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In Vitro Study of Drug Release from the Metal-organic Frameworks (MOFs) for Melanoma Cancer Drug Delivery

Barjasteh, Mahdi | 2022

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  1. Type of Document: Ph.D. Dissertation
  2. Language: Farsi
  3. Document No: 55450 (48)
  4. University: Sharif University of Technology
  5. Department: Institute for Nanoscience and Nanotechnology
  6. Advisor(s): Vossoughi, Manouchehr; Bagherzadeh, Mojtaba; Pooshang Bagheri, Kamran
  7. Abstract:
  8. Metal-organic frameworks (MOFs) are a new class of biocompatible nanomaterials with high specific surface area, which provide the possibility of loading various therapeutic agents. Considering the few studies on the use of MOFs in melanoma cancer treatment, the main goal of this research is to investigate the loading and controlling the release of dacarbazine (DTIC) and also the interaction of DTIC and MOF structure in aqueous environments. Based on this, this study was done in three main parts. In the first part, several types of well-known and often used structures in the drug delivery field, including ZIF-8 (based on zinc), MIL-101-NH2(Fe), and MIL-100(Fe) (both based on iron), were synthesized to select the most suitable metal-organic framework for DTIC loading. MIL-100(Fe) was selected as the best structure for drug loading and release because of its large surface area, amphiphilic nature, and green synthesis at room temperature, which facilitates in situ drug loading. In the second part, the drug loading was performed during the green synthesis of MIL-100(Fe) in an aqueous media without using any harmful solvents to obtain MIL-DTIC. The surface of this structure was then coated with polyethylene glycol (PEG) in the same aqueous solution to synthesize MIL-DTIC-PEG. The synthesized samples were characterized using various methods. Their release profile was studied in phosphate-buffered saline (PBS) and simulated cutaneous medium (SCM). The cytotoxicity of DTIC and its nano-MOF formulation were investigated against melanoma A375 cell lines. The results revealed that the PEG coating (PEGylation) changed the surface charge of MOF from -2.8 ± 0.9 mV to -42.8 ± 1.2 mV, which can contribute to the colloidal stability of MOF. The PEGylation showed a significant effect on controlled drug release, especially in SCM, which increases the complete release time from 60 hours to 12 days. Moreover, both drug-containing MOFs showed more toxicity than DTIC and unloaded MOFs, confirming that the cumulative release of drugs and better cellular uptake of NPs lead to increased toxicity. In the third part, the interaction of the drug and the structure of the MIL-100(Fe) was investigated by DTIC adsorption experiments and molecular docking calculations. In this regard, MIL-100(Fe) was synthesized using a rapid and green synthesis technique. The crystallinity, as well as the porosity of the prepared particles against air for a long period of time (more than three years), was also investigated. The synthesized MOF particles exhibited a high adsorption capacity of 292.87 mg/g for DTIC at optimum conditions, mainly because of their high surface area and suitable porous structure. The experimental adsorption kinetic and isotherm results demonstrated that the adsorption of DTIC onto this adsorbent followed the pseudo-second-order kinetic model and Freundlich isotherm model, respectively. Moreover, the thermodynamic investigations showed that the adsorption of DTIC molecules on MIL-100(Fe) was spontaneous and exothermic. Furthermore, the pH effect studies revealed that the electrostatic interaction is the main adsorption mechanism. Additionally, molecular docking calculation results suggested that the DTIC molecules can interact with the MIL-100(Fe) particles via hydrogen bonding with a binding energy of about -5.1 kcal/mol. It was found that the MIL-100(Fe) particles can be easily recovered by simple washing with ethanol solution and can be reused for further adsorption process
  9. Keywords:
  10. Drug Delivery ; Docking ; Melanoma Cancer ; Metal-Organic Framework ; Molecular Docking ; Controlled Release ; Dacarbazine (DTIC)

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