藥物釋放用環糊精超分子結構凝膠的備製與特性｜國立臺灣科技大學博碩士論文系統

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研究生：	Chittimma Chandaka Chittimma - Chandaka
論文名稱：	藥物釋放用環糊精超分子結構凝膠的備製與特性 Preparation and Characterization of Cyclodextrin Based Supramolecular Hydrogels for Drug Delivery
指導教授：	洪伯達 Po-Da Hong
口試委員:	Ming-Kung Yeh Ming-Kung Yeh 白孟宜 Meng-Yi Bai
學位類別：	碩士 Master
系所名稱：	應用科技學院 - 醫學工程研究所 Graduate Institute of Biomedical Engineering
論文出版年：	2013
畢業學年度：	101
語文別：	英文
論文頁數：	49
中文關鍵詞：	No
外文關鍵詞：	Supramolecular gelation, Prodrug, Biological activity.
相關次數：	點閱：165 下載：7
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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.

Abstract ……………………………………………………………………………………..i
Acknowledgement ………………………………………………………………………….ii
Abbreviations ………………………………………………………………………….......ix
Chapter 1 General Introduction ……………………………………………………...........1
1.1	Cyclodextrins (CD’s) ………………………………………………………………..1
            1.1.1 History of cyclodextrin …………………………………………………………2
            1.1.2 Properties of cyclodextrins……………………………………………………...3
            1.1.3 Applications of cyclodextrins……………………………………………………6
1.2	Supramolecular Hydrogels …………………………………………………………7
1.2.1 Hydrogels………………………………………………………………………..7
1.2.2 Mechanism of network formation………………………………………………8
1.2.3 Physical hydrogels...............................................................................................8
1.2.4 Physical hydrogel from supramolecular inclusion complex …………………...9
1.2.5 Characterization of hydrogels …………………………………………………10
1.2.6 Application of hydrogels ………………………………………………………11
1.2.7 Injectable drug delivery systems based on α-CD–PEO supramolecular hydrogels…………………………………………………………………………….11
1.2.8 Modification of cyclodextrins or guest on inclusion complex for drug delivery……………………………………………………………………………….15
1.2.9 Polymeric guest–drug conjugates for controlled drug delivery………………..16
1.3	Aim ………………………………………………………………………………….17
1.4       Overall work flow…………………………………………………………………..18
Chapter 2 Experimental Section…………………………………………………………..19
2.1	Materials ……………………………………………………………………………19
2.2	Methods …………………………………………………………………………….19
	2.2.1 Synthesis of prodrug (MPEG-FA) …………………………………………….19
	2.2.2 Supramolecular hydrogelation and its characterization ……………………….20
	2.2.3 Determination of cell viability…………………………………………………20
            2.2.4 RNA extraction ……………………………………………………………......21
            2.2.5 Quantitative real-time PCR (qRT-PCR) ………………………………………21
            2.2.6 Statistical analysis..............................................................................................22
2.3	Measurements ………………………………………………………………………22
          2.3.1 1H NMR spectroscopy………………………………………………………….22
          2.3.2 FT-IR spectroscopy …………………………………………………………….22
          2.3.3 X-ray diffraction (XRD)	……………………………………………………….22
          2.3.4 Differential scanning calorimetry (DSC)	……………………………………….23
          2.3.5 UV-Vis spectroscopy …………………………………………………………...23
          2.3.6 Rheological analyses ……………………………………………………………23
         2.3.7 Scanning electron microscope (SEM) …………………………………………..23
Chapter 3 Preparation and Characterization of Cyclodextrin Based Supramolecular Hydrogels for Drug Delivery…………………………………………………………….24
    3.1 Introduction ……………………………………………………………………….24
   3.2 Results and Discussions ……………………………………………………………27
	3.2.1 Synthesis of prodrug (MPEG-FA) and its characterization………………….27
            3.2.2 Preparation and characterisation of MPEG-FA-α-CD supramolecular hydrogen ……………………………………………………………………………………………….29
	3.2.3 Rheological study: to determine the gelation kinetics ……………………….31
	3.2.4 Release behaviour of encapsulated MPEG-FA/α-CD: in vitro ……………...34
	3.2.5 Effect of encapsulated MPEG-FA on cell viability…………………………...36
            3.2.6 Evaluation of encapsulated FA effect on IGF-IR expression…………………37

3.3 Concluding Remarks…………………………………………………………………..38
Chapter 4 Supramolecular Gelation Based on Polymer-Cyclodextrin Inclusion   Complexes for Drug Delivery…………………………………………………………….39
4.1 Introduction……………………………………………………………………………..39
4.2 Results and Discussions………………………………………………………………...40
4.2.1 Synthesis and encapsulation of Prodrug (MPEG-indo) and its Characterization …….40
4.3 Conclusion………………………………………………………………………………43
Conclusion and Future Prospective………………………………………………………..43
 References ...………………………………………………………………………………..44
Figure Index
Figure 1.1 Structure of cyclodextrin ………………………………………………………….1
Figure 1.2 Parent CDs and CD derivatives formation ……………………………………......2
Figure 1.3 Chemical structures of the three types of cyclodextrin and the glucose units are connected through α-1, 4 chemical bonds ………………………………………………….…4
Figure 1.4 CDs structure in torus-like macro ring shape, with the hydroxyls groups………..5
Figure 1.5 Applications of cyclodextrin ……………………………………………………...6
Figure 1.6 Formation of polypseudorotaxane hydrogel from α -cyclodextrin (α-CD) and high molecular weight PEG ………………………………………………………………………..7
Figure 1.7 Classification of gelation mechanism and relevant examples ……………………9
Figure 1.8 Formation of polypseudorotaxane hydrogel from α-cyclodextrin (α-CD) and high molecular weight PEG. When α-CD is added into a clear PEG solution (a) α-CD threads onto the polymer to form polypseudorotaxane (b) and finally gives a hydrogel due to polypseudorotaxane aggregation (c) ………………………………………………………...10
Figure 1.9 Partial inclusion complexation of high molecular weight PEO with α-CD leading to formation of a supramolecular hydrogel ………………………………………………….12
Figure 1.10 (a) Use of amphiphilic blocks copolymer as a guest polymer to enhance hydrogel rheological properties. Hydrophobic interactions afforded by atactic poly[(R,S)-3-hydroxybutyrate] (aPHB) segments resulted in hydrogels b) Using PEG-grafted high molecular weight hydrophilic polymer as guest polymer to obtain hydrogel with high stiffness and long protein release profile……………………………………………………..13
Figure 1.11 schematic illustrations of possible structures and gelation mechanism of supramolecular hydrogels. (Left) Micellar hydrogel. (Right) Reverse micellar hydrogel. Stages: (1) micellization of copolymer; 2) micellar hydrogel formation by supramolecular inclusion complexation; 3) reverse micellization of copolymer; 4) reverse micellar hydrogelation ………………………………………………………………………………...14
Figure 1.12 Preparation of the photoresponsive hydrogels …………………………………14
Figure 1.13 Structures of the complexes formed between CDs and guests attached to a gel. (β-CD-gel/Ad-gel α-CD-gel/n-Bu-gel β-CD-gel/t-Bu-gel)…………………………………..15
Figure 1.14 The schematic illustration of drug-conjugated polyrotaxane and the concept of triggered drug release via enzymatic degradations ………………………………………….16
Figure 2.1 Synthesis of MPEG-FA …………………………………………………………19
Figure.2.2 The basic principle of PCR assay ……………………………………………….22
Figure 3.1 the schematic representation of IGF-1 signaling pathway ……………………..26
Scheme 3.2 Synthetic route to PEGylated FA (MPEG-FA) …………………………….…27
Figure 3.3 1H NMR spectrum of PEGylated FA (MPEG-FA) in d6-DMSO ………………28
Figure 3.4 FT-IR spectrum of MPEG, FA and Prod rug (MPEG-FA) …………………….29
Figure 3.5 Photographs for the formation of a supramolecular hydrogel sample from 3.0 wt% (in the mixed system) of MPEG-FA and 7.0 wt% (in the mixed system) of α-CD at room temperature ………………………………………………………………………………....29
Figure 3.6 (a) XRD patterns and (b) FT-IR spectra of MPEG-FA, α-CD and freeze-dried hydrogel sample formed from 3.0 wt% MPEG-FA and 7.0 wt% α-CD ……………………30
Figure 3.7 DSC-curves of prodrug (MPEG-FA), α-CD, and freeze dried hydrogel sample formed in situ from 3.0 wt% MPEG-FA and 7.0 wt% α-CD ……………………………….29
Figure 3.8 Effects of MPEG -FA and α-CD amounts on the supramolecular gelation kinetics for aqueous MPEG-FA /α-CD systems. Test conditions: frequency, 1.0 rad/s; strain, 0.05%......................................................................................................................................32
Figure 3.9 The SEM image of the freeze-dried hydrogel. The sample was coated with Au before observation …………………………………………………………………………..33
Figure 3.10 (a) UV spectra of the solution with a known concentration of FA and (b) graph of the linear relationship between FA concentration (mg/ml) and absorbance at 348.5 nm as obtained from the samples with known FA concentration ………………………………….33
Figure 3.11 Cumulative release proﬁles of encapsulated MPEG-FA from the supramolecular hydrogels formed under various MPEG-FA amounts (a) and α-CD amounts (b).Test conditions: pH 7.4 PBS, 25 oc ……………………………………………………………….35
Figure 3.12 (a) Microscopic morphology observation b) cell viability of MC-SV-HUC T-2 cells incubated in the media without prodrug (Control), as well as the media containing FA, FPD and EPD released from the supramolecular hydrogel (50 ug/ml--3.0 wt % Prodrug (MPEG-FA) + 7.0 wt % α-CD, for 3 days)………………………………………………………………………………………36
Figure 3.13 Microscopic morphology observation b) cell viability of HCT116 cells incubated in the media without prodrug (Control), as well as the media containing FA, FPD and EPD released from the supramolecular hydrogel (50 ug/ml--3.0 wt % Prodrug (MPEG-FA) + 7.0 wt % α-CD, for 3 days)…………………………………………………………………………………………………..37
Figure 3.14 Action of EPD on IGF-1R gene expression. a) HCT116 cells were treated with control, 50μg/ml of FA, FPD and EP for 3 days. The cells were harvested and total RNA was prepared and converted to cDNA for qRT-PCR analysis of IGF-1R and Beta-Actin.* indicates significance of IGF-1R expression (P<0.05) relative to the control.b) The PCR products were run on 2% agarose gel for monitoring the quality cDNA levels using autoradiography……………………………………………………………………………...38
Scheme 4.1 Synthetic route to PEGylated indo (MPEG- indo) …………………………….40
Figure 4.2 1H NMR spectrum of PEGylated indo (MPEG-indo) in CDCl3 (25 oC) ……….41
Figure 4.3 Photographs for the formation of a supramolecular hydrogel sample from 3.0 wt% (in the mixed system) of MPEG-indo and 7.0 wt% (in the mixed system) of α-CD at room temperature……......................................................................................................................42
Figure 4.4 (a) XRD patterns and (b) DSC curves of prodrug (MPEG-indo), α-CD, and freeze-dried hydrogel sample formed from 3.0 wt% prodrug (MPEG-indo) and 7.0 wt% α-CD …………………………………………………………………………………………...43
Table Index
Table 1.2 Physicochemical properties of cyclodextrins ……………………………………..4
Table 3.2 Release characteristics of encapsulated prodrug (MPEG-FA) from supramolecular hydrogels with different compositions-- fitting with Higuchi model………………………...35

                                

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