Folate-targeted albumin modified silica-gelatin hybrid nanocarrier. Synthesis and release characterization

Folate-targeted albumin modified silica-gelatin hybrid nanocarrier. 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Synthesis and release characterization Zahra Niazi, Mohsen Ashjari This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4443482/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 30 Jul, 2024 Read the published version in Journal of Porous Materials → Version 1 posted 11 You are reading this latest preprint version Abstract A novel hybrid of BSA-folate modified silica-gelatin nanocarrier with surface area of about 422 m 2 /g was designed in the current study and loaded by fluorouracil with 70 % entrapment efficiency. The nanocarrier was evaluated in terms of pH-sensitive release behavior in simulated acidic condition of cancer tissue (pH=5.), and the normal physiological condition of the body (pH=7.4) for 96 h. In vitro drug release from nanocarriers indicated a partial burst release in the early times (34 and 21 % after 12 h in acidic and neutral media), which was followed by a sustained and gradual release profile until 96 h. In addition, an enhanced drug release was observed at acidic pH (65 % after 96 h) compared to natural medium (42 % after 96 h), confirming the pH-responsive behavior of the developed nanocarrier. The MTT assay showed low toxicity of drug-free carrier against normal HDF fibroblast, and the OVCAR-3 ovarian cancer cells. These outcomes support the proper function of designed hybrid nanocarrier in targeted drug delivery. Drug Delivery Hybrid Nanocarrier Silica-Gelatin pH-Sensitive Sustained Release Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 1. Introduction Conventional methods of drug release in the body, which are mainly digestive and non-digestive, take place at specific intervals of drug consumption [ 1 ]. In most of these methods, the efficiency of the drug decreases due to various reasons such as exposure to the acidic environment of the stomach, passing through the cells of the intestinal wall, drug interaction with the body's immune system [ 2 ]. In addition, the treatment of some diseases such as cancer involves the use of some toxic drugs that have adverse side effects on other healthy cells [ 3 ]. Considering these problems, the need to design new drug delivery systems (DDS) for targeted and effective drug delivery seems necessary [ 4 , 5 ]. The main advantage of DDSs is to increase the therapeutic effects of the drug along with the effective reduction of side effects on healthy tissue and cells [ 6 ]. Recently, by combining different sciences and using nanotechnology, various nanocarriers such as liposomes, dendrimers, magnetic nanoparticles and porous silica nanoparticles for efficient delivery of therapeutic agent is developing [ 6 , 7 ]. In this regard, silica nanoparticles based nanocarriers have been developed as a promising platform for drug delivery system [ 8 , 9 ]. Silica mesopores with porous structure and high surface area are able to load large amounts of drugs in their matrix [ 10 ]. biocompatibility, good thermal and chemical stability, low toxicity, protection of drugs against physiological degradation and long-term presence in the blood circulation system are considered advantages of these nanocarriers [ 11 ]. However, to use these carriers, challenges such as the improvement of drug loading, temporal and spatial control of release, burst release problem, and proper targeting need to be overcome [ 12 ]. Different strategies have been proposed to improve silica nanocarriers. Development of an organic-inorganic hybrid using natural and biocompatible polymers can result in improvement of release properties [ 13 , 14 ]. Hybrid materials are considered multifunctional platforms for biological applications due to their remarkable properties originating the advantages of both organic and inorganic components [ 15 ]. The properties of hybrid materials can be related to the ratio of organic and inorganic phases in the hybrid formulation and the interaction created between these components at the nanoscale [ 16 ]. In this regard, some biopolymers such as gelatin are preferred for use in hybrid nanocarriers due to having biocompatibility, biodegradability, and low cost [ 15 , 17 ]. Thanks to the presence of a large number of amine and carboxylic acid groups in the gelatin backbone, the use of this biopolymer is suggested for chemical modification and obtaining advanced hybrid materials [ 15 , 18 ]. However, gelatin suffers from low thermal properties and insufficient mechanical strength [ 19 ]. Therefore, it seems that combining gelatin with silica leads to the preparation of a hybrid network with further structural robustness, higher thermal stability along with better chemical properties that can be suitable for multifunctional drug carriers [ 15 ]. In addition, approaches like modification of the carrier’s surface and using the stimuli-sensitive agents in designing these carriers are some of the well-adopted techniques to achieve the desired release behavior [ 20 ]. Bovine serum albumin (BSA) is one of the potential biopolymers for improving the performance of drug systems due to its ability for more drug encapsulation, improvement of surface functionality, creation of pH-triggered properties, and selective delivery capabilities [ 21 – 23 ]. In addition, equipping the surface of the nanocarrier with some specific ligands such as folate receptor increases the local release properties of the drug [ 24 ]. With the aim to achieve a targeted delivery in silica mesopores carriers, a novel BSA-folate modified silica-gelatin hybrid nanocarrier was designed in this study. The pH-sensitive release behavior of developed drug carrier systems was evaluated using the release profile of fluorouracil as model drug in simulated acidic condition of cancer tissue and the normal physiological condition of the body. The toxicity and biocompatibility of designed carrier was addressed by MTT assay against normal HDF fibroblast, and the OVCAR-3 ovarian cancer cells. 2. Experimental 2.1. Chemicals Chemicals of tetraethyl orthosilicate (TEOS, 99%), gelatin (type A, from porcine skin), fluorouracil (5FU, purity > 95%), bovine serum albumin (BSA, 99%), folic acid (FA, > 99%), glutaraldehyde (GA, 25%), 1-ethyl-3-[3-dimethylaminopropyl] carbodiimide (EDC, 99%), and N-Hydroxy succinimide (NHS, 99%) were provided by Sigma-Aldrich. Ethanol, hydrochloric acid, ammonia, and dimethyl sulfoxide (DMSO, 98%) were provided from Merck Chemical Co. 2.2. Preparation of BSA-folate The attachment of folate to BSA was performed through amidation reaction with amino-groups in the BSA [ 10 ]. Briefly, solutions of 7 mg of folic acid in 3 mL of sodium carbonate buffer, and separately 50 mg of BSA in 5 mL sodium carbonate buffer were prepared at room temperature. Then folate solution was added into BSA solution, and mixed by 6 mg of EDC and 4 mg of NHS. The reaction mixture was stirred for 5 h at 4°C under dark medium to form BSA-FA. After that, the solution was injected into a dialysis bag (Sigma-Aldrich, MWCO: 12 KDa), and dialyzed against sodium carbonate buffer and then deionized water for 2 days to remove unreacted reagents and created by products. Finally, BSA-FA was obtained by lyophilization of the resulted solution at -40°C for 24 h. 2.3. Preparation of silica-gelatin hybrid The preparation of silica-gelatin nanohybrid, signed as SiGe sample, was as follows: 1 mL of TEOS was dissolved in 2 mL of 0.01 M HCl and dropwise added to a solution containing 50 mg of gelatin dissolved in 10 mL of deionized water. The This mixture was stirred for 5 h at 40°C, obtaining a clear solution. After that, 1 mL of glutaraldehyde solution (2% v/v) was added to above solution and mixed for 1 h at 50°C, and then diluted ammonia was dropwise added to the resulted sol at room temperature to enhance pH up to 8. The reaction medium was kept in static condition for 5 h at 40°C and then 3 h at 4°C until gelling, crosslinking and aging. The prepared SiGe hybrid was washed twice by isopropanol and n-hexane, and followed by drying under vacuum at 40°C for 12 h. 2.4. Preparation of BSA-folate modified silica-gelatin Homogeneous dispersion of 20 mg SiGe hybrid in 3 mL deionized water was prepared using ultrasound waves for 10 min. Separately, 10 mg of BSA-FA was completely dissolved in 2 mL of deionized water, and mixed with 8 mg of EDC and 5 mg of NHS for 2 h at room temperature. After that, the BSA-folate solution was dropwise added to the resulted dispersion containing SiGe nanoparticles, and stirred for 5 h at 37°C. The mixture was then centrifuged for 15 min, and washed twice with deionized water. Final, the BSA-FA modified silica-gelatin nanohybrid complex under the name of SiGe/BSA-FA was obtained by drying the resulted solid in oven at 50°C for 12 h. The efficiency of BSA-FA modification was determined using concentration of BSA-FA in the supernatant, and applying UV-visible spectroscopy method. 2.5. Loading of drug The encapsulation of fluorouracil (5FU) into SiGe/BSA-FA nanohybrid was performed as follows: a suspension containing 10 mg of SiGe/BSA-FA in 3 mL aqueous solution of 5FU (2 mg/mL) was prepared, and slowly stirred overnight at room temperature and darkness. The suspension was finally centrifuged for 15 min, and washed three times with deionized water. The drug-loaded SiGe/BSA-FA nanohybrid, signed as SiGe/BSA-FA@5FU was achieved by lyophilization at -40°C for 24 h. To determine the loaded 5FU, the UV-visible spectrum of resulted supernatant was recorded and analyzed at 264 nm. All drug loaded experiments were caried out in triplicate. Encapsulation efficiency (EE%) and drug loading content (LC) were calculated as follow: \(EE \%=\frac{weight of loaded 5FU }{Initial weight of 5FU }\) Eq. 1 \(LC \%=\frac{weight of loaded 5FU}{weight of loaded 5FU+weight of hybrid }\) Eq. 2 2.6. Drug release The release tests were performed in the centrifuge tubes under phosphate-buffered saline (PBS) medium with two different pH of 7.4 and 5.6 in a period of 96 h. Briefly, 5 mg of prepared drug-loaded SiGe/BSA-FA sample was dispersed in 5 mL PBS at 37°C under dark condition. At predetermined time intervals, the suspension was centrifuged, and 2 mL of the resulting supernatant containing the released drug was taken out and simultaneously 2 mL of fresh buffer was poured into mixture and stirred to continue the release test. Samples containing the released drug were analyzed using UV-visible spectroscopy at 264 nm, and the cumulative drug release was drawn as a function of time. All these experiments were carried out triplicate. 2.7. Cell viability The in-vitro cytotoxicity of 5FU drug, SiGe/BSA-FA and SiGe/BSA-FA@5FU samples were evaluated by applying MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay against normal human dermal fibroblast (HDF) in type 4, and the OVCAR-3 human ovarian cancer cell line provided by Royan Research Institute Cell Bank, Tehran, Iran. For these tests, the cells were seeded in a culture medium at density of 3000 cell/cm 2 in 96-well plates and incubated an overnight. Then, the medium was replaced by 100 µL of fresh RPMI containing 100 µg/mL samples along with FBS 10% and 100 µg/mL penicillin, and incubated at 37 ºC and 5% CO 2 . After 24 h and 48 h of samples or drug exposure, medium was replaced by a mixture of MTT solution and serum-free culture medium, and incubated for 3 h at 37 ºC and 5% CO 2 . Then, DMSO was added into medium and the UV absorbance was analyzed at 570 nm. The cell viability was calculated as ratio of mean absorbance of sample to mean absorbance of control. 2.8. Characterization X-ray diffraction (XRD) pattern in the range of 10–80° was monitored on PANalytical X'Pert-Pro to evaluate structure and phase identification of prepared nanocarrier. Fourier transform infrared spectrum (FTIR) in the range of 400–4000 cm − 1 was recorded on Magna-IR 550 spectrometer to investigate the chemical properties of nanocarriers. N 2 adsorption-desorption was recorded on Tristar 3020, Micrometrics to calculate surface area, based on Brunauer–Emmet–Teller (BET) technique. Pore volume, and pore size were also computed according to Barrett-Joyner-Halenda (BJH) technique. The samples were degassed under vacuum for 3 h at 250°C. Scanning electron microscopy (SEM) was performed on EM-3200-KYKY to investigate the morphology of nanocarriers. 3. Results and Discussion 3.1. Characterization of prepared carriers The crystallographic data of the prepared SiGe hybrid was addressed by X-ray diffraction analysis, as indicated in Fig. 1 . The appeared XRD pattern shows a broad peak at 2θ = 15–35 ° which is coressponded to formation of amorphous phase of the silica according to JCPDSn PDF data (29–0085) [ 25 ], as well as amorphous structure of gelatin [ 26 ]. The chemical properties and formation of prepared carriers was evaluated using FTIR analysis, as indicated in Fig. 2 . The broad band around 3400 cm − 1 in all spectra is due to stretching vibrations of the O‒H or N‒H bonds [ 27 ]. In the FTIR spectra of the SiGe, and SiGe/BSA-FA, the observed bands around 1100, 470 and 800 cm − 1 are related to Si − O−Si stretching, Si − O stretching, and Si − O bending mode of silica network, respectively [ 28 ]. Also, the appeared bands around 1670 cm − 1 (C = O stretching or amide-I), 1540 cm − 1 (amide-II), and 1240 cm − 1 (amide-III ) in FTIR spectra of BSA-FA, and SiGe/BSA-FA show characteristic bonds of gelatin and BSA [ 15 , 21 ]. Futhermore, the observed bands around 2920 cm − 1 in all spectra are due to stretching vibrations of C − H bonds [ 29 ]. The surface area, mean pore size and total pore volume of the prepared samples measured using BET and BJH methods were reported in Table 1 . Accordingly, the Bet surface area of the SiGe, and SiGe/BSA-FA hybrid nanocarriers were measured about 374, and 378 m 2 /g, respectively, indicating proper surface area of prepared porous nanocarriers. However, loading of 5FU into the pores of the SiGe/BSA-FA caused in significant decrease of S BET , confirming the successful encapsulation of the 5FU into the SiGe/BSA-FA. Table 1 The surface area, mean pore size and total pore volume of the prepared samples Samples Surface area (m 2 /g) Mean pore size (nm) Total pore volume (cm 3 /g) SiGe 374 5.1 0.74 SiGe/BSA-FA 378 6.5 0.67 SiGe/BSA-FA@5FU 271 8.7 0.78 Figure 3 displays the nitrogen adsorption-desorption isotherms and pore size distribution of SiGe, SiGe/BSA-FA, and drug loaded nanocarrier. Regarding the IUPAC classification, the adsorption isotherms of the prepared nanocarriers were in line with type-IV, confirming the formation of mesoporous structure in all samples [ 30 , 31 ]. Furthermore, the appeared hysteresis loops in these isotherms shows the occurrence of capillary condensation in mesoporous structure of nanocarriers. Here, the type of hysteresis loops refers to type H-2, which indicates interconnected pore networks along with a partially agglomeration in structure [ 27 , 32 ].In addition, the pore size distribution in Fig. 4 .b shows a narrow and uniform distribution in the range of 2–40 nm. The morphology and surface properties of the SiGe, and SiGe/BSA-FA were investigated using FE-SEM micrographs. The results in Fig. 4 clearly exhibited a porous structure with spherical shape for SiGe in the range of 200–300 nm. However, systematic changes due to surface modification of the SiGe nanocarrier with BSA-FA was observed in the SEM image of the SiGe/BSA-FA system, so that an approximately spherical and porous particles along with a rough surface is visible for SiGe/BSA-FA sample. Similar SEM results were also observed by Maheswari, when the surface of the calcium ferrite spherical nanoparticles was modified with BSA [ 21 ]. 3.2. Entrapment efficiency and release study The prepared SiGe/BSA-FA carrier was used to evaluate the entrapment property and delivery behavior of 5FU. Here, the content loading (LC) and entrapment efficiency (EE) of 5FU, measured using UV–Visible spectroscopy method, were obtained at about 70% and 29%, respectively. The high entrapment efficiency of 5FU is mainly thought to be related to penetration of drug molecules and chemical interactions between hydrophilic drug of the 5FU and proper functional groups in the SiGe/BSA-FA structure [ 33 ]. In cancerous tissue, changes in the body's metabolic conditions and the uncontrolled proliferation of cancer cells lead to an acidic microenvironment [ 21 ]. Based on these properties of cancer conditions, stimuli-responsive drug delivery platforms such as pH-sensitive systems are of great interest for targeted delivery [ 34 ]. Here, the pH-responsive release behavior of the drug from the SiGe/BSA-FA@5FU nanocarrier was investigated under two different pH media of 5.6 and 7.4, similar to the acidic condition of cancer tissue and the normal physiological condition of the body. It should be noted that the in-vitro drug release under acidic condition was carried out to evaluate the pH-responsive behavior of nanocarrier, effect of acidic microenvironment of cells on release profile. Figure 5 indicates the cumulative 5FU release from the SiGe/BSA-FA@5FU hybrid nanocarrier under two different PBS solution during 96 h and temperature of 37°C. The results showed a partial burst release from the nanocarrier at the early times (less than 12 h) for both release media, and a sustained and gradual release profile until 96 h. The chemical interactions between 5FU and main matrix of the SiGe/BSA-FA nanocarrier can control the diffusion of drug towards PBS solution and create a sustained and gradual release behavior after 12 h [ 21 , 35 ]. However, the rapid release rate of 5FU duration of first 12 h can be due to high surface area of the carrier, as well as the dissolution of drugs deposited at surface layers [ 36 ]. In addition, it was observed that the amount of cumulative drug release was enhanced as the pH of the medium increased, which confirms the pH-responsive behavior of the developed nanocarrier. The maximum amount of 5FU release from the SiGe/BSA-FA@5FU nanocarrier was obtained at about 42.2% at natural pH of 7.4 after 96 h. Whereas, maximum 5FU release was reached to 65.44% at a pH of 5.6, which is thought to be related to the partial solubility of the carrier structure in this acidic condition after 96 h. 3.3. Kinetic models and mechanism study The Higuchi, and Korsmeyer-Peppas kinetic models were used to describe the release mechanism and investigate the behavior of drug release, as presented in Fig. 6 . According to the results, Higuchi's kinetic model is able to adequately describe the cumulative release data of fluorouracil from the SiGe/BSA-FA@5FU nanocarrier. These results show that the diffusion mechanism mainly controls the drug release from the carrier. It has been reported that the release of poorly soluble or insoluble drugs from silica mesoporous carriers often follows the Higuchi model [ 37 , 38 ]. The details related to the estimated kinetic parameters of Higuchi and Korsmeyer-Peppas kinetic models were reported in Table 2 . According to the results, the value of n estimated from Korsmeyer-Peppas model was found to be less than 0.5, which indicates the effect of both penetration and swelling mechanisms in controlling the fluorouracil release process. Table 2 Results of Higuchi and Korsmeyer-Peppas kinetic models for SiGe/BSA-FA@5FU carrier in acidic and basic media Sample Higuchi Korsmeyer-Peppas R 2 K H R 2 n SiGe/BSA-FA@5FU (pH = 5.6) 0.988 7.36 0.965 0.45 SiGe/BSA-FA@5FU (pH = 7.4) 0.989 4.68 0.962 0.41 3.4. Toxicity Studies One of the most important issues encountered in chemotherapy is acute side effects of the cytotoxic drugs that occur after treatment [ 39 ]. This issue can be solved to a great extent by using bioactive materials in smart drug delivery systems and encapsulating cytotoxic drugs in these systems [ 40 , 41 ]. Within this realm, the biocompatibility and interactions between the developed carriers with the living cells are of significant importance [ 42 ]. Here, MTT assay as a non-animal approach was applied to detect the toxicity of 100 µg/mL of SiGe/BSA-FA@5FU and drug-free carrier against HDF normal cells and OVCAR-3 human ovarian cancer cells after 24 and 48 h, as reported in Fig. 7 . Each reported data is the average of three performed test. For both HDF and OVCAR-3 cells, a slight difference from control samples was observed in viability of cells treated with SiGe/BSA-FA. These results support the low toxicity and biocompatibility of designed carrier [ 43 ]. Considering the non-toxicity and biocompatibility of silica, gelatin and BSA, these findings seem to be logical [ 44 , 45 ]. However, a toxic response was obtained by exposure the SiGe/BSA-FA@5FU carrier to both cancer and normal cells, which is due to the presence of 5FU. In addition, the drug-loaded carrier showed less cell viability against OVCAR-3 cells than HDF cells after 24 and 48 h, at about 69 and 51%, respectively, which confirmed more cytotoxic effect of SiGe/BSA-FA@5FU against cancerous cells compared to the normal cells [ 27 ]. In addition, increasing exposure time from 24 to 48 h, was led to less cell viability from 69% down to 51% in cancerous cells, and from 81–73% in normal cells, respectively. Conclusion Here, a novel BSA-folate modified silica-gelatin hybrid nanocarrier was developed and examined in terms of the pH-sensitive release behavior in simulated acidic condition of cancer cells and the normal physiological condition of the body. The fluorouracil was applied as a model drug. The high encapsulation of drug can be due to penetration of drug molecules and chemical interactions between hydrophilic drug and proper functional groups in the carrier. A partial burst release was observed at the early times for both release media which followed by a sustained and gradual release profile. The chemical interactions between drug and main matrix of the nanocarrier can control the diffusion of drug towards release media. In addition, a further drug release was observed as the pH of the medium increased, which confirms the pH-responsive behavior of the developed nanocarrier. These finding along with the low toxicity of developed nanocarrier confirmed smart function of designed carrier for targeted drug delivery. Declarations Funding This work was financial supported by University of Kashan. Acknowledgments The authors wish to express gratitude to Institute of Nanoscience and Nanotechnology, University of Kashan for financial support (grant pazhouhaneh) to this study. Authors contributions: Zahra Niazi: Investigation, Data curation, Formal analysis, Methodology, Resources, Writing. Mohsen Ashjari: Conceptualization, Formal analysis, Methodology, Validation, review & editing. Conflicts of interest The authors declare that they have no potential conflict of interest. Data and code availability The data that support the findings of this study are available from the corresponding author upon reasonable request. Ethical approval This manuscript doesn't consist of studies with human and animal subjects. Corresponding author & ORCID Correspondence to Mohsen Ashjari: http://orcid.org/0000-0001-7461-9883. References Zhang, WJ., Babu, A., Yan, YZ. et al. ROS/GSH dual-responsive selenium-containing mesoporous silica nanoparticles for drug delivery. J Porous Mater 30 (2023), 1469–1484. S. Sur, A. Rathore, V. Dave, K.R. Reddy, R.S. Chouhan and V. Sadhu, Recent developments in functionalized polymer nanoparticles for efficient drug delivery system. Nano-Structures & Nano-Objects. 20 (2019) 100397. K. Paunovska, D. Loughrey and J.E. Dahlman, Drug delivery systems for RNA therapeutics. Nature Reviews Genetics. 23 (2022) 265-280. B. Bahrami, M. Hojjat-Farsangi, H. Mohammadi, E. Anvari, G. Ghalamfarsa, M. Yousefi and F. 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Yazdian and H. Rashedi, Ultra pH-sensitive nanocarrier based on Fe2O3/chitosan/montmorillonite for quercetin delivery. International Journal of Biological Macromolecules. 191 (2021) 738-745. S.T. Jagdeep, G.S. Chauhan, K.V. Diwana, C.D. Chauhan and T. Anamika, Extravasational side effects of cytotoxic drugs: A preventable catastrophe. Indian Journal of Plastic Surgery. 41 (2008) 145-150. P. Sanchez-Moreno, J.L. Ortega-Vinuesa, J.M. Peula-Garcia, J.A. Marchal and H. Boulaiz, Smart drug-delivery systems for cancer nanotherapy. Current drug targets. 19 (2018) 339-359. M. Kazemi, M. Nazarabi, Z. Niazi and M. Ashjari, Well-defined synthesis of poly (2-isopropyl-2-oxazoline)-based copolymer for delivery of doxorubicin by multi-sensitive nano-micelle. International Journal of Polymeric Materials and Polymeric Biomaterials. 71 (2022) 1359-1368. X. Yu, I. Trase, M. Ren, K. Duval, X. Guo and Z. Chen, Design of nanoparticle-based carriers for targeted drug delivery. Journal of nanomaterials. 2016 (2016). K. AbouAitah, A. Farghali, A. Swiderska-Sroda, W. Lojkowski, A. Razin and M. Khedr, Mesoporous silica materials in drug delivery system: pH/glutathione-responsive release of poorly water-soluble pro-drug quercetin from two and three-dimensional pore-structure nanoparticles. J. Nanomed. Nanotechnol. 7 (2016). P. Veres, G. Király, G. Nagy, I. Lázár, I. Fábián and J. Kalmár, Biocompatible silica-gelatin hybrid aerogels covalently labeled with fluorescein. Journal of Non-Crystalline Solids. 473 (2017) 17-25. A.I. Albosultan, M. Ghobeh and M.H. Tabrizi, The Anticancer, Anti-metastatic, Anti-oxidant, and Anti-angiogenic Activity of Chitosan-coated Parthenolide/Bovine Serum Albumin Nanoparticles. Journal of Inorganic and Organometallic Polymers and Materials. (2023) 1-12. Additional Declarations No competing interests reported. Supplementary Files Graphicalabstract.png Graphical abstract Caption: The pH-sensitive release behavior of novel BSA-folate modified silica-gelatin hybrid nanocarrier in acidic and natural condition Cite Share Download PDF Status: Published Journal Publication published 30 Jul, 2024 Read the published version in Journal of Porous Materials → Version 1 posted Editorial decision: Revision requested 30 Jun, 2024 Reviews received at journal 13 Jun, 2024 Reviews received at journal 09 Jun, 2024 Reviewers agreed at journal 28 May, 2024 Reviewers agreed at journal 26 May, 2024 Reviewers agreed at journal 25 May, 2024 Reviewers agreed at journal 25 May, 2024 Reviewers invited by journal 25 May, 2024 Submission checks completed at journal 20 May, 2024 Editor assigned by journal 20 May, 2024 First submitted to journal 19 May, 2024 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. 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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-4443482","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":307624593,"identity":"1b1b1115-3f10-46a5-abc2-7e18931d26df","order_by":0,"name":"Zahra Niazi","email":"","orcid":"","institution":"University of Kashan","correspondingAuthor":false,"prefix":"","firstName":"Zahra","middleName":"","lastName":"Niazi","suffix":""},{"id":307624594,"identity":"c48b273e-3f20-404e-a32f-dc6abda8e409","order_by":1,"name":"Mohsen Ashjari","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/klEQVRIiWNgGAWjYFACHgYDBgYJBgb2NgYGxgaYqAExWniOkaAFAiTSkLXgAfz9Zw8U/NxjwaA781nix5877PIMDjA//MBQcA+nFokbeQmGPc8kGMxupx2W5j2TXGxwgM1YgsGgGLc1N3gMDHgOgLSkN0gztjEnbjjAYAb0SwJOHfLnzxgY/gFpuXm8+efPtnqgFvZveLUYHMgxMAbbcoPtmARv22GgFh78thjeAGqROSDBY3YmLc2at+144szDPMUSCXi0yJ0/Y2b45kCdnNnxY8Y3f7ZVJ/Ydb9/44cMf3FqAgA0UbTwIPjMQ49UAVPIAv/woGAWjYBSMeAAASj1StEJX7AAAAAAASUVORK5CYII=","orcid":"","institution":"University of Kashan","correspondingAuthor":true,"prefix":"","firstName":"Mohsen","middleName":"","lastName":"Ashjari","suffix":""}],"badges":[],"createdAt":"2024-05-19 08:23:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4443482/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4443482/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10934-024-01664-y","type":"published","date":"2024-07-30T15:57:27+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":57492030,"identity":"abb280f3-7a38-40b3-a472-c45468d58d8b","added_by":"auto","created_at":"2024-05-31 11:40:03","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":126162,"visible":true,"origin":"","legend":"\u003cp\u003eXRD pattern of prepared SiGe\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4443482/v1/cca639020578a504d475d137.png"},{"id":57492031,"identity":"96f76835-357c-4cb5-ab67-23e8f2a4b4a6","added_by":"auto","created_at":"2024-05-31 11:40:03","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":253617,"visible":true,"origin":"","legend":"\u003cp\u003eFTIR spectra of SiGe, BSA-FA, and SiGe/BSA-FA.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4443482/v1/df7121d3f7b0213f8b4931c6.png"},{"id":57492034,"identity":"cd8f84a6-2eb2-4cf0-92eb-f517ce1ac045","added_by":"auto","created_at":"2024-05-31 11:40:04","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":313726,"visible":true,"origin":"","legend":"\u003cp\u003e(a) N\u003csub\u003e2\u003c/sub\u003e adsorption-desorption isotherms, and (b) pore size distribution of nanocarriers\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4443482/v1/b83619656b2138d3f9e32d29.png"},{"id":57492038,"identity":"dbee6f8d-0f6f-4276-a9df-0f8addeaaa24","added_by":"auto","created_at":"2024-05-31 11:40:04","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":757558,"visible":true,"origin":"","legend":"\u003cp\u003eFE-SEM micrographs of the (a) SiGe, and (b) SiGe/BSA-FA samples\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-4443482/v1/d00721f968e66ce804f9cbb3.png"},{"id":57492037,"identity":"fada439a-62fb-46a0-9ef3-00161466c6fa","added_by":"auto","created_at":"2024-05-31 11:40:04","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":163112,"visible":true,"origin":"","legend":"\u003cp\u003epH responsive drug release profile of SiGe/BSA-FA@5FU nanocarrier at two different pH media at 37 °C\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-4443482/v1/6a996d4eaa690c3a30f64c63.png"},{"id":57492035,"identity":"9dc2b25e-1263-459e-81fd-aab902423aa3","added_by":"auto","created_at":"2024-05-31 11:40:04","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":266509,"visible":true,"origin":"","legend":"\u003cp\u003eThe results of the (a) Higuchi kinetic, and (b) Korsmeyer-Peppas for in vitro 5-FU release from SiGe/BSA-FA@5FU carrier.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-4443482/v1/025d524ca2b32e149d876604.png"},{"id":57492036,"identity":"96d7d797-b5a7-4f20-beaf-dbc4688c7ca2","added_by":"auto","created_at":"2024-05-31 11:40:04","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":205270,"visible":true,"origin":"","legend":"\u003cp\u003eResults of cell viability of (a) HDF normal cells (b) OVCAR-3 human ovarian cancer cells after 24 h and 48 h treatment with SiGe/BSA-FA@5FU and drug-free carrier\u003c/p\u003e","description":"","filename":"7.png","url":"https://assets-eu.researchsquare.com/files/rs-4443482/v1/7533b51f1b33ebe23e215934.png"},{"id":61793536,"identity":"fb240f6f-06ee-4bed-b932-48fabf834c6a","added_by":"auto","created_at":"2024-08-05 16:13:37","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3186581,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4443482/v1/5e1fae00-0ac7-4013-8240-bcc30d9e41c5.pdf"},{"id":57492032,"identity":"beda4238-0df7-4f5e-b993-11156d47208a","added_by":"auto","created_at":"2024-05-31 11:40:04","extension":"png","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1048231,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eGraphical abstract Caption:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe pH-sensitive release behavior of novel BSA-folate modified silica-gelatin hybrid nanocarrier in acidic and natural condition\u003c/p\u003e","description":"","filename":"Graphicalabstract.png","url":"https://assets-eu.researchsquare.com/files/rs-4443482/v1/a0c80ef892cfd2b2704d10b3.png"}],"financialInterests":"No competing interests reported.","formattedTitle":"Folate-targeted albumin modified silica-gelatin hybrid nanocarrier. Synthesis and release characterization","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eConventional methods of drug release in the body, which are mainly digestive and non-digestive, take place at specific intervals of drug consumption [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. In most of these methods, the efficiency of the drug decreases due to various reasons such as exposure to the acidic environment of the stomach, passing through the cells of the intestinal wall, drug interaction with the body's immune system [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. In addition, the treatment of some diseases such as cancer involves the use of some toxic drugs that have adverse side effects on other healthy cells [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Considering these problems, the need to design new drug delivery systems (DDS) for targeted and effective drug delivery seems necessary [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. The main advantage of DDSs is to increase the therapeutic effects of the drug along with the effective reduction of side effects on healthy tissue and cells [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Recently, by combining different sciences and using nanotechnology, various nanocarriers such as liposomes, dendrimers, magnetic nanoparticles and porous silica nanoparticles for efficient delivery of therapeutic agent is developing [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn this regard, silica nanoparticles based nanocarriers have been developed as a promising platform for drug delivery system [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Silica mesopores with porous structure and high surface area are able to load large amounts of drugs in their matrix [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. biocompatibility, good thermal and chemical stability, low toxicity, protection of drugs against physiological degradation and long-term presence in the blood circulation system are considered advantages of these nanocarriers [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. However, to use these carriers, challenges such as the improvement of drug loading, temporal and spatial control of release, burst release problem, and proper targeting need to be overcome [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Different strategies have been proposed to improve silica nanocarriers. Development of an organic-inorganic hybrid using natural and biocompatible polymers can result in improvement of release properties [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHybrid materials are considered multifunctional platforms for biological applications due to their remarkable properties originating the advantages of both organic and inorganic components [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The properties of hybrid materials can be related to the ratio of organic and inorganic phases in the hybrid formulation and the interaction created between these components at the nanoscale [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. In this regard, some biopolymers such as gelatin are preferred for use in hybrid nanocarriers due to having biocompatibility, biodegradability, and low cost [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Thanks to the presence of a large number of amine and carboxylic acid groups in the gelatin backbone, the use of this biopolymer is suggested for chemical modification and obtaining advanced hybrid materials [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. However, gelatin suffers from low thermal properties and insufficient mechanical strength [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Therefore, it seems that combining gelatin with silica leads to the preparation of a hybrid network with further structural robustness, higher thermal stability along with better chemical properties that can be suitable for multifunctional drug carriers [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In addition, approaches like modification of the carrier\u0026rsquo;s surface and using the stimuli-sensitive agents in designing these carriers are some of the well-adopted techniques to achieve the desired release behavior [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Bovine serum albumin (BSA) is one of the potential biopolymers for improving the performance of drug systems due to its ability for more drug encapsulation, improvement of surface functionality, creation of pH-triggered properties, and selective delivery capabilities [\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. In addition, equipping the surface of the nanocarrier with some specific ligands such as folate receptor increases the local release properties of the drug [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWith the aim to achieve a targeted delivery in silica mesopores carriers, a novel BSA-folate modified silica-gelatin hybrid nanocarrier was designed in this study. The pH-sensitive release behavior of developed drug carrier systems was evaluated using the release profile of fluorouracil as model drug in simulated acidic condition of cancer tissue and the normal physiological condition of the body. The toxicity and biocompatibility of designed carrier was addressed by MTT assay against normal HDF fibroblast, and the OVCAR-3 ovarian cancer cells.\u003c/p\u003e"},{"header":"2. Experimental","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Chemicals\u003c/h2\u003e \u003cp\u003eChemicals of tetraethyl orthosilicate (TEOS, 99%), gelatin (type A, from porcine skin), fluorouracil (5FU, purity\u0026thinsp;\u0026gt;\u0026thinsp;95%), bovine serum albumin (BSA, 99%), folic acid (FA, \u0026gt; 99%), glutaraldehyde (GA, 25%), 1-ethyl-3-[3-dimethylaminopropyl] carbodiimide (EDC, 99%), and N-Hydroxy succinimide (NHS, 99%) were provided by Sigma-Aldrich. Ethanol, hydrochloric acid, ammonia, and dimethyl sulfoxide (DMSO, 98%) were provided from Merck Chemical Co.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2. Preparation of BSA-folate\u003c/h2\u003e \u003cp\u003eThe attachment of folate to BSA was performed through amidation reaction with amino-groups in the BSA [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Briefly, solutions of 7 mg of folic acid in 3 mL of sodium carbonate buffer, and separately 50 mg of BSA in 5 mL sodium carbonate buffer were prepared at room temperature. Then folate solution was added into BSA solution, and mixed by 6 mg of EDC and 4 mg of NHS. The reaction mixture was stirred for 5 h at 4\u0026deg;C under dark medium to form BSA-FA. After that, the solution was injected into a dialysis bag (Sigma-Aldrich, MWCO: 12 KDa), and dialyzed against sodium carbonate buffer and then deionized water for 2 days to remove unreacted reagents and created by products. Finally, BSA-FA was obtained by lyophilization of the resulted solution at -40\u0026deg;C for 24 h.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3. Preparation of silica-gelatin hybrid\u003c/h2\u003e \u003cp\u003eThe preparation of silica-gelatin nanohybrid, signed as SiGe sample, was as follows: 1 mL of TEOS was dissolved in 2 mL of 0.01 M HCl and dropwise added to a solution containing 50 mg of gelatin dissolved in 10 mL of deionized water. The This mixture was stirred for 5 h at 40\u0026deg;C, obtaining a clear solution. After that, 1 mL of glutaraldehyde solution (2% v/v) was added to above solution and mixed for 1 h at 50\u0026deg;C, and then diluted ammonia was dropwise added to the resulted sol at room temperature to enhance pH up to 8. The reaction medium was kept in static condition for 5 h at 40\u0026deg;C and then 3 h at 4\u0026deg;C until gelling, crosslinking and aging. The prepared SiGe hybrid was washed twice by isopropanol and n-hexane, and followed by drying under vacuum at 40\u0026deg;C for 12 h.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4. Preparation of BSA-folate modified silica-gelatin\u003c/h2\u003e \u003cp\u003eHomogeneous dispersion of 20 mg SiGe hybrid in 3 mL deionized water was prepared using ultrasound waves for 10 min. Separately, 10 mg of BSA-FA was completely dissolved in 2 mL of deionized water, and mixed with 8 mg of EDC and 5 mg of NHS for 2 h at room temperature. After that, the BSA-folate solution was dropwise added to the resulted dispersion containing SiGe nanoparticles, and stirred for 5 h at 37\u0026deg;C. The mixture was then centrifuged for 15 min, and washed twice with deionized water. Final, the BSA-FA modified silica-gelatin nanohybrid complex under the name of SiGe/BSA-FA was obtained by drying the resulted solid in oven at 50\u0026deg;C for 12 h. The efficiency of BSA-FA modification was determined using concentration of BSA-FA in the supernatant, and applying UV-visible spectroscopy method.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5. Loading of drug\u003c/h2\u003e \u003cp\u003eThe encapsulation of fluorouracil (5FU) into SiGe/BSA-FA nanohybrid was performed as follows: a suspension containing 10 mg of SiGe/BSA-FA in 3 mL aqueous solution of 5FU (2 mg/mL) was prepared, and slowly stirred overnight at room temperature and darkness. The suspension was finally centrifuged for 15 min, and washed three times with deionized water. The drug-loaded SiGe/BSA-FA nanohybrid, signed as SiGe/BSA-FA@5FU was achieved by lyophilization at -40\u0026deg;C for 24 h. To determine the loaded 5FU, the UV-visible spectrum of resulted supernatant was recorded and analyzed at 264 nm. All drug loaded experiments were caried out in triplicate. Encapsulation efficiency (EE%) and drug loading content (LC) were calculated as follow:\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(EE \\%=\\frac{weight of loaded 5FU }{Initial weight of 5FU }\\)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEq.\u0026nbsp;1\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(LC \\%=\\frac{weight of loaded 5FU}{weight of loaded 5FU+weight of hybrid }\\)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEq.\u0026nbsp;2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e2.6. Drug release\u003c/h2\u003e \u003cp\u003eThe release tests were performed in the centrifuge tubes under phosphate-buffered saline (PBS) medium with two different pH of 7.4 and 5.6 in a period of 96 h. Briefly, 5 mg of prepared drug-loaded SiGe/BSA-FA sample was dispersed in 5 mL PBS at 37\u0026deg;C under dark condition. At predetermined time intervals, the suspension was centrifuged, and 2 mL of the resulting supernatant containing the released drug was taken out and simultaneously 2 mL of fresh buffer was poured into mixture and stirred to continue the release test. Samples containing the released drug were analyzed using UV-visible spectroscopy at 264 nm, and the cumulative drug release was drawn as a function of time. All these experiments were carried out triplicate.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e2.7. Cell viability\u003c/h2\u003e \u003cp\u003eThe in-vitro cytotoxicity of 5FU drug, SiGe/BSA-FA and SiGe/BSA-FA@5FU samples were evaluated by applying MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay against normal human dermal fibroblast (HDF) in type 4, and the OVCAR-3 human ovarian cancer cell line provided by Royan Research Institute Cell Bank, Tehran, Iran. For these tests, the cells were seeded in a culture medium at density of 3000 cell/cm\u003csup\u003e2\u003c/sup\u003e in 96-well plates and incubated an overnight. Then, the medium was replaced by 100 \u0026micro;L of fresh RPMI containing 100 \u0026micro;g/mL samples along with FBS 10% and 100 \u0026micro;g/mL penicillin, and incubated at 37 \u0026ordm;C and 5% CO\u003csup\u003e2\u003c/sup\u003e. After 24 h and 48 h of samples or drug exposure, medium was replaced by a mixture of MTT solution and serum-free culture medium, and incubated for 3 h at 37 \u0026ordm;C and 5% CO\u003csup\u003e2\u003c/sup\u003e. Then, DMSO was added into medium and the UV absorbance was analyzed at 570 nm. The cell viability was calculated as ratio of mean absorbance of sample to mean absorbance of control.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e2.8. Characterization\u003c/h2\u003e \u003cp\u003eX-ray diffraction (XRD) pattern in the range of 10\u0026ndash;80\u0026deg; was monitored on PANalytical X'Pert-Pro to evaluate structure and phase identification of prepared nanocarrier. Fourier transform infrared spectrum (FTIR) in the range of 400\u0026ndash;4000 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e was recorded on Magna-IR 550 spectrometer to investigate the chemical properties of nanocarriers. N\u003csub\u003e2\u003c/sub\u003e adsorption-desorption was recorded on Tristar 3020, Micrometrics to calculate surface area, based on Brunauer\u0026ndash;Emmet\u0026ndash;Teller (BET) technique. Pore volume, and pore size were also computed according to Barrett-Joyner-Halenda (BJH) technique. The samples were degassed under vacuum for 3 h at 250\u0026deg;C. Scanning electron microscopy (SEM) was performed on EM-3200-KYKY to investigate the morphology of nanocarriers.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results and Discussion","content":"\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.1. Characterization of prepared carriers\u003c/h2\u003e \u003cp\u003eThe crystallographic data of the prepared SiGe hybrid was addressed by X-ray diffraction analysis, as indicated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The appeared XRD pattern shows a broad peak at 2θ = 15–35 ° which is coressponded to formation of amorphous phase of the silica according to JCPDSn PDF data (29–0085) [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], as well as amorphous structure of gelatin [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe chemical properties and formation of prepared carriers was evaluated using FTIR analysis, as indicated in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The broad band around 3400 cm\u003csup\u003e− 1\u003c/sup\u003e in all spectra is due to stretching vibrations of the O‒H or N‒H bonds [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. In the FTIR spectra of the SiGe, and SiGe/BSA-FA, the observed bands around 1100, 470 and 800 cm\u003csup\u003e− 1\u003c/sup\u003e are related to Si − O−Si stretching, Si − O stretching, and Si − O bending mode of silica network, respectively [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Also, the appeared bands around 1670 cm\u003csup\u003e− 1\u003c/sup\u003e (C = O stretching or amide-I), 1540 cm\u003csup\u003e− 1\u003c/sup\u003e (amide-II), and 1240 cm\u003csup\u003e− 1\u003c/sup\u003e (amide-III ) in FTIR spectra of BSA-FA, and SiGe/BSA-FA show characteristic bonds of gelatin and BSA [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Futhermore, the observed bands around 2920 cm\u003csup\u003e− 1\u003c/sup\u003e in all spectra are due to stretching vibrations of C − H bonds [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe surface area, mean pore size and total pore volume of the prepared samples measured using BET and BJH methods were reported in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Accordingly, the Bet surface area of the SiGe, and SiGe/BSA-FA hybrid nanocarriers were measured about 374, and 378 m\u003csup\u003e2\u003c/sup\u003e/g, respectively, indicating proper surface area of prepared porous nanocarriers. However, loading of 5FU into the pores of the SiGe/BSA-FA caused in significant decrease of S\u003csub\u003eBET\u003c/sub\u003e, confirming the successful encapsulation of the 5FU into the SiGe/BSA-FA.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\u003cdiv class=\"gridtable\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe surface area, mean pore size and total pore volume of the prepared samples\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003c/colgroup\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSamples\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSurface area (m\u003csup\u003e2\u003c/sup\u003e/g)\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMean pore size\u003c/p\u003e \u003cp\u003e(nm)\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTotal pore volume (cm\u003csup\u003e3\u003c/sup\u003e/g)\u003c/p\u003e \u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSiGe\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e374\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5.1\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.74\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSiGe/BSA-FA\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e378\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6.5\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.67\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSiGe/BSA-FA@5FU\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e271\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8.7\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.78\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/table\u003e\u003c/div\u003e \u003cp\u003e\u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e displays the nitrogen adsorption-desorption isotherms and pore size distribution of SiGe, SiGe/BSA-FA, and drug loaded nanocarrier. Regarding the IUPAC classification, the adsorption isotherms of the prepared nanocarriers were in line with type-IV, confirming the formation of mesoporous structure in all samples [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Furthermore, the appeared hysteresis loops in these isotherms shows the occurrence of capillary condensation in mesoporous structure of nanocarriers. Here, the type of hysteresis loops refers to type H-2, which indicates interconnected pore networks along with a partially agglomeration in structure [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e].In addition, the pore size distribution in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e.b shows a narrow and uniform distribution in the range of 2–40 nm.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe morphology and surface properties of the SiGe, and SiGe/BSA-FA were investigated using FE-SEM micrographs. The results in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e clearly exhibited a porous structure with spherical shape for SiGe in the range of 200–300 nm. However, systematic changes due to surface modification of the SiGe nanocarrier with BSA-FA was observed in the SEM image of the SiGe/BSA-FA system, so that an approximately spherical and porous particles along with a rough surface is visible for SiGe/BSA-FA sample. Similar SEM results were also observed by Maheswari, when the surface of the calcium ferrite spherical nanoparticles was modified with BSA [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e3.2. Entrapment efficiency and release study\u003c/h2\u003e \u003cp\u003eThe prepared SiGe/BSA-FA carrier was used to evaluate the entrapment property and delivery behavior of 5FU. Here, the content loading (LC) and entrapment efficiency (EE) of 5FU, measured using UV–Visible spectroscopy method, were obtained at about 70% and 29%, respectively. The high entrapment efficiency of 5FU is mainly thought to be related to penetration of drug molecules and chemical interactions between hydrophilic drug of the 5FU and proper functional groups in the SiGe/BSA-FA structure [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn cancerous tissue, changes in the body's metabolic conditions and the uncontrolled proliferation of cancer cells lead to an acidic microenvironment [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Based on these properties of cancer conditions, stimuli-responsive drug delivery platforms such as pH-sensitive systems are of great interest for targeted delivery [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Here, the pH-responsive release behavior of the drug from the SiGe/BSA-FA@5FU nanocarrier was investigated under two different pH media of 5.6 and 7.4, similar to the acidic condition of cancer tissue and the normal physiological condition of the body. It should be noted that the in-vitro drug release under acidic condition was carried out to evaluate the pH-responsive behavior of nanocarrier, effect of acidic microenvironment of cells on release profile. Figure\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e indicates the cumulative 5FU release from the SiGe/BSA-FA@5FU hybrid nanocarrier under two different PBS solution during 96 h and temperature of 37°C. The results showed a partial burst release from the nanocarrier at the early times (less than 12 h) for both release media, and a sustained and gradual release profile until 96 h. The chemical interactions between 5FU and main matrix of the SiGe/BSA-FA nanocarrier can control the diffusion of drug towards PBS solution and create a sustained and gradual release behavior after 12 h [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. However, the rapid release rate of 5FU duration of first 12 h can be due to high surface area of the carrier, as well as the dissolution of drugs deposited at surface layers [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. In addition, it was observed that the amount of cumulative drug release was enhanced as the pH of the medium increased, which confirms the pH-responsive behavior of the developed nanocarrier. The maximum amount of 5FU release from the SiGe/BSA-FA@5FU nanocarrier was obtained at about 42.2% at natural pH of 7.4 after 96 h. Whereas, maximum 5FU release was reached to 65.44% at a pH of 5.6, which is thought to be related to the partial solubility of the carrier structure in this acidic condition after 96 h.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e3.3. Kinetic models and mechanism study\u003c/h2\u003e \u003cp\u003eThe Higuchi, and Korsmeyer-Peppas kinetic models were used to describe the release mechanism and investigate the behavior of drug release, as presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e. According to the results, Higuchi's kinetic model is able to adequately describe the cumulative release data of fluorouracil from the SiGe/BSA-FA@5FU nanocarrier. These results show that the diffusion mechanism mainly controls the drug release from the carrier. It has been reported that the release of poorly soluble or insoluble drugs from silica mesoporous carriers often follows the Higuchi model [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe details related to the estimated kinetic parameters of Higuchi and Korsmeyer-Peppas kinetic models were reported in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. According to the results, the value of n estimated from Korsmeyer-Peppas model was found to be less than 0.5, which indicates the effect of both penetration and swelling mechanisms in controlling the fluorouracil release process.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\u003cdiv class=\"gridtable\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eResults of Higuchi and Korsmeyer-Peppas kinetic models for SiGe/BSA-FA@5FU carrier in acidic and basic media\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003c/colgroup\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eSample\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eHiguchi\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eKorsmeyer-Peppas\u003c/p\u003e \u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eR\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eK\u003csub\u003eH\u003c/sub\u003e\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eR\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSiGe/BSA-FA@5FU (pH = 5.6)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.988\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7.36\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.965\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.45\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSiGe/BSA-FA@5FU (pH = 7.4)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.989\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4.68\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.962\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.41\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/table\u003e\u003c/div\u003e \u003cp\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003e3.4. Toxicity Studies\u003c/h2\u003e \u003cp\u003eOne of the most important issues encountered in chemotherapy is acute side effects of the cytotoxic drugs that occur after treatment [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. This issue can be solved to a great extent by using bioactive materials in smart drug delivery systems and encapsulating cytotoxic drugs in these systems [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. Within this realm, the biocompatibility and interactions between the developed carriers with the living cells are of significant importance [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. Here, MTT assay as a non-animal approach was applied to detect the toxicity of 100 µg/mL of SiGe/BSA-FA@5FU and drug-free carrier against HDF normal cells and OVCAR-3 human ovarian cancer cells after 24 and 48 h, as reported in Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e. Each reported data is the average of three performed test. For both HDF and OVCAR-3 cells, a slight difference from control samples was observed in viability of cells treated with SiGe/BSA-FA. These results support the low toxicity and biocompatibility of designed carrier [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. Considering the non-toxicity and biocompatibility of silica, gelatin and BSA, these findings seem to be logical [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. However, a toxic response was obtained by exposure the SiGe/BSA-FA@5FU carrier to both cancer and normal cells, which is due to the presence of 5FU. In addition, the drug-loaded carrier showed less cell viability against OVCAR-3 cells than HDF cells after 24 and 48 h, at about 69 and 51%, respectively, which confirmed more cytotoxic effect of SiGe/BSA-FA@5FU against cancerous cells compared to the normal cells [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. In addition, increasing exposure time from 24 to 48 h, was led to less cell viability from 69% down to 51% in cancerous cells, and from 81–73% in normal cells, respectively.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eHere, a novel BSA-folate modified silica-gelatin hybrid nanocarrier was developed and examined in terms of the pH-sensitive release behavior in simulated acidic condition of cancer cells and the normal physiological condition of the body. The fluorouracil was applied as a model drug. The high encapsulation of drug can be due to penetration of drug molecules and chemical interactions between hydrophilic drug and proper functional groups in the carrier. A partial burst release was observed at the early times for both release media which followed by a sustained and gradual release profile. The chemical interactions between drug and main matrix of the nanocarrier can control the diffusion of drug towards release media. In addition, a further drug release was observed as the pH of the medium increased, which confirms the pH-responsive behavior of the developed nanocarrier. These finding along with the low toxicity of developed nanocarrier confirmed smart function of designed carrier for targeted drug delivery.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was financial supported by University of Kashan.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors wish to express gratitude to Institute of Nanoscience and Nanotechnology, University of Kashan for financial support (grant pazhouhaneh) to this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eZahra Niazi: Investigation, Data curation, Formal analysis, Methodology, Resources, Writing. Mohsen Ashjari: Conceptualization, Formal analysis, Methodology, Validation, review \u0026amp; editing.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no potential conflict of interest.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData and code availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis manuscript doesn\u0026apos;t consist of studies with human and animal subjects.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorresponding author \u0026amp; ORCID\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCorrespondence to Mohsen Ashjari: http://orcid.org/0000-0001-7461-9883.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eZhang, WJ., Babu, A., Yan, YZ. et al. 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Tabrizi, The Anticancer, Anti-metastatic, Anti-oxidant, and Anti-angiogenic Activity of Chitosan-coated Parthenolide/Bovine Serum Albumin Nanoparticles. \u003cem\u003eJournal of Inorganic and Organometallic Polymers and Materials. \u003c/em\u003e (2023) 1-12.\u003c/li\u003e\n\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":true,"email":"[email protected]","identity":"journal-of-porous-materials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jopo","sideBox":"Learn more about [Journal of Porous Materials](http://link.springer.com/journal/10934)","snPcode":"10934","submissionUrl":"https://submission.nature.com/new-submission/10934/3","title":"Journal of Porous Materials","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Drug Delivery, Hybrid Nanocarrier, Silica-Gelatin, pH-Sensitive, Sustained Release","lastPublishedDoi":"10.21203/rs.3.rs-4443482/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4443482/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eA novel hybrid of BSA-folate modified silica-gelatin nanocarrier with surface area of about 422 m\u003csup\u003e2\u003c/sup\u003e/g was designed in the current study and loaded by fluorouracil with 70 % entrapment efficiency. The nanocarrier was evaluated in terms of pH-sensitive release behavior in simulated acidic condition of cancer tissue (pH=5.), and the normal physiological condition of the body (pH=7.4) for 96 h. In vitro drug release from nanocarriers indicated a partial burst release in the early times (34 and 21 % after 12 h in acidic and neutral media), which was followed by a sustained and gradual release profile until 96 h. In addition, an enhanced drug release was observed at acidic pH (65 % after 96 h) compared to natural medium (42 % after 96 h), confirming the pH-responsive behavior of the developed nanocarrier. The MTT assay showed low toxicity of drug-free carrier against normal HDF fibroblast, and the OVCAR-3 ovarian cancer cells. These outcomes support the proper function of designed hybrid nanocarrier in targeted drug delivery.\u003c/p\u003e","manuscriptTitle":"Folate-targeted albumin modified silica-gelatin hybrid nanocarrier. 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