SYNTHESIS AND OPTIMIZATION OF GEMCITABINE-LOADED MIL-101NH2 (Fe) NANOCARRIERS: RESPONSE SURFACE METHODOLOGY APPROACH
GEMCITABINE LOADED MIL-101 NH2 (Fe) NANOCARRIERS
Keywords:MIL-101NH, (Fe), Gemcitabine, Optimization, Central composite design, Response surface methodology, Encapsulation efficiency, Perturbation plot
Objective: The objective of the present study is to synthesize and optimize gemcitabine (GEM)-loaded MIL-101NH2 (Fe) nanocarriers. The design of experiments is used to optimize the formulation for higher encapsulation efficiency (EE) for effective drug delivery.
Materials and Methods: MIL-101NH2 (Fe) was synthesized by microwave-assisted hydrothermal method. Central composite design (CCD) under response surface methodology was used for the optimization of GEM encapsulation into the MIL-101NH2 (Fe). The most influential variable that affects the EE was investigated by Perturbation plot. Validation of the design was carried out by performing the experiments under optimal conditions. Further optimized formulation was physicochemically characterized for particle size, surface charge, and surface morphology using zetasizer and scanning electron microscopy (SEM), respectively. Structural integrity of the optimized formulation was carried out by Powder X ray crystallography (PXRD). Fourier-transform infrared (FTIR) spectroscopy was used for the confirmation of GEM loading. Accelerated storage stability analysis was also performed to find out the related parameters.
Results: Here in this work, crystalline MIL-101NH2 (Fe) has been successfully synthesized by microwave radiation method. The optimization result revealed that process variables such as GEM concentration, pH, and time significantly affect the desired constraint, EE. Perturbation plot evidenced that among all the variables, pH is the most significant factor followed by drug concentration and time. The optimized formulation exhibited 76.4 ± 7% EE and average particle size of 252.9 ± 9.23 nm. PXRD and SEM results demonstrated that the optimized formulation was crystalline in nature. FTIR spectroscopy confirms the presence of drug inside the MIL-101NH2 (Fe). In vitro release profile revealed that MIL-101NH2 (Fe)-GEM exhibited the sustained release up to 72 h in comparison to the native GEM. Storage-stability studies also indicate that MIL-101NH2 (Fe)-GEM has a shelf life of 6 months.
Conclusion: The EE of GEM in MIL-101NH2 (Fe) can be altered by varying the drug concentration and pH during the impregnation.
Hertel LW, Boder GB, Kroin JS, Rinzel SM, Poore GA, Todd GC, et al. Evaluation of the antitumor activity of gemcitabine (2’,2’-difluoro-2’- deoxycytidine). Cancer Res 1990;50:4417-22.
Plunkett W, Huang P, Gandhi V. Preclinical characteristics of gemcitabine. Anticancer Drugs 1995;6 Suppl 6:7-13.
Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomized trial. J Clin Oncol 1997;15:2403-13.
Mackey JR, Mani RS, Selner M, Mowles D, Young JD, Belt JA, et al. Functional nucleoside transporters are required for gemcitabine influx and manifestation of toxicity in cancer cell lines. Cancer Res 1998;58:4349-57.
Pastor-Anglada M, Molina-Arcas M, Casado FJ, Bellosillo B, Colomer D, Gil J, et al. Nucleoside transporters in chronic lymphocytic leukaemia. Leukemia 2004;18:385-93.
Gourdeau H, Clarke ML, Ouellet F, Mowles D, Selner M, Richard A, et al. Mechanisms of uptake and resistance to troxacitabine, a novel deoxycytidine nucleoside analogue, in human leukemic and solid tumor cell lines. Cancer Res 2001;61:7217-24.
Razzazan A, Atyabi F, Kazemi B, Dinarvand R. In vivo drug delivery of gemcitabine with PEGylated single-walled carbon nanotubes. Mater Sci Eng C Mater Biol Appl 2016;62:614-25.
Abbruzzese JL, Grunewald R, Weeks EA, Gravel D, Adams T, Nowak B, et al. A phase I clinical, plasma, and cellular pharmacology study of gemcitabine. J Clin Oncol 1991;9:491-8.
Reid JM, Qu W, Safgren SL, Ames MM, Krailo MD, Seibel NL, et al. Phase I trial and pharmacokinetics of gemcitabine in children with advanced solid tumors. J Clin Oncol 2004;22:2445-51.
Moog R, Burger AM, Brandl M, Schüler J, Schubert R, Unger C, et al. Change in pharmacokinetic and pharmacodynamic behavior of gemcitabine in human tumor xenografts upon entrapment in vesicular phospholipid gels. Cancer Chemother Pharmacol 2002;49:356-66.
Immordino ML, Brusa P, Rocco F, Arpicco S, Ceruti M, Cattel L, et al. Preparation, characterization, cytotoxicity and pharmacokinetics of liposomes containing lipophilic gemcitabine prodrugs. J Control Release 2004;100:331-46.
Derakhshandeh K, Fathi S. Role of chitosan nanoparticles in the oral absorption of gemcitabine. Int J Pharm 2012;437:172-7.
Taranjit K, Sukhjinder K, Parminderjit K. Development and validation of UV-spectrophotometric methods for determination of gemcitabine hydrochloride in bulk and polymeric nanoparticles. Int J Appl Pharm 2017;9:60-5.
Yang J, Lee H, Hyung W, Park SB, Haam S. Magnetic PECA nanoparticles as drug carriers for targeted delivery: Synthesis and release characteristics. J Microencapsul 2006;23:203-12.
Wang J, Zhang X, Cen Y, Lin X, Wu Q. Antitumor gemcitabine conjugated micelles from amphiphilic comb-like random copolymers. Colloids Surf B Biointerfaces 2016;146:707-15.
Patra CR, Bhattacharya R, Wang E, Katarya A, Lau JS, Dutta S, et al. Targeted delivery of gemcitabine to pancreatic adenocarcinoma using cetuximab as a targeting agent. Cancer Res 2008;68:1970-8.
Bersani S, Vila-Caballer M, Brazzale C, Barattin M, Salmaso S. PH-sensitive stearoyl-PEG-poly(methacryloyl sulfadimethoxine) decorated liposomes for the delivery of gemcitabine to cancer cells. Eur J Pharm Biopharm 2014;88:670-82.
Arpicco S, Lerda C, Dalla Pozza E, Costanzo C, Tsapis N, Stella B, et al. Hyaluronic acid-coated liposomes for active targeting of gemcitabine. Eur J Pharm Biopharm 2013;85:373-80.
Brusa P, Immordino ML, Rocco F, Cattel L. Antitumor activity and pharmacokinetics of liposomes containing lipophilic gemcitabine prodrugs. Anticancer Res 2007;27:195-9.
Cattel L, Ceruti M, Dosio F. From conventional to stealth liposomes: A new frontier in cancer chemotherapy. Tumori 2003;89:237-49.
Horcajada P, Chalati T, Serre C, Gillet B, Sebrie C, Baati T, et al. Porous metal-organic-framework nanoscale carriers as a potential platform for drug delivery and imaging. Nat Mater 2010;9:172-8.
Agostoni V, Chalati T, Horcajada P, Willaime H, Anand R, Semiramoth N, et al. Towards an improved anti-HIV activity of NRTI via metal-organic frameworks nanoparticles. Adv Healthc Mater 2013;2:1630-7.
Huxford RC, Della Rocca J, Lin W. Metal-organic frameworks as potential drug carriers. Curr Opin Chem Biol 2010;14:262-8.
Horcajada P, Serre C, Vallet-Regí M, Sebban M, Taulelle F, Férey G, et al. Metal-organic frameworks as efficient materials for drug delivery. Angew Chem Int Ed Engl 2006;45:5974-8.
Kush P, Madan J, Kumar P. Application of central composite design and response surface methodology for optimization of metal organic framework: Novel carrier for drug delivery. Asian J Pharm Clin Res. Available from: https://www.innovareacademics.in/journals/index.php/ ajpcr/issue/archive its my first paper i.e 34299) 2019;12:34299.
He C, Liu D, Lin W. Nanomedicine applications of hybrid nanomaterials built from metal-ligand coordination bonds: Nanoscale metal-organic frameworks and nanoscale coordination polymers. Chem Rev 2015;115:11079-108.
Dey C, Kundu T, Biswal BP, Mallick A, Banerjee R. Crystalline metal-organic frameworks (MOFs): Synthesis, structure and function. Acta Crystallogr B Struct Sci Cryst Eng Mater 2014;70:3-10.
Férey G, Mellot-Draznieks C, Serre C, Millange F, Dutour J, Surblé S, et al. A chromium terephthalate-based solid with unusually large pore volumes and surface area. Science 2005;309:2040-2.
Agostoni V, Horcajada P, Noiray M, Malanga M, Aykaç A, Jicsinszky L, et al. A “green” strategy to construct non-covalent, stable and bioactive coatings on porous MOF nanoparticles. Nature 2015;5:7925-32.
di Nunzio MR, Agostoni V, Cohen B, Gref R, Douhal A. A “ship in a bottle” strategy to load a hydrophilic anticancer drug in porous metal organic framework nanoparticles: Efficient encapsulation, matrix stabilization, and photodelivery. J Med Chem 2014;57:411-20.
Horcajada P, Gref R, Baati T, Allan PK, Maurin G, Couvreur P, et al. Metal-organic frameworks in biomedicine. Chem Rev 2012;112:1232-68.
Ke F, Yuan YP, Qiu LG, Shen YH, Xie AJ, Zhu JF, et al. Facile fabrication of magnetic metal-organic framework nanocomposites for potential targeted drug delivery.J Mater Chem 2011;21:3843-8.
Amir AS, Praveen DC, Sagar SH. A design of experiment approach for optimization and characterization of etodolac ternary system using spray drying. Int J Pharm Pharm Sci 2017;9:223-40.
Shekar P, Kumar KS, Jabasingh SA, Radhakrishnan M, Balagurunathan R. Optimization of medium components for antibacterial metabolite production from marine streptomyces SP. PUA2 using response surface methodology. Int J Pharm Pharm Sci 2014;6:475-80.
Khan NA, Kang IJ, Seok HY, Jhung SH. Facile synthesis of nano-sized metal-organic frameworks, chromium-benzenedicarboxylate, MIL- 101. Chem Eng J 2011;166:1152-7.
Agostoni V, Anand R, Monti S, Hall S, Maurin G, Horcajada P, et al. Impact of phosphorylation on the encapsulation of nucleoside analogues within porous iron(iii) metal-organic framework MIL- 100(Fe) nanoparticles. J Mater Chem B 2013;1:4231-42.
Chalati T, Horcajada P, Couvreur P, Serre C, Ben Yahia M, Maurin G, et al. Porous metal organic framework nanoparticles to address the challenges related to busulfan encapsulation. Nanomedicine (Lond) 2011;6:1683-95.
Myers RH, Montgomery DC, Vining GG, Borror CM, Kowalski SM. Response surface methodology: A retrospective and literature survey. J Qual Technol 2004;36:53-77.
Naeimi S, Faghihian H. Application of novel metal organic framework, MIL-53(Fe) and its magnetic hybrid: For removal of pharmaceutical pollutant, doxycycline from aqueous solutions. Environ Toxicol Pharmacol 2017;53:121-32.
Massoudinejad M, Ghaderpoori M, Shahsavani A, Amini MM. Adsorption of fluoride over a metal organic framework Uio-66 functionalized with amine groups and optimization with response surface methodology. J Mol Liq 2016;221:279-86.
Hamarat Sanlıer S, Yasa M, Cihnioglu AO, Abdulhayoglu M, Yılmaz H, Ak G, et al. Development of gemcitabine-adsorbed magnetic gelatin nanoparticles for targeted drug delivery in lung cancer. Artif Cells Nanomed Biotechnol 2016;44:943-9.
Chau VT, Minhthanh HT, Du PD, Toan TT, Tuyen TN, Mau TX, et al. Metal-organic framework-101 (MIL-101): Synthesis, kinetics, thermodynamics, and equilibrium isotherms of remazol deep black RGB adsorption. J Chem 2018;2018:1-14.
Bornmann C, Graeser R, Esser N, Ziroli V, Jantscheff P, Keck T, et al. A new liposomal formulation of gemcitabine is active in an orthotopic mouse model of pancreatic cancer accessible to bioluminescence imaging. Cancer Chemother Pharmacol 2008;61:395-405.
Sumithra S, Shanmugasundaram P, Ravichandiran V. Quality by design-based optimization and validation of new reverse phase-high-performance liquid chromatography method for simultaneous estimation of levofloxacin hemihydrate and ambroxol hydrochloride in bulk and its pharmaceutical dosage form. Asian J Pharm Clin Res 2016;9:190-6.
Wyszogrodzka G, Dorożyński P, Gil B, Roth WJ, Strzempek M, Marszałek B, et al. Iron-based metal-organic frameworks as a theranostic carrier for local tuberculosis therapy. Pharm Res 2018;35:144.
Wu B, Lin X, Ge L, Wu L, Xu T. A novel route for preparing highly proton conductive membrane materials with metal-organic frameworks. Chem Commun (Camb) 2013;49:143-5.
How to Cite
The publication is licensed under CC By and is open access. Copyright is with author and allowed to retain publishing rights without restrictions.