| Summary: | 碩士 === 國立臺灣科技大學 === 醫學工程研究所 === 101 === The supramolecular self-assembly of cyclodextrins (CDs) and polymers based on supramolecular hydrogels have gained immense attention due to their versatile applications in the biomedical field. CDs can spontaneously form the inclusion complex structures with guest molecules, which can be used for understanding natural supramolecular self-assembly, molecular recognition, and also as precursors for designing novel materials to electronics, biomedical and pharmaceutical applications. In this dissertation, we have prepared a prodrug by attaching folic acid (FA) with Poly (ethylene glycol) methyl ether (MPEG). The supramolecular hydrogel was formed when α-CD was mixed with MPEG based prodrug, mainly due to the formation of inclusion complex between α-CD and MPEG based prodrug. We also investigated the releasing rate of inclusion complexes and their biological activity in cancer cell lines. This dissertation starts with a detailed introduction followed by description of the experiments in the second chapter. The third and fourth chapters explain the synthesis of prodrug by using FA and indomethacin (indo) that are covalently incorporated into a supramolecular hydrogel network, respectively.
In order to prepare the polymeric prodrug (MPEG-FA), first FA was conjugated with MPEG through the ester bonding, wherein N, N’-dicyclohexyl carbodiimide (DCC) and 4-dimethylaninopyridine (DMAP) were used as condensing agents for the esterification reaction. The formation of polymeric prodrug was confirmed by nuclear magnetic resonance (1H NMR) and fourier transform infrared spectroscopy (FTIR). For the formation of supramolecular hydrogel, the required concentrations of MPEG-FA and α-CD amounts were mixed in an aqueous solution at room temperature. This formed supramolecular hydrogel was characterized by 1H NMR, powder X-ray diffraction (XRD), and FTIR techniques, and the effect of MPEG-FA and α-CD amounts on the supramolecular gelation was investigated through time sweep measurements.
In order to synthesize indo based polymeric prodrug, indo was first conjugated with MPEG in an dimethyl sulfoxode (DMSO) solvent, and subsequently N,N’-dicyclohexyl carbodiimide (DCC) and 4-dimethylaninopyridine (DMAP) were added. This led to the formation of MPEG-indo. To form the supramolecular hydrogels, MPEG-indo was interacted with α-CD in their aqueous mixed system. The gel was prepared in deionized water at room temperature. The characteristic features of supramolecular hydrogel were investigated by using 1H NMR, XRD, FTIR and rheological measurements with respect to the effects of MPEG-indo and α-CD amounts.
In order to evaluate the effect of MPEG-FA at cellular level, cell viability assay was carried using human colorectal cancer (HCT116) and bladder cancer (MC-SV-HUC T-2) cell lines, in which encapsulated prodrug (EPD) reduced the growth of cells effectively compared to free prodrug (FPD). Based on these results, we suggest that the encapsulated MPEG–FA could enhance the anticancer effects. In addition, effect of EPD at molecular level was also analyzed by quantifying the human insulin-like growth factor 1 receptor (IGF-IR), due to its role in the development of colorectal cancer. Interestingly, IGF-IR levels were drastically reduced upon treatment with EPD than free FA and FPD (P< 0.05). Thus, our current findings suggest that the hydrogels could play tremendous role in the delivery of FA to the target site that may further inactivate the IGF-IR mediated signalling cascades related to tumor development.
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