrophotometry at 480 nm. The measured amount was then compared with the initial amount of drug used in the loading process (4 mg) and the encapsulation efficiency was calculated by the following equation: EE%= (W initial CU – W free CU / W initial CU ) Release profile of drug from nanoparticles Since the tumor tissue has a lower pH compared to the normal tissue, the drug release from nanoparticles was evaluated in PBS buffer with acidic (pH = 6) and neutral (pH = 7.4) pH values. 10 mg of the PLA/Fe 3 O 4 /curcumin and PLA-HA/Fe 3 O 4 nanoparticles were added separately to 2 ml of PBS buffer and stored at 37°C. The nanoparticles supernatant was then collected by centrifugation (13,000 rpm for 10 minutes) at predetermined time intervals and nanoparticles were resuspended in 2 ml of PBS until the next collection. The amount of drug present in the supernatant was evaluated using spectrophotometry. The cumulative release percentage was then calculated using the following equation. Cumulative release percentage = \\(\\frac{{Dr}^{t}+ {Dr}^{t+1}}{DE}\\) Dr t = The measured amount of drug in the supernatant at any time (t) Dr t+1 = The measured amount of drug in the supernatant at time (t + 1) De = The amount of drug encapsulated in the nanoparticles In vitro evaluation of cytotoxicity The HCT116 colorectal cancer cell line was used to evaluate the toxicity and drug delivery efficiency of PLA-HA/Fe 3 O 4 nanoparticles. First, Human Colorectal Carcinoma cell line HCT116 cells were grown in 10% fetal bovine serum and RPMI cell media at 37°C in 5% CO 2 . The cytotoxic effect of Fucosterol alone or in combination with curcumin in colon cells was evaluated by an MTT reduction assay. For the MTT assay, 100 µl of HCT116 cells at a density of 7 ×10 4 cells per milliliter were transferred to 96-well plates. Then, the cells were kept in a CO 2 incubator (at 37 ° C, 90% humidity, and 5% CO 2 ) for 24 hours. The HCT116 cells were then treated with different concentrations of PLA-HA/Fe 3 O 4 / curcumin nanoparticle (25، 50، 75، 100، 200 µg/ml), as well as free curcumin. To evaluate the toxicity of nanoparticles, PLA-HA/Fe 3 O 4 was used. The cells were exposed to each treatment for 24 hours. Then, the cell viability was assessed using an MTT assay. Results 1. Characterization of PLA-HA copolymer The H-NMR spectra of PLA and PLA-HA are presented in Fig. 1 . As shown in the H-NMR spectrum of PLA, the peaks observed at 5.75 (b) and 1.72 (a) ppm were assigned to methine and methylene groups in PLA. Whereas in the H-NMR spectrum of PLA-HA, new peaks were observed at 8.19 and 3.97 ppm, which were related to the alcohol (OH) (d) and amide (NH) (c) protons present in the structure of hyaluronic acid, respectively. The FT-IR spectra of PLA and PLA-HA copolymer shown in Fig. 2 , confirms the synthesis of PLA-HA. As shown in the FT-IR spectrum of PLA, the IR bands observed at 1750 cm − 1 and 2900–3000 cm − 1 were related to C = O and C-H groups present in PLA. The FT-IR spectrum of PLA-HA revealed new peaks at 1596 and 3532 cm − 1 which were respectively related to N-H and O-H bonds in hyaluronic acid. These findings can indicate the bonding of HA to PLA. TGA analysis is mostly performed to study the thermal stability of samples, but this method can also estimate the percentage of constituents present in the sample. The TGA analysis of PLA, shown in Fig. 3 , represents a severe weight loss stage which is indicative of the purity of the PLA polymer. On the other hand, several stages of weight loss were observed in the TGA analysis of PLA-HA polymer in the temperature range of 200–250, 300–320, and 350–380 ºC, which indicated the presence of several materials in PLA-HA compared to PLA. Considering that the weight loss of PLA was observed in the temperature range of 200 to 320 ºC, it can be concluded that the weight loss in the temperature range of 350 to 380 ºC is related to the hyaluronic acid present in the structure of PLA-HA copolymer. 2. Characterization of PLA-HA/Fe 3 O 4 /curcumin nanoparticles The results of studying the morphological properties and size of PLA-HA/Fe 3 O 4 /curcumin nanoparticles by transmission electron microscope (TEM) indicated that these nanoparticles had a spherical structure and a size of about 100–200 nm (Fig. 4 ). The DLS results shown in Fig. 5 confirm the nanoscale dimensions of the synthesized nanoparticles. PLA/Fe 3 O 4 /curcumin nanoparticles had an average size of 208 ± 12.8 nm. 3. Drug release pattern The drug encapsulation efficiency in PLA-HA/Fe 3 O 4 nanoparticles was 42/18 ± 2.7 percent. The drug release pattern in acidic and neutral media (shown in Fig. 6 ) involved two different phases: burst release and sustained release. More than 50% of the drug released within 3 days was released. For example, the amount of released drug of PLA-HA/Fe 3 O 4 /curcumin within 14 days of incubation with PBS buffer, pH = 7.4 was 43.6 ± 3.1 percent (Fig. 6). Also, it was found that the drug release rate was higher in acidic pH compared to the neutral media. For example, the amount of curcumin drug released from nanoparticles in 14 days at pH = 7.4 was 57.36 ± 2.9%, while this amount increased to more than 85% at pH = 6. 4. In vitro cytotoxicity MTT assay results, shown in Fig. 7 , demonstrated that PLA-HA/Fe 3 O 4 nanoparticles are biocompatible on HCT116 cells since the encapsulation of the drug curcumin inside these nanoparticles significantly increased its toxicity on the HCT116 cell line. Although the encapsulation of curcumin drug inside PLA-HA/Fe 3 O 4 nanoparticles increased the antitumor properties of these nanoparticles, however, the lowest cell viability of HCT116 cells was observed after its treatment with free curcumin drug. For example, the survival rate of cells after treatment with 200 µg/ml of PLA-HA/Fe 3 O 4 /curcumin nanoparticles was 58.63 ± 5.1%, while this rate was for an equal amount of curcumin drug encapsulated in 0 µg/mL of PLA-HA/Fe 3 O 4 /curcumin nanoparticles was 52.26 ± 4.3. Discussion In this study, PLA-HA/Fe 3 O 4 /curcumin nanoparticles were synthesized successfully to deliver curcumin as a drug into HCT116 Colorectal cancer cells. First, PLA-HA copolymer synthesized successfully and characterized by H-NMR, FT-IR spectra, and TGA analysis. Second, PLA-HA/Fe 3 O 4 /curcumin and PLA/Fe 3 O 4 nanoparticles synthesized, and TEM and DLS analysis were conducted to investigate the morphological characteristics and size of nanoparticles. According to the TEM results, the synthesized PLA-HA/Fe 3 O 4 /curcumin nanoparticles were found to have a spherical structure. In agreement with the results obtained from the research of other researchers, it has been determined that the efficiency of drug transfer to target tissues directly depends on the morphology of nanoparticles. For example, among the types of spatial structure, nanoparticles with spherical structure have high transfer efficiency. According to the results obtained in this research, due to the spherical structure, PLA-HA/Fe 3 O 4 /curcumin nanoparticles will have a high potential in drug delivery to cancer cells and tissues. [ 58 ] The size and surface charge of nanoparticles are two other important factors in the successful delivery of the drug encapsulated inside the nanoparticles. In accordance with the results obtained from other research, by decreasing the size of nanoparticles, the possibility of success in transferring them to cancer cells increases, while non-specific absorption by normal cells increases in nanoparticles with a size smaller than 50 nm. In other words, by reducing the size of nanoparticles to less than 50 nm, in addition to increasing the transfer efficiency, the amount of side effects also increases with non-specific absorption by normal cells. [ 59 ] Based on the results, nanoparticles with a size of 200 nm are considered a suitable option for targeted drug delivery to cancer tissues. This group of nanoparticles has a higher transfer efficiency due to their size smaller than 200 nm, and the non-specific absorption of these nanoparticles by normal cells is less than nanoparticles with a size smaller than 100 nm. According to the results obtained in this research, the size of PLA-HA/Fe 3 O 4 /curcumin nanoparticles was in the range of 200 nm, so it is expected that these nanoparticles have a high penetration ability to cancer cells and minimal absorption by normal cells in vivo. In the study conducted by Noor Alaam and colleagues on designing and determining the properties of PLGA-HA nanoparticles loaded with Cisplatin, a slight increase in the size of nanoparticles conjugated with hyaluronic acid was seen compared to PLGA nanoparticles. The possible reason for this increase in size is the presence of hyaluronic acid segments. Nanoparticles containing HA in this study also had more negative zeta potential, which is due to the negative carboxylic groups present in hyaluronic acid. [ 60 ] After that, based on the obtained results of the Drug release pattern, this phenomenon is consistent with the results observed in previous studies which have stated the biochemical mechanisms involved in the separation of drugs from nanoparticles as the probable reason for the different release rates in an acidic and neutral environment. Therefore, due to the lower pH of tumor tissues compared to healthy tissues, encapsulation of curcumin into the synthesized nanoparticles can lead to a lower incidence of side effects. Many researchers are interested in using iron oxide nanoparticles in drug delivery systems because of their biocompatibility and favorable magnetic properties. These nanoparticles provide the possibility of drug accumulation in the tumor site by applying an external magnetic field. Also, these nanoparticles have a high potential in imaging applications as well as hyperthermia. The results of past research have shown that magnetic nanoparticles increase the contrast of images in MRI imaging. Also, these nanoparticles significantly increase the efficiency of drug transfer to the tumor tissue. [ 61 ] In previous studies, drug release from polymer nanoparticles with a magnetic core was also examined. Amani et al. conducted a study in which, in terms of the design and evaluation of iron oxide nanoparticles coated with a PLA-PEG-PLA copolymer, the burst and continuous release patterns of drug release were observed in both neutral and acidic environments. In a similar condition, compared to a neutral medium, the rate of drug release from nanoparticles in an acidic medium was significantly higher. The chemical and biochemical processes involved in the separation of drugs from nanoparticles, as well as the reason for the difference in release rate between an acidic and a neutral environment, were discussed in this study. It was likewise expressed that, as a general rule, the course of medication partition from nanoparticles in an impartial climate is slower than in an acidic climate. When compared to healthy cells or tissues, cancer cells or tumor tissues have a lower pH, so a high rate of release in acidic tissue may result fewer side effects than when the free drug is used. [ 62 ] In addition, polymer degradation was cited as the cause of the continuous phase release of Berberine from PLGA-HA copolymer nanoparticles in the study by Bhatnagar and colleagues. Additionally, the hydrolysis of PLGA ester bonds in an acidic environment is the cause of the faster release of Berberine than in a neutral environment. Berberine release from PLGA-HA nanoparticles was higher than that of PLGA nanoparticles in this study. Due to the hydrophilic nature of hyaluronic acid, Bhatnagar believes that the increased interaction of nanoparticles with the aqueous environment is to blame for this phenomenon. [ 63 ] In this research, the PLA polymer surface was targeted by using hyaluronic acid in order to increase the efficiency of drug transfer to cancer cells. In addition, the ability to transport curcumin drug through these nanoparticles and its effect on the viability of HCT116 cells was also evaluated through the MTT test. Similar outcomes have been observed in other studies employing hyaluronic acid as a targeted component against cancer cells. Also, the findings of this research are consistent with other studies which have employed Hyaluronic acid as a tumor-targeting moiety in nanoparticles. The reason for this phenomenon could be the increased adsorption of nanoparticles by cells due to the specific interaction between hyaluronic acid present in the nanoparticle’s structure and CD44 receptors which are over-expressed on the surface of the HCT116 cell membrane. Noor Alaam's research found that when PLGA-HA nanoparticles were used instead of hyaluronic acid nanoparticles, the internalization of the nanoparticles improved because hyaluronic acid specifically interacted with CD44 receptors in SKOV-3 cells. It is excessive, and the rally is necessary for the nanoparticles' endocytosis. The cell toxicity of the drug-containing nanoparticles and the free drug was not significantly different, in contrast to the results of the current study. This is due to the ability of post-endocytosis nanoparticles to transmit drugs in greater volumes and the cellular toxicity of the materials used in their preparation, despite the sluggishness of this process in comparison to the release of the free drug. [ 60 ] Conclusion Chemotherapy drugs are effective at reducing cancer cell survival, although they have many side problems such as their effect on healthy cells and resistance to the drug. In addition, due to the fast catabolism and short half-life of these drugs, continuous intravenous infusion is often used. In order to solve the obstacles mentioned above, it is possible to use drug loading in targeted nanoparticles. Encapsulation of curcumin in the magnetite (Fe 3 O 4 ) nanoparticles prepared by green synthesis method and coated with PLA-HA copolymer could be a proper approach for addressing its non-specific effect on healthy cells. Prepared PLA-HA/Fe 3 O 4 /curcumin nanoparticles have a spherical shape and a size of about 200–300 nm. According to the results obtained in this research, due to the spherical structure, PLA-HA/Fe 3 O 4 /curcumin nanoparticles will have a high potential in drug delivery to cancer cells and tissues. The drug encapsulation efficiency in PLA-HA/Fe 3 O 4 nanoparticles was 42/18 ± 2.7 percent. The synthesized nanoparticles are able to create a two-phase release pattern explosively and continuously for 14 days. More than 50% of the drug released within 3 days was released. Furthermore, the amount of drug release in acidic pH is significantly higher than in neutral pH. Considering the acidity of the pH of cancer cells and tumor tissue compared to healthy tissue, this capability can lead to a decrease in the release of the drug in the healthy tissue and, as a result, reduce the side effects of the drug. Therefore, PLA-HA/Fe 3 O 4 /curcumin nanoparticles can be a potential approach for targeted drug delivery due to the presence of physicochemical properties and release profile, appropriate toxicity, and efficiency in the transfer of curcumin drug to colorectal cancer cells. Declarations Data availability The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. Author Contribution S.B. Led the writing of the article and Proofreading of the final version of the manuscript, S.A. conducted the research and investigation process, M.N. analyzed the statistical, mathematical, and computational, and Wrote the original Draft of the article, A.M. Performed the experiments, S.A. Provided the study materials, materials, laboratory samples, H A.E. Supervised: Oversight and leadership responsibility for the research activity planning (Correspondence) and V.AH. 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Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 20 Feb, 2024 Reviews received at journal 14 Feb, 2024 Reviewers agreed at journal 06 Feb, 2024 Reviews received at journal 21 Jan, 2024 Reviewers agreed at journal 16 Jan, 2024 Reviewers agreed at journal 14 Jan, 2024 Reviewers invited by journal 14 Jan, 2024 Editor assigned by journal 09 Jan, 2024 Submission checks completed at journal 09 Jan, 2024 First submitted to journal 12 Dec, 2023 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. We do this by developing innovative software and high quality services for the global research community. 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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-3745071\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":false,\"archivedVersions\":[],\"articleType\":\"Research Article\",\"associatedPublications\":[],\"authors\":[{\"id\":266157394,\"identity\":\"31b7ef8f-7491-48a5-909f-6efebbeaac3d\",\"order_by\":0,\"name\":\"Shima Bourang\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Ardabil University of Medical Sciences\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Shima\",\"middleName\":\"\",\"lastName\":\"Bourang\",\"suffix\":\"\"},{\"id\":266157395,\"identity\":\"79eda89a-9271-4bc3-ae5c-febb7631de8c\",\"order_by\":1,\"name\":\"Sina 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structure.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"1.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-3745071/v1/86051c2f9538b522e7c02221.png\"},{\"id\":49447473,\"identity\":\"ace3470a-6e13-42b7-ab48-38b970de41d4\",\"added_by\":\"auto\",\"created_at\":\"2024-01-11 03:06:04\",\"extension\":\"png\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":122470,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eThe FT-IR spectra of A) PLA and B) PLA-HA.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"image2.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-3745071/v1/b1713ebbed3e7fc5f1bead80.png\"},{\"id\":49447475,\"identity\":\"a64631a1-9696-47c0-8852-9a9572d0b029\",\"added_by\":\"auto\",\"created_at\":\"2024-01-11 03:06:04\",\"extension\":\"png\",\"order_by\":3,\"title\":\"Figure 3\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":108414,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eA) TGA and B) DTG analysis of PLA and PLA-HA.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"image3.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-3745071/v1/0bfdd456528dedaca955af34.png\"},{\"id\":49447535,\"identity\":\"a95cc54b-3b0e-4fb7-9dc8-d5dd7561378c\",\"added_by\":\"auto\",\"created_at\":\"2024-01-11 03:14:03\",\"extension\":\"png\",\"order_by\":4,\"title\":\"Figure 4\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":377043,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eTEM image of PLA-HA/Fe\\u003csub\\u003e3\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003e/curcumin nanoparticles.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"image4.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-3745071/v1/82bbcfefe79ea20b1e89427d.png\"},{\"id\":49447537,\"identity\":\"e3af01a2-b894-43f9-9a4a-621949094d4d\",\"added_by\":\"auto\",\"created_at\":\"2024-01-11 03:14:04\",\"extension\":\"png\",\"order_by\":5,\"title\":\"Figure 5\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":106406,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eThe DLS results of PLA-HA/Fe\\u003csub\\u003e3\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003e/ curcumin.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"image5.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-3745071/v1/ed7496881617c4fb3f81d855.png\"},{\"id\":49447471,\"identity\":\"65c239f1-a242-43c0-b24e-66aff3e17d4d\",\"added_by\":\"auto\",\"created_at\":\"2024-01-11 03:06:03\",\"extension\":\"png\",\"order_by\":6,\"title\":\"Figure 6\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":67924,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eDrug release profile of PLA/Fe\\u003csub\\u003e3\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003e/curcumin nanoparticles in acidic and neutral pH.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"image6.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-3745071/v1/c9db0561cb2229804b55e2ec.png\"},{\"id\":49447536,\"identity\":\"b30c10dc-10e9-45da-8fab-e801252e756a\",\"added_by\":\"auto\",\"created_at\":\"2024-01-11 03:14:04\",\"extension\":\"png\",\"order_by\":7,\"title\":\"Figure 7\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":58980,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eEvaluation of toxicity and drug delivery efficiency of curcumin drug, PLA/Fe\\u003csub\\u003e3\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003e and PLA-HA/Fe\\u003csub\\u003e3\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003e/curcumin nanoparticles.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"image7.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-3745071/v1/07d3344b7e4880dd4365b9de.png\"},{\"id\":49447746,\"identity\":\"0fc7121e-a566-4e4b-862a-4cc77a857ad9\",\"added_by\":\"auto\",\"created_at\":\"2024-01-11 03:22:05\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":1398249,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-3745071/v1/c52fff3e-8382-4377-bb95-812d1816db53.pdf\"}],\"financialInterests\":\"No competing interests reported.\",\"formattedTitle\":\"PLA-HA/Fe3O4 magnetic nanoparticles loaded with Curcumin: Physicochemical characterization and toxicity evaluation in HCT116 Colorectal cancer cells\",\"fulltext\":[{\"header\":\"Study Highlights\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eWhat is the current knowledge?\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cul\\u003e\\n \\u003cli\\u003eInvestigating the characteristics of loading, release, drug transfer efficiency and toxicity of PLA-HA/Fe\\u003csub\\u003e3\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003e nanoparticles loaded with curcumin.\\u003c/li\\u003e\\n \\u003cli\\u003eDetermining the characteristics of a drug delivery system for effective cancer treatment without side effects on healthy tissues.\\u003c/li\\u003e\\n\\u003c/ul\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eWhat is new here?\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cul\\u003e\\n \\u003cli\\u003eUsing curcumin as drug to treat HCT116 colorectal cancer cells.\\u003c/li\\u003e\\n \\u003cli\\u003eInvestigating the toxicity of PLA-HA/Fe\\u003csub\\u003e3\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003e nanoparticles.\\u003c/li\\u003e\\n \\u003cli\\u003eComparing the efficiency of nanocarrier in drug delivery to cancer tissue compared to free drug.\\u003c/li\\u003e\\n \\u003cli\\u003ePLA-HA/Fe\\u003csub\\u003e3\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003e/curcumin nanoparticles can be a potential approach for targeted drug delivery due to the presence of physicochemical properties and release profile, appropriate toxicity and efficiency in the transfer of curcumin drug to colorectal cancer cells.\\u003c/li\\u003e\\n\\u003c/ul\\u003e\"},{\"header\":\"Introduction\",\"content\":\"\\u003cp\\u003eColorectal cancer (CRC) is the third most common, harmful, and universal cancer and the second lethal type. In 2020, an estimated 1,880,725 people were diagnosed with colon cancer. By 2035, there may be nearly 2.5\\u0026nbsp;million new cases. [\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e] According to the pathological characteristics of the tumor, there are various therapeutic options for CRC. The principal therapeutic strategy for mCRC (Metastatic colorectal cancer) patients is palliative chemotherapy, while non-systematic therapy (such as surgery and optional radiation and ablative techniques) is optional for patients with respectable metastatic lesions to improve survival. The early-stage primary disease typically requires laparoscopic surgery; cases involving metastases necessitate open surgery for tumor resection, and nonresectable cases typically require adjuvant radiotherapy. Neoadjuvant and palliative chemotherapies, [\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e] immunotherapy, [\\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e] and tyrosine kinase inhibitor (TKI) [\\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e] therapy are additional CRC treatments. Currently, targeted drug delivery through nanoparticles has been an emerging approach for addressing various problems associated with chemotherapeutic agents. [\\u003cspan additionalcitationids=\\\"CR6\\\" citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e]\\u003c/p\\u003e \\u003cp\\u003eCurcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)- 1,6-heptadiene-3,5-dione), likewise alluded to as diferuloylmethane, comprises one of the major curcuminoids existing in the substructure of plant \\u003cem\\u003eCurcuma longa\\u003c/em\\u003e (turmeric). [\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e] Curcumin has been practically studied for the majority of human diseases and is highly adequate in treating a diversity of medical conditions, including, but not limited to, cancer, arthritis, major depression, liver disease, dyslipidemia, and chronic obstructive pulmonary disease. [\\u003cspan additionalcitationids=\\\"CR9 CR10 CR11\\\" citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e] Curcumin has the ability to encourage a wide range of chemical reactions in living things, such as hydrolysis, enzymatic reactions, reversible and irreversible nucleophilic addition (Michael reaction), and hydrogen donation leading to oxidation. [\\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e] Evidence demonstrates that curcumin disrupts a variety of cellular signaling pathways by directly targeting bioactive proteins or epigenetically regulating gene expression in key disease-associated signaling pathways, according to mounting evidence. [\\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e] Curcumin's therapeutic potential against CRC has been validated in a number of preclinical and clinical studies, and its effectiveness in suppressing various stages of CRC development is noteworthy. [\\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR17\\\" class=\\\"CitationRef\\\"\\u003e17\\u003c/span\\u003e] In spite of these advantages, curcumin suffers from some limitations in drug administration. Low solubility and bioavailability are major problems of this drug. Also, the passive distribution of curcumin, as to other chemical entities, is another important obstacle to the effective anticancer properties of this drug. The incorporation of curcumin into nanocarriers is a promising strategy to solve the mentioned problems. Nanoparticles have many important potentials to overcome these obstacles. They could increase the solubility and dissolution profile of less soluble drugs. Also, the absorption pathway of drugs may be improved using nanocarriers. However, the most attractive capability of nanocarriers is the ability to modify drug distribution in the body. [\\u003cspan citationid=\\\"CR18\\\" class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e] Since the drug is entrapped inside the nanoparticles, they can release the drug actively, and also through interaction with different organs, and biological or cell components, the fate of the drug could be changed according to treatment goals. Numerous nanocarriers were used for this strategy and among them, the conjugation of polymeric nanoparticles with magnetic cores is very advantageous.\\u003c/p\\u003e \\u003cp\\u003eBioanalytical methods and biomedical applications completely rely on magnetic nanoparticles. With bio-type specimens, they encounter less background interference, making bio-type samples' magnetic susceptibilities nearly nonexistent. [\\u003cspan citationid=\\\"CR19\\\" class=\\\"CitationRef\\\"\\u003e19\\u003c/span\\u003e] As a result of this benefit, and biological samples can be easily accessed in the direction of the external magnetic field. Analytical tools, bioimaging, biosensors, contrast agents (CAs), hyperthermia, photoablation therapy, physical therapy applications, separation, signal markers, and targeted drug delivery (TDD) are just a few of the many biomedical applications that can now be designed into magnetic nanoparticles. [\\u003cspan citationid=\\\"CR20\\\" class=\\\"CitationRef\\\"\\u003e20\\u003c/span\\u003e] Iron oxide nanoparticles (IONPs) are used in most studies because of their biocompatibility, high saturation magnetization, high magnetic susceptibility, chemical stability, and innocuousness. Nickel and cobalt, two examples of IONPs with high magnetic properties, are toxic and easily oxidized. Magnetite (Fe\\u003csub\\u003e3\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003e) nanoparticles (MNPs) are by far the most commonly used IONPs in biomedical applications. [\\u003cspan citationid=\\\"CR21\\\" class=\\\"CitationRef\\\"\\u003e21\\u003c/span\\u003e] As a result of ion transfer from Fe2\\u0026thinsp;+\\u0026thinsp;ions to Fe\\u003csup\\u003e3+\\u003c/sup\\u003e ions, magnetite nanoparticles have unique electrical and magnetic properties.[\\u003cspan citationid=\\\"CR22\\\" class=\\\"CitationRef\\\"\\u003e22\\u003c/span\\u003e] Most biomedical MNPs have superparamagnetism properties because they are smaller than 20 nm. [\\u003cspan citationid=\\\"CR22\\\" class=\\\"CitationRef\\\"\\u003e22\\u003c/span\\u003e] They are also widely used in this field due to their biocompatible surface chemistry, high magnetization saturation value, narrow particle size distribution (100 nm), and superparamagnetism property compared to other magnetic IONPs (M-IONPs). [\\u003cspan additionalcitationids=\\\"CR20\\\" citationid=\\\"CR19\\\" class=\\\"CitationRef\\\"\\u003e19\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR21\\\" class=\\\"CitationRef\\\"\\u003e21\\u003c/span\\u003e] In addition to targeting tumors using an external magnetic field, magnetite nanoparticles can also cause hyperthermia-induced apoptosis of cancer cells. [\\u003cspan citationid=\\\"CR23\\\" class=\\\"CitationRef\\\"\\u003e23\\u003c/span\\u003e] One of the most employed polymers for coating Fe\\u003csub\\u003e3\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003e is PLA which is readily oxidized and agglomerated, they are often coated with natural or synthetic polymers. [\\u003cspan citationid=\\\"CR24\\\" class=\\\"CitationRef\\\"\\u003e24\\u003c/span\\u003e]\\u003c/p\\u003e \\u003cp\\u003ePolylactic acid (PLA) is a flexible polymer that is fermented into a carboxylic acid from sustainable agricultural waste. [\\u003cspan additionalcitationids=\\\"CR26\\\" citationid=\\\"CR25\\\" class=\\\"CitationRef\\\"\\u003e25\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR27\\\" class=\\\"CitationRef\\\"\\u003e27\\u003c/span\\u003e] The lactic acid is then polymerized using a cyclic dilactone, lactide, and ring for product modification. [\\u003cspan citationid=\\\"CR28\\\" class=\\\"CitationRef\\\"\\u003e28\\u003c/span\\u003e] PLA and its copolymers have been utilized to encapsulate many classes of drugs, such as hormones, proteins, and chemotherapeutic agents. [\\u003cspan additionalcitationids=\\\"CR30\\\" citationid=\\\"CR29\\\" class=\\\"CitationRef\\\"\\u003e29\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR31\\\" class=\\\"CitationRef\\\"\\u003e31\\u003c/span\\u003e] Slow degradation rate and high hydrophobicity are some of the disadvantages that restrict the biomedical application of PLA. [\\u003cspan citationid=\\\"CR32\\\" class=\\\"CitationRef\\\"\\u003e32\\u003c/span\\u003e] On the other hand, nanoparticles can actively target tumor cells by recruiting targeting moieties that bind specifically to over-expressed receptors on cancerous cells. CD44, a transmembrane glycoprotein receptor, is abundantly expressed in tumor cells and plays an important role in tumor progression and metastasis. [\\u003cspan citationid=\\\"CR33\\\" class=\\\"CitationRef\\\"\\u003e33\\u003c/span\\u003e] Hyaluronic acid, a natural mucopolysaccharide found in the extracellular matrix, is a CD44 ligand that has been recently used in tumor-targeting nanoparticle formulations. The great biocompatibility, biodegradability, and hydrophilicity of hyaluronic acid make it a proper candidate for the targeted delivery of drugs and genes to tumor cells. [\\u003cspan citationid=\\\"CR34\\\" class=\\\"CitationRef\\\"\\u003e34\\u003c/span\\u003e]\\u003c/p\\u003e\\n\\u003ch3\\u003eLiterature Review\\u003c/h3\\u003e\\n\\u003cp\\u003eCurcumin, a polyphenol derived from the turmeric plant, has shown potential in cancer treatment. It reduces inflammation, encourages cell apoptosis, and inhibits cell proliferation to demonstrate anticancer effects.[\\u003cspan citationid=\\\"CR35\\\" class=\\\"CitationRef\\\"\\u003e35\\u003c/span\\u003e] Nevertheless, curcumin's low bioavailability and poor water solubility restrict its efficacy. Curcumin's stability and cellular bioavailability have been enhanced through the use of nanotechnologies in order to overcome these obstacles.[\\u003cspan citationid=\\\"CR36\\\" class=\\\"CitationRef\\\"\\u003e36\\u003c/span\\u003e] To improve curcumin's absorption and delivery, nano-based formulations like cubosomes and nanocarriers have been created.[\\u003cspan citationid=\\\"CR37\\\" class=\\\"CitationRef\\\"\\u003e37\\u003c/span\\u003e] Curcumin's bioavailability, retention in target tissues, and cytotoxic effects against cancer cells have all improved with these formulations, which have demonstrated encouraging outcomes. Curcumin's anticancer properties have also been shown in clinical trials for a variety of cancers, including brain tumors, lung, breast, prostate, pancreatic, gastric, leukemia, and colorectal cancers.[\\u003cspan citationid=\\\"CR38\\\" class=\\\"CitationRef\\\"\\u003e38\\u003c/span\\u003e] It's common knowledge that curcumin inhibits the cell cycle and speeds up cell death in relation to colorectal cancer, two factors that can help prevent the disease from spreading. According to in vitro studies done on different cancer cell lines, curcumin stopped the growth of the cells by molecularly interacting with several targets, which in turn regulated a number of distinct signaling cascade series.[\\u003cspan citationid=\\\"CR39\\\" class=\\\"CitationRef\\\"\\u003e39\\u003c/span\\u003e] In line with He et al., curcumin stopped the cell cycle that was partially in the G1 phase and present in the cells, which inhibited their growth.[\\u003cspan citationid=\\\"CR40\\\" class=\\\"CitationRef\\\"\\u003e40\\u003c/span\\u003e]\\u003c/p\\u003e \\u003cp\\u003eOne key feature that makes PLA useful for drug carriers is its biodegradability. PLA readily dissolves in extracellular settings.[\\u003cspan citationid=\\\"CR41\\\" class=\\\"CitationRef\\\"\\u003e41\\u003c/span\\u003e] Aside from this capability, the rate of degradation can be changed to accomplish a particular result. Drug carrier systems might be able to sustain a continuous release of therapeutic agents by prolonging the kinetics of this breakdown.[\\u003cspan citationid=\\\"CR42\\\" class=\\\"CitationRef\\\"\\u003e42\\u003c/span\\u003e] This is crucial because metabolic processes could potentially reduce the effectiveness of this therapeutic approach. It also gives the medication enough time to take effect. Through better drug delivery and fewer side effects, PLA-HA has demonstrated promise in the treatment of cancer. They can reduce toxicity and increase the effectiveness of anticancer medications like arenobufagin (ArBu), tamoxifen, docetaxel, daunorubicin, and ibuprofen.[\\u003cspan citationid=\\\"CR43\\\" class=\\\"CitationRef\\\"\\u003e43\\u003c/span\\u003e] Exploring new avenues for targeted treatment and overcoming multidrug resistance, nanotechnology-based chemotherapy employing nanoparticles has opened up new possibilities. In vitro, cytotoxicity against breast cancer cells has been shown for polymeric nanoparticles of polylactic acid-poly (ethylene glycol) (PLA-PEG) copolymers encapsulating a novel biosurfactant. [\\u003cspan citationid=\\\"CR44\\\" class=\\\"CitationRef\\\"\\u003e44\\u003c/span\\u003e]Biosurfactant has been shown to release under controlled conditions via these nanoparticles, and they are capable of actively delivering anticancer cargo to the cancer site. Biological components attached to nanoparticles can also improve their targetability to the cancerous area.\\u003c/p\\u003e \\u003cp\\u003eSuperparamagnetic Fe\\u003csub\\u003e3\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003e NPs have drawn interest due to their versatility in applications such as localized hyperthermia therapy, target-based carriage, stem cell labeling and tracking, and magnetic resonance imaging (MRI) contrast agents. When an external alternating magnetic field is applied, it can produce heat in tumor regions through hyperthermia therapy.[\\u003cspan citationid=\\\"CR45\\\" class=\\\"CitationRef\\\"\\u003e45\\u003c/span\\u003e] The material of choice for generating magnetism in these nanoparticles is iron oxide. The combination of magnetic hyperthermia and chemotherapeutic drug-loaded nanoparticles has shown remarkable antitumor effects. [\\u003cspan citationid=\\\"CR46\\\" class=\\\"CitationRef\\\"\\u003e46\\u003c/span\\u003e]By enhancing drug targeting, solubility, and bioavailability, nanoparticles can also enhance colorectal cancer diagnosis and treatment.[\\u003cspan citationid=\\\"CR47\\\" class=\\\"CitationRef\\\"\\u003e47\\u003c/span\\u003e] Specifically, nanomagnetic iron oxides have demonstrated potential as drug-delivery vehicles in the context of cancer treatment.\\u003c/p\\u003e \\u003cp\\u003eDeveloping an intravenous injectable aqueous formulation of curcumin is an intriguing idea, as curcumin's bioavailability in vivo is significantly reduced when administered orally. Hydrophobic drugs' poor water solubility can be addressed with biodegradable nanodrug carriers, offering promise for future use.[\\u003cspan citationid=\\\"CR48\\\" class=\\\"CitationRef\\\"\\u003e48\\u003c/span\\u003e] There have been a lot of studies done on this subject to deliver curcumin conjugation with micelles, liposomes, polymeric nanoparticles, and lipid based nanoparticles. In a recent study, CUR and doxorubicin (DOX) co-encapsulated in long circulating liposomes (LCL) at a molar ratio of 1:167 significantly reduced C26 cell proliferation when compared to free DOX in vitro. It was also reported that the amount of CUR encapsulated determines the degree of the synergistic cytotoxic effects of DOX and CUR, with higher amounts of CUR resulting in greater cytotoxic effects. [\\u003cspan citationid=\\\"CR49\\\" class=\\\"CitationRef\\\"\\u003e49\\u003c/span\\u003e] Sesarman et al., revealed a similar result when employing the same liposomal formulation as Tefas et al. to co-deliver CUR and DOX. (LCL-CUR-DOX) in cells of C26. The increased cytotoxic activity of LCL-CUR-DOX in comparison to free CUR-DOX prompted the authors to look into the protumor mechanism causing the C26 cell cytotoxicity. In addition to slightly inhibiting NF-κB activation, LCL-CUR-DOX also inhibits most of the proteins involved in the development of tumors. In contrast to free CUR-DOX, it has less of an effect on oxidative stress reduction in vitro. This might be the result of liposomes' distinct uptake mechanism from that of free medications. The process of endocytosis allows liposomes to enter cells, facilitating a higher degree of CUR internalization. On the other hand, transmembrane diffusion is how free CUR enters the cells. [\\u003cspan citationid=\\\"CR50\\\" class=\\\"CitationRef\\\"\\u003e50\\u003c/span\\u003e] In an effort to enhance CUR encapsulation, Dash and Konkimalla have recently loaded CUR into hydroxypropyl-β-cyclodextrin (HP-β-CD) using polyvinyl alcohol (PVA) as a stabilizer. The solubility of CUR in water has been improved by this formulation of nano-curcumin. It was applied in combination therapy to address the issue of drug resistance resulting from overexpression of p-glycoprotein (P-gp) to DOX. Following prescreening, CUR was chosen as combinatorial agents in this study over other P-gp inhibitors because it sensitized DOX-resistant Colo205 cells at the lowest concentration of 40 \\u0026micro;M. CUR-loaded HP-β-CD dramatically reversed DOX resistance, which was obtained by administering DOX liposomes at concentrations ranging from 0.1 to 10 \\u0026micro;M, once it reached 40 \\u0026micro;M.[\\u003cspan citationid=\\\"CR51\\\" class=\\\"CitationRef\\\"\\u003e51\\u003c/span\\u003e]\\u003c/p\\u003e \\u003cp\\u003eDrug delivery systems containing folate can penetrate cells through receptor-mediated endocytosis, preventing non-specific attacks on healthy tissues. Additionally, the agents can enhance cellular uptake in target cells and deliver the therapeutic agents to tumor cells. [\\u003cspan citationid=\\\"CR52\\\" class=\\\"CitationRef\\\"\\u003e52\\u003c/span\\u003e]According to reports, the lower micelle concentration resulting from folate conjugation can enhance the stability of the FA-copolymer micelle when compared to copolymer (PLAMPEG) alone. [\\u003cspan citationid=\\\"CR53\\\" class=\\\"CitationRef\\\"\\u003e53\\u003c/span\\u003e]Baek and Cho. have demonstrated that Nutlin-3a's therapeutic potential can be enhanced by folate-decorated, curcumin-loaded nanoparticles, which reverse multidrug resistance. [\\u003cspan citationid=\\\"CR54\\\" class=\\\"CitationRef\\\"\\u003e54\\u003c/span\\u003e]As demonstrated by Kazemi et al. (2020) and Zhang et al. (2019), also demonstrated that folate-drug delivery systems can improve drug targeting and uptake to tumor cells while also extending the drug's half-life in the body.[\\u003cspan citationid=\\\"CR55\\\" class=\\\"CitationRef\\\"\\u003e55\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR56\\\" class=\\\"CitationRef\\\"\\u003e56\\u003c/span\\u003e] Additionally, Phan et al. developed a folate-modified curcumin-loaded micelle delivery system (Cur/PLA-PEG-Fol) using poly(lactic acid)-poly(ethylene glycol) to improve curcumin's solubility in aqueous solution and increase its targeting ability. As per their research, Folate-modified micelles exhibit promise as a nanocarrier to enhance Cur's solubility, anticancer activity, and systemic targeting capabilities.[\\u003cspan citationid=\\\"CR57\\\" class=\\\"CitationRef\\\"\\u003e57\\u003c/span\\u003e] Therefore, we decided to use the nanotechnology-targeted drug delivery method using PLA-HA copolymer with Fe3O4 magnetic core to increase the efficiency of drug transfer and drug solubility to transfer curcumin drug and increase the efficiency of colorectal cancer treatment.\\u003c/p\\u003e \\u003cdiv id=\\\"Sec3\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eResearch gap\\u003c/h2\\u003e \\u003cp\\u003eBased on the aforementioned information, the prescribed treatment options demonstrate efficacy in the management of cancer. However, in contemporary times, with the advancement of integrated therapeutic sciences, the conventional and conventional approaches used in the past are of minimal utility in addressing critical disease, including cancer. Therefore, contemporary researchers primarily attribute to integrating diverse methodologies in order to enhance effectiveness and overcome the limitations imposed by different techniques. In recent times, several investigations have been conducted, focusing on the utilization of various chemotherapy medications in combination with different copolymers and nanoparticles. Despite the studies conducted, based on the investigations carried out by our team, until today there is no research on the simultaneous use of curcumin, PLA-HA copolymer, and Fe3O4 nanoparticles for colorectal cancer treatment, to enhance drug efficacy, biodegradability, water solubility, release kinetics, and targeted delivery.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec4\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eObjective and contributions\\u003c/h2\\u003e \\u003cp\\u003eThe purpose of this work is to assess the physicochemical properties of curcumin-loaded PLA-HA/Fe\\u003csub\\u003e3\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003e MNPs and determine their level of toxicity in HCT116 colorectal cancer cells. We predict that these nanoparticles will present with the right physicochemical characteristics to facilitate drug delivery and cause cytotoxicity in HCT116 cells.\\u003c/p\\u003e \\u003c/div\\u003e\"},{\"header\":\"Materials and methods\",\"content\":\"\\u003cdiv id=\\\"Sec6\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eMaterials\\u003c/h2\\u003e \\u003cp\\u003ePoly Vinyl Alcohol (PVA) were purchased from Merck (Germany). PLA, HA, FeCl\\u003csub\\u003e3\\u003c/sub\\u003e.6H\\u003csub\\u003e2\\u003c/sub\\u003eO, FeCl\\u003csub\\u003e2\\u003c/sub\\u003e.4H\\u003csub\\u003e2\\u003c/sub\\u003eO, RPMI 1640, penicillin/streptomycin, FBS, and DMSO were obtained from Sigma-Aldrich (USA). The MTT solution was purchased from Atocel (Hungary) and amphotericin B was obtained from Biowest (France). Other solutions, reagents, and solvents were at analytical grade and obtained domestically.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec7\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eGreen synthesis of magnetite (Fe\\u003csub\\u003e3\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003e) nanoparticles using the hydroalcoholic extract of Silybum marianum\\u003c/h2\\u003e \\u003cp\\u003eEqual amounts of FeCl\\u003csub\\u003e3\\u003c/sub\\u003e and FeCl\\u003csub\\u003e2\\u003c/sub\\u003e (3.3 g) were dissolved separately in 50 ml of water. The reaction was initiated by mixing 15 ml of \\u003cem\\u003eSilybum marianum\\u003c/em\\u003e methanolic extract, FeCl\\u003csub\\u003e3\\u003c/sub\\u003e, and FeCl\\u003csub\\u003e2\\u003c/sub\\u003e solution under nitrogen gas at 80 \\u0026deg; C for 30 minutes using a stirrer. Then, 60 ml of NaOH (1 mM) was added to the above solution and incubated for another 4 hours under similar conditions. The nanoparticles were centrifuged (10000 rpm for 10 minutes) and washed several times with phosphate buffer (PBS). The resulting iron oxide nanoparticles were then freeze-dried.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec8\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eSynthesis of PLA-HA copolymer\\u003c/h2\\u003e \\u003cp\\u003eTo polymerize poly lactic acid-hyaluronic acid (PLA-HA), the NH\\u003csub\\u003e2\\u003c/sub\\u003e-Hyaluronic acid and Acrylate-PLA solutions in chloroform were mixed slowly by 24 hours of stirring at 50\\u0026deg;C. To remove impurities, the resulting product was centrifuged for half an hour at 4\\u0026deg;C (10000 rpm) using equal volumes of water and methanol. The copolymer was further purified using dialysis membranes (10000 MW) and then the PLA-HA polymer was centrifuged again under the above-mentioned conditions and freeze-dried.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec9\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eCharacterization of PLA-HA copolymer\\u003c/h2\\u003e \\u003cp\\u003eH-NMR spectroscopy was carried out to investigate the structure of PLA-HA copolymer using CDCl\\u003csub\\u003e3\\u003c/sub\\u003e as the solvent (Varian Unityinova 500 NMR Spectrometer, USA). Additionally, the FTIR technique (1B-AR-010, Biotec, USA) was used for confirming the synthesis of PLA-HA synthesis. Also, the thermal stability of PLA and PLA-HA copolymer was evaluated by Thermogravimetric analysis (TGA, STA-PT1000, License, Germany) in a thermal range of 40 \\u0026ordm;C to 700 \\u0026ordm;C with a heating rate of 10 \\u0026ordm;C/min.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec10\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eSynthesis of PLA-HA/Fe\\u003csub\\u003e3\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003e/curcumin and PLA/Fe\\u003csub\\u003e3\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003e nanoparticles\\u003c/h2\\u003e \\u003cp\\u003eA solvent diffusion technique was used to prepare PLA-HA/Fe\\u003csub\\u003e3\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003e/curcumin and PLA/Fe\\u003csub\\u003e3\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003e without drug nanoparticles. 5 mg of Fe\\u003csub\\u003e3\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003e nanoparticles coated by Oleic Acid was added to PLA-HA solutions (30 mg in 1 ml chloroform). Then, 4 mg of curcumin and 1 ml of PVA solutions (1% w/v) were added to the mixture and sonicated for another 30 seconds, respectively. The resulting emulsions were then collected using a syringe and slowly injected into 25 ml of PVA solution (0.3% w/v) under stirring. The final emulsion was stirred at room temperature for 24 hours. The yielded nanoparticles were washed 3 times with centrifugation using deionized water (13000 rpm for 1 hour) and freeze-dried.\\u003c/p\\u003e \\u003cp\\u003eIn order to prepare drug-free nanoparticles (PLA-HA/Fe\\u003csub\\u003e3\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003e), the aforementioned procedure was used either. With the difference that curcumin was not added in the loading phase.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec11\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eCharacterization of nanoparticles\\u003c/h2\\u003e \\u003cp\\u003eThe average size and zeta potential of PLA-HA/Fe\\u003csub\\u003e3\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003e/curcumin and PLA/Fe\\u003csub\\u003e3\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003e nanoparticles were determined using dynamic light scattering (DLS, SZ100, Horiba, Japan) techniques. The morphology and size distribution of synthesized nanoparticles were investigated by TEM images (LEO906, Zeiss, Germany). The formation of magnetite nanoparticles was confirmed by FTIR and UV-Vis (Thermo Scientific, USA) spectroscopy. VSM (Vibrating Sample Magnetometer, MDKF-Co., Iran) technique was used to measure the magnetic properties of nanoparticles.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec12\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eDetermination of drug encapsulation efficiency of synthesized nanoparticles\\u003c/h2\\u003e \\u003cp\\u003eTo calculate the drug (curcumin) encapsulation efficiency, the supernatant of the nanoparticle\\u0026rsquo;s mixture was centrifuged (13000 rpm for 1 hour) and the amount of free curcumin present in the supernatant was determined using spectrophotometry at 480 nm. The measured amount was then compared with the initial amount of drug used in the loading process (4 mg) and the encapsulation efficiency was calculated by the following equation:\\u003c/p\\u003e \\u003cp\\u003eEE%= (W\\u003csub\\u003einitial CU\\u003c/sub\\u003e \\u0026ndash; W\\u003csub\\u003efree CU\\u003c/sub\\u003e / W\\u003csub\\u003einitial CU\\u003c/sub\\u003e)\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec13\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eRelease profile of drug from nanoparticles\\u003c/h2\\u003e \\u003cp\\u003eSince the tumor tissue has a lower pH compared to the normal tissue, the drug release from nanoparticles was evaluated in PBS buffer with acidic (pH\\u0026thinsp;=\\u0026thinsp;6) and neutral (pH\\u0026thinsp;=\\u0026thinsp;7.4) pH values. 10 mg of the PLA/Fe\\u003csub\\u003e3\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003e/curcumin and PLA-HA/Fe\\u003csub\\u003e3\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003e nanoparticles were added separately to 2 ml of PBS buffer and stored at 37\\u0026deg;C. The nanoparticles supernatant was then collected by centrifugation (13,000 rpm for 10 minutes) at predetermined time intervals and nanoparticles were resuspended in 2 ml of PBS until the next collection. The amount of drug present in the supernatant was evaluated using spectrophotometry. The cumulative release percentage was then calculated using the following equation.\\u003c/p\\u003e \\u003cp\\u003eCumulative release percentage =\\u003cspan class=\\\"InlineEquation\\\"\\u003e\\u003cspan class=\\\"mathinline\\\"\\u003e\\\\(\\\\frac{{Dr}^{t}+ {Dr}^{t+1}}{DE}\\\\)\\u003c/span\\u003e\\u003c/span\\u003e\\u003c/p\\u003e \\u003cp\\u003eDr\\u003csup\\u003et\\u003c/sup\\u003e= The measured amount of drug in the supernatant at any time (t)\\u003c/p\\u003e \\u003cp\\u003eDr\\u003csup\\u003et+1\\u003c/sup\\u003e= The measured amount of drug in the supernatant at time (t\\u0026thinsp;+\\u0026thinsp;1)\\u003c/p\\u003e \\u003cp\\u003eDe\\u0026thinsp;=\\u0026thinsp;The amount of drug encapsulated in the nanoparticles\\u003c/p\\u003e \\u003cp\\u003e \\u003cb\\u003eIn vitro\\u003c/b\\u003e \\u003cb\\u003eevaluation of cytotoxicity\\u003c/b\\u003e\\u003c/p\\u003e \\u003cp\\u003eThe HCT116 colorectal cancer cell line was used to evaluate the toxicity and drug delivery efficiency of PLA-HA/Fe\\u003csub\\u003e3\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003e nanoparticles. First, Human Colorectal Carcinoma cell line HCT116 cells were grown in 10% fetal bovine serum and RPMI cell media at 37\\u0026deg;C in 5% CO\\u003csub\\u003e2\\u003c/sub\\u003e. The cytotoxic effect of Fucosterol alone or in combination with curcumin in colon cells was evaluated by an MTT reduction assay. For the MTT assay, 100 \\u0026micro;l of HCT116 cells at a density of 7 \\u0026times;10\\u003csup\\u003e4\\u003c/sup\\u003e cells per milliliter were transferred to 96-well plates. Then, the cells were kept in a CO\\u003csub\\u003e2\\u003c/sub\\u003e incubator (at 37 \\u0026deg; C, 90% humidity, and 5% CO\\u003csub\\u003e2\\u003c/sub\\u003e) for 24 hours. The HCT116 cells were then treated with different concentrations of PLA-HA/Fe\\u003csub\\u003e3\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003e/ curcumin nanoparticle (25، 50، 75، 100، 200 \\u0026micro;g/ml), as well as free curcumin. To evaluate the toxicity of nanoparticles, PLA-HA/Fe\\u003csub\\u003e3\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003e was used. The cells were exposed to each treatment for 24 hours. Then, the cell viability was assessed using an MTT assay.\\u003c/p\\u003e \\u003c/div\\u003e\"},{\"header\":\"Results\",\"content\":\"\\u003cdiv id=\\\"Sec15\\\" class=\\\"Section2\\\"\\u003e\\n \\u003ch2\\u003e1. Characterization of PLA-HA copolymer\\u003c/h2\\u003e\\n \\u003cp\\u003eThe H-NMR spectra of PLA and PLA-HA are presented in Fig. \\u003cspan class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e. As shown in the H-NMR spectrum of PLA, the peaks observed at 5.75 (b) and 1.72 (a) ppm were assigned to methine and methylene groups in PLA. Whereas in the H-NMR spectrum of PLA-HA, new peaks were observed at 8.19 and 3.97 ppm, which were related to the alcohol (OH) (d) and amide (NH) (c) protons present in the structure of hyaluronic acid, respectively.\\u003c/p\\u003e\\n \\u003cp\\u003eThe FT-IR spectra of PLA and PLA-HA copolymer shown in Fig.\\u0026nbsp;\\u003cspan class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e, confirms the synthesis of PLA-HA. As shown in the FT-IR spectrum of PLA, the IR bands observed at 1750 cm\\u003csup\\u003e\\u0026minus;\\u0026thinsp;1\\u003c/sup\\u003e and 2900\\u0026ndash;3000 cm\\u003csup\\u003e\\u0026minus;\\u0026thinsp;1\\u003c/sup\\u003e were related to C\\u0026thinsp;=\\u0026thinsp;O and C-H groups present in PLA. The FT-IR spectrum of PLA-HA revealed new peaks at 1596 and 3532 cm\\u003csup\\u003e\\u0026minus;\\u0026thinsp;1\\u003c/sup\\u003e which were respectively related to N-H and O-H bonds in hyaluronic acid. These findings can indicate the bonding of HA to PLA.\\u003c/p\\u003e\\n \\u003cp\\u003eTGA analysis is mostly performed to study the thermal stability of samples, but this method can also estimate the percentage of constituents present in the sample. The TGA analysis of PLA, shown in Fig.\\u0026nbsp;\\u003cspan class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003e, represents a severe weight loss stage which is indicative of the purity of the PLA polymer. On the other hand, several stages of weight loss were observed in the TGA analysis of PLA-HA polymer in the temperature range of 200\\u0026ndash;250, 300\\u0026ndash;320, and 350\\u0026ndash;380 \\u0026ordm;C, which indicated the presence of several materials in PLA-HA compared to PLA. Considering that the weight loss of PLA was observed in the temperature range of 200 to 320 \\u0026ordm;C, it can be concluded that the weight loss in the temperature range of 350 to 380 \\u0026ordm;C is related to the hyaluronic acid present in the structure of PLA-HA copolymer.\\u003c/p\\u003e\\n\\u003c/div\\u003e\\n\\u003cdiv id=\\\"Sec16\\\" class=\\\"Section2\\\"\\u003e\\n \\u003ch2\\u003e2. Characterization of PLA-HA/Fe\\u003csub\\u003e3\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003e/curcumin nanoparticles\\u003c/h2\\u003e\\n \\u003cp\\u003eThe results of studying the morphological properties and size of PLA-HA/Fe\\u003csub\\u003e3\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003e/curcumin nanoparticles by transmission electron microscope (TEM) indicated that these nanoparticles had a spherical structure and a size of about 100\\u0026ndash;200 nm (Fig.\\u0026nbsp;\\u003cspan class=\\\"InternalRef\\\"\\u003e4\\u003c/span\\u003e).\\u003c/p\\u003e\\n \\u003cp\\u003eThe DLS results shown in \\u003cstrong\\u003eFig.\\u0026nbsp;5\\u003c/strong\\u003e confirm the nanoscale dimensions of the synthesized nanoparticles. PLA/Fe\\u003csub\\u003e3\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003e/curcumin nanoparticles had an average size of 208\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;12.8 nm.\\u003c/p\\u003e\\n\\u003c/div\\u003e\\n\\u003cdiv id=\\\"Sec17\\\" class=\\\"Section2\\\"\\u003e\\n \\u003ch2\\u003e3. Drug release pattern\\u003c/h2\\u003e\\n \\u003cp\\u003eThe drug encapsulation efficiency in PLA-HA/Fe\\u003csub\\u003e3\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003e nanoparticles was 42/18\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.7 percent. The drug release pattern in acidic and neutral media (shown in \\u003cstrong\\u003eFig.\\u0026nbsp;6\\u003c/strong\\u003e) involved two different phases: burst release and sustained release. More than 50% of the drug released within 3 days was released. For example, the amount of released drug of PLA-HA/Fe\\u003csub\\u003e3\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003e/curcumin within 14 days of incubation with PBS buffer, pH\\u0026thinsp;=\\u0026thinsp;7.4 was 43.6\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;3.1 percent (Fig.\\u0026nbsp;6). Also, it was found that the drug release rate was higher in acidic pH compared to the neutral media. For example, the amount of curcumin drug released from nanoparticles in 14 days at pH\\u0026thinsp;=\\u0026thinsp;7.4 was 57.36\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.9%, while this amount increased to more than 85% at pH\\u0026thinsp;=\\u0026thinsp;6.\\u003c/p\\u003e\\n\\u003c/div\\u003e\\n\\u003cdiv id=\\\"Sec18\\\" class=\\\"Section2\\\"\\u003e\\n \\u003ch2\\u003e4. In vitro cytotoxicity\\u003c/h2\\u003e\\n \\u003cp\\u003eMTT assay results, shown in \\u003cstrong\\u003eFig.\\u0026nbsp;7\\u003c/strong\\u003e, demonstrated that PLA-HA/Fe\\u003csub\\u003e3\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003e nanoparticles are biocompatible on HCT116 cells since the encapsulation of the drug curcumin inside these nanoparticles significantly increased its toxicity on the HCT116 cell line. Although the encapsulation of curcumin drug inside PLA-HA/Fe\\u003csub\\u003e3\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003e nanoparticles increased the antitumor properties of these nanoparticles, however, the lowest cell viability of HCT116 cells was observed after its treatment with free curcumin drug. For example, the survival rate of cells after treatment with 200 \\u0026micro;g/ml of PLA-HA/Fe\\u003csub\\u003e3\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003e/curcumin nanoparticles was 58.63\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;5.1%, while this rate was for an equal amount of curcumin drug encapsulated in 0 \\u0026micro;g/mL of PLA-HA/Fe\\u003csub\\u003e3\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003e/curcumin nanoparticles was 52.26\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;4.3.\\u003c/p\\u003e\\n\\u003c/div\\u003e\"},{\"header\":\"Discussion\",\"content\":\"\\u003cp\\u003eIn this study, PLA-HA/Fe\\u003csub\\u003e3\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003e/curcumin nanoparticles were synthesized successfully to deliver curcumin as a drug into HCT116 Colorectal cancer cells. First, PLA-HA copolymer synthesized successfully and characterized by H-NMR, FT-IR spectra, and TGA analysis. Second, PLA-HA/Fe\\u003csub\\u003e3\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003e/curcumin and PLA/Fe\\u003csub\\u003e3\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003e nanoparticles synthesized, and TEM and DLS analysis were conducted to investigate the morphological characteristics and size of nanoparticles. According to the TEM results, the synthesized PLA-HA/Fe\\u003csub\\u003e3\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003e/curcumin nanoparticles were found to have a spherical structure. In agreement with the results obtained from the research of other researchers, it has been determined that the efficiency of drug transfer to target tissues directly depends on the morphology of nanoparticles. For example, among the types of spatial structure, nanoparticles with spherical structure have high transfer efficiency. According to the results obtained in this research, due to the spherical structure, PLA-HA/Fe\\u003csub\\u003e3\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003e/curcumin nanoparticles will have a high potential in drug delivery to cancer cells and tissues. [\\u003cspan citationid=\\\"CR58\\\" class=\\\"CitationRef\\\"\\u003e58\\u003c/span\\u003e] The size and surface charge of nanoparticles are two other important factors in the successful delivery of the drug encapsulated inside the nanoparticles. In accordance with the results obtained from other research, by decreasing the size of nanoparticles, the possibility of success in transferring them to cancer cells increases, while non-specific absorption by normal cells increases in nanoparticles with a size smaller than 50 nm. In other words, by reducing the size of nanoparticles to less than 50 nm, in addition to increasing the transfer efficiency, the amount of side effects also increases with non-specific absorption by normal cells. [\\u003cspan citationid=\\\"CR59\\\" class=\\\"CitationRef\\\"\\u003e59\\u003c/span\\u003e] Based on the results, nanoparticles with a size of 200 nm are considered a suitable option for targeted drug delivery to cancer tissues. This group of nanoparticles has a higher transfer efficiency due to their size smaller than 200 nm, and the non-specific absorption of these nanoparticles by normal cells is less than nanoparticles with a size smaller than 100 nm. According to the results obtained in this research, the size of PLA-HA/Fe\\u003csub\\u003e3\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003e/curcumin nanoparticles was in the range of 200 nm, so it is expected that these nanoparticles have a high penetration ability to cancer cells and minimal absorption by normal cells in vivo. In the study conducted by Noor Alaam and colleagues on designing and determining the properties of PLGA-HA nanoparticles loaded with Cisplatin, a slight increase in the size of nanoparticles conjugated with hyaluronic acid was seen compared to PLGA nanoparticles. The possible reason for this increase in size is the presence of hyaluronic acid segments. Nanoparticles containing HA in this study also had more negative zeta potential, which is due to the negative carboxylic groups present in hyaluronic acid. [\\u003cspan citationid=\\\"CR60\\\" class=\\\"CitationRef\\\"\\u003e60\\u003c/span\\u003e]\\u003c/p\\u003e \\u003cp\\u003eAfter that, based on the obtained results of the Drug release pattern, this phenomenon is consistent with the results observed in previous studies which have stated the biochemical mechanisms involved in the separation of drugs from nanoparticles as the probable reason for the different release rates in an acidic and neutral environment. Therefore, due to the lower pH of tumor tissues compared to healthy tissues, encapsulation of curcumin into the synthesized nanoparticles can lead to a lower incidence of side effects. Many researchers are interested in using iron oxide nanoparticles in drug delivery systems because of their biocompatibility and favorable magnetic properties. These nanoparticles provide the possibility of drug accumulation in the tumor site by applying an external magnetic field. Also, these nanoparticles have a high potential in imaging applications as well as hyperthermia. The results of past research have shown that magnetic nanoparticles increase the contrast of images in MRI imaging. Also, these nanoparticles significantly increase the efficiency of drug transfer to the tumor tissue. [\\u003cspan citationid=\\\"CR61\\\" class=\\\"CitationRef\\\"\\u003e61\\u003c/span\\u003e] In previous studies, drug release from polymer nanoparticles with a magnetic core was also examined. Amani et al. conducted a study in which, in terms of the design and evaluation of iron oxide nanoparticles coated with a PLA-PEG-PLA copolymer, the burst and continuous release patterns of drug release were observed in both neutral and acidic environments. In a similar condition, compared to a neutral medium, the rate of drug release from nanoparticles in an acidic medium was significantly higher. The chemical and biochemical processes involved in the separation of drugs from nanoparticles, as well as the reason for the difference in release rate between an acidic and a neutral environment, were discussed in this study. It was likewise expressed that, as a general rule, the course of medication partition from nanoparticles in an impartial climate is slower than in an acidic climate. When compared to healthy cells or tissues, cancer cells or tumor tissues have a lower pH, so a high rate of release in acidic tissue may result fewer side effects than when the free drug is used. [\\u003cspan citationid=\\\"CR62\\\" class=\\\"CitationRef\\\"\\u003e62\\u003c/span\\u003e] In addition, polymer degradation was cited as the cause of the continuous phase release of Berberine from PLGA-HA copolymer nanoparticles in the study by Bhatnagar and colleagues. Additionally, the hydrolysis of PLGA ester bonds in an acidic environment is the cause of the faster release of Berberine than in a neutral environment. Berberine release from PLGA-HA nanoparticles was higher than that of PLGA nanoparticles in this study. Due to the hydrophilic nature of hyaluronic acid, Bhatnagar believes that the increased interaction of nanoparticles with the aqueous environment is to blame for this phenomenon. [\\u003cspan citationid=\\\"CR63\\\" class=\\\"CitationRef\\\"\\u003e63\\u003c/span\\u003e]\\u003c/p\\u003e \\u003cp\\u003eIn this research, the PLA polymer surface was targeted by using hyaluronic acid in order to increase the efficiency of drug transfer to cancer cells. In addition, the ability to transport curcumin drug through these nanoparticles and its effect on the viability of HCT116 cells was also evaluated through the MTT test. Similar outcomes have been observed in other studies employing hyaluronic acid as a targeted component against cancer cells. Also, the findings of this research are consistent with other studies which have employed Hyaluronic acid as a tumor-targeting moiety in nanoparticles. The reason for this phenomenon could be the increased adsorption of nanoparticles by cells due to the specific interaction between hyaluronic acid present in the nanoparticle\\u0026rsquo;s structure and CD44 receptors which are over-expressed on the surface of the HCT116 cell membrane. Noor Alaam's research found that when PLGA-HA nanoparticles were used instead of hyaluronic acid nanoparticles, the internalization of the nanoparticles improved because hyaluronic acid specifically interacted with CD44 receptors in SKOV-3 cells. It is excessive, and the rally is necessary for the nanoparticles' endocytosis. The cell toxicity of the drug-containing nanoparticles and the free drug was not significantly different, in contrast to the results of the current study. This is due to the ability of post-endocytosis nanoparticles to transmit drugs in greater volumes and the cellular toxicity of the materials used in their preparation, despite the sluggishness of this process in comparison to the release of the free drug. [\\u003cspan citationid=\\\"CR60\\\" class=\\\"CitationRef\\\"\\u003e60\\u003c/span\\u003e]\\u003c/p\\u003e\"},{\"header\":\"Conclusion\",\"content\":\"\\u003cp\\u003eChemotherapy drugs are effective at reducing cancer cell survival, although they have many side problems such as their effect on healthy cells and resistance to the drug. In addition, due to the fast catabolism and short half-life of these drugs, continuous intravenous infusion is often used. In order to solve the obstacles mentioned above, it is possible to use drug loading in targeted nanoparticles. Encapsulation of curcumin in the magnetite (Fe\\u003csub\\u003e3\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003e) nanoparticles prepared by green synthesis method and coated with PLA-HA copolymer could be a proper approach for addressing its non-specific effect on healthy cells. Prepared PLA-HA/Fe\\u003csub\\u003e3\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003e/curcumin nanoparticles have a spherical shape and a size of about 200\\u0026ndash;300 nm. According to the results obtained in this research, due to the spherical structure, PLA-HA/Fe\\u003csub\\u003e3\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003e/curcumin nanoparticles will have a high potential in drug delivery to cancer cells and tissues. The drug encapsulation efficiency in PLA-HA/Fe\\u003csub\\u003e3\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003e nanoparticles was 42/18\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.7 percent. The synthesized nanoparticles are able to create a two-phase release pattern explosively and continuously for 14 days. More than 50% of the drug released within 3 days was released. Furthermore, the amount of drug release in acidic pH is significantly higher than in neutral pH. Considering the acidity of the pH of cancer cells and tumor tissue compared to healthy tissue, this capability can lead to a decrease in the release of the drug in the healthy tissue and, as a result, reduce the side effects of the drug. Therefore, PLA-HA/Fe\\u003csub\\u003e3\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003e/curcumin nanoparticles can be a potential approach for targeted drug delivery due to the presence of physicochemical properties and release profile, appropriate toxicity, and efficiency in the transfer of curcumin drug to colorectal cancer cells.\\u003c/p\\u003e \"},{\"header\":\"Declarations\",\"content\":\"\\u003cdiv id=\\\"Sec21\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eData availability\\u003c/h2\\u003e \\u003cp\\u003eThe datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.\\u003c/p\\u003e \\u003c/div\\u003e\\u003ch2\\u003eAuthor Contribution\\u003c/h2\\u003e\\u003cp\\u003eS.B. Led the writing of the article and Proofreading of the final version of the manuscript, S.A. conducted the research and investigation process, M.N. analyzed the statistical, mathematical, and computational, and Wrote the original Draft of the article, A.M. Performed the experiments, S.A. Provided the study materials, materials, laboratory samples, H A.E. Supervised: Oversight and leadership responsibility for the research activity planning (Correspondence) and V.AH. Performed the numerical calculations for the suggested experiment.All authors reviewed the manuscript\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\u003cli\\u003e\\u003cspan\\u003eDekker E, Tanis PJ, Vleugels J, Kasi PM, Wallace M. (2019) Pure-AMC. Lancet 394:1467\\u0026ndash;80.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eHeemskerk-Gerritsen BA, Rookus MA, Aalfs CM, Ausems MG, Coll\\u0026eacute;e JM, Jansen L, et al. 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Drug delivery and translational research 8:565\\u0026thinsp;\\u0026ndash;\\u0026thinsp;79. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003ehttps://doi.org/10.1007/s13346-020-00784-7\\u003c/span\\u003e\\u003cspan address=\\\"10.1007/s13346-020-00784-7\\\" 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\":false,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":true,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":false,\"email\":\"\",\"identity\":\"sn-applied-sciences\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"\",\"sideBox\":\"\",\"snPcode\":\"\",\"submissionUrl\":\"\",\"title\":\"SN Applied Sciences\",\"twitterHandle\":\"\",\"acdcEnabled\":false,\"dfaEnabled\":false,\"editorialSystem\":\"\",\"reportingPortfolio\":\"VoR Journals\",\"inReviewEnabled\":false,\"inReviewRevisionsEnabled\":false},\"keywords\":\"Curcumin, targeted drug delivery, nanoparticles, green synthesis, metastatic disease, CD44\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-3745071/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-3745071/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003cp\\u003eColorectal cancer (CRC) is the third most common, harmful, and universal cancer and the second lethal type. This paper discusses the therapeutic potential of curcumin, a major curcuminoid found in the substructure of plant \\u003cem\\u003eCurcuma longa\\u003c/em\\u003e (turmeric), against CRC. Curcumin has the ability to disrupt a variety of cellular signaling pathways and has been validated in several preclinical and clinical studies, but suffers from low solubility and bioavailability. To address these issues, PLA-HA/Fe\\u003csub\\u003e3\\u003c/sub\\u003eO4 magnetic nanoparticles were synthesized and loaded with curcumin. The average size and zeta potential of the nanoparticles and the magnetic properties were measured. The drug encapsulation efficiency and cumulative release of curcumin from the nanoparticles under acidic and neutral pH values were evaluated, as well as the cytotoxic effect of the nanoparticles on HCT116 colorectal cancer cells. The results demonstrated that nanoparticles have a high degree of biocompatibility and the ability to carry Curcumin medications. HCT116 cells with 200 \\u0026micro;g/ml PLA-HA/Fe\\u003csub\\u003e3\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003e/Curcumin nanoparticles have 58.63\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;3.7% percent cell viability. Ultimately, PLA-HA, Fe\\u003csub\\u003e3\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003e, and Curcumin's physicochemical characteristics and impact on cell viability render them valuable instruments for precisely delivering drugs to colorectal cancer cells. The PLA-HA/Fe\\u003csub\\u003e3\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003e-curcumin nanoparticles demonstrated a well-targeted drug delivery system for upcoming colorectal cancer treatments, as evidenced by their overall strong cytotoxic effects on colorectal cancer cells and negligible toxicity towards non-cancerous cells.\\u003c/p\\u003e\",\"manuscriptTitle\":\"PLA-HA/Fe3O4 magnetic nanoparticles loaded with Curcumin: Physicochemical characterization and toxicity evaluation in HCT116 Colorectal cancer cells\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2024-01-11 03:05:59\",\"doi\":\"10.21203/rs.3.rs-3745071/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0},{\"type\":\"decision\",\"content\":\"Revision requested\",\"date\":\"2024-02-20T06:21:02+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorInvitedReview\",\"content\":\"\",\"date\":\"2024-02-14T22:40:53+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"aae86c3b-63a7-4ffe-81f9-638d8acca2a5\",\"date\":\"2024-02-06T19:07:59+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"editorInvitedReview\",\"content\":\"\",\"date\":\"2024-01-21T19:26:47+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"e817710b-e01d-4354-8787-e5d2544c24dc\",\"date\":\"2024-01-16T20:55:43+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"d9135ad3-ed7a-41b9-82ee-970216261008\",\"date\":\"2024-01-15T03:23:16+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewersInvited\",\"content\":\"\",\"date\":\"2024-01-14T20:54:49+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorAssigned\",\"content\":\"\",\"date\":\"2024-01-09T09:14:32+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"checksComplete\",\"content\":\"\",\"date\":\"2024-01-09T09:14:15+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"submitted\",\"content\":\"SN Applied Sciences\",\"date\":\"2023-12-12T17:35:44+00:00\",\"index\":\"\",\"fulltext\":\"\"}],\"status\":\"published\",\"journal\":{\"display\":false,\"email\":\"\",\"identity\":\"sn-applied-sciences\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"\",\"sideBox\":\"\",\"snPcode\":\"\",\"submissionUrl\":\"\",\"title\":\"SN Applied Sciences\",\"twitterHandle\":\"\",\"acdcEnabled\":false,\"dfaEnabled\":false,\"editorialSystem\":\"\",\"reportingPortfolio\":\"VoR Journals\",\"inReviewEnabled\":false,\"inReviewRevisionsEnabled\":false}}],\"origin\":\"\",\"ownerIdentity\":\"842cec65-cc5e-406e-82c9-a69e35f335b5\",\"owner\":[],\"postedDate\":\"January 11th, 2024\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"under-review\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2024-03-26T10:17:21+00:00\",\"versionOfRecord\":[],\"versionCreatedAt\":\"2024-01-11 03:05:59\",\"video\":\"\",\"vorDoi\":\"\",\"vorDoiUrl\":\"\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-3745071\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-3745071\",\"identity\":\"rs-3745071\",\"version\":[\"v1\"]},\"buildId\":\"qtupq5eGEP_6zYnWcrvyt\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}