DSpace at EWHA: Synthesis and Physico-Chemical Properties of Cyclotriphosphazene-Paclitaxel Conjugate

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DSpace at EWHA일반대학원 화학·나노과학과 Theses_Master

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DC Field	Value	Language
dc.contributor.author	지다은	-
dc.creator	지다은	-
dc.date.accessioned	2016-08-25T02:08:50Z	-
dc.date.available	2016-08-25T02:08:50Z	-
dc.date.issued	2007	-
dc.identifier.other	OAK-000000018067	-
dc.identifier.uri	https://dspace.ewha.ac.kr/handle/2015.oak/173132	-
dc.identifier.uri	http://dcollection.ewha.ac.kr/jsp/common/DcLoOrgPer.jsp?sItemId=000000018067	-
dc.description.abstract	Paclitaxel (Taxol) is a diterpenoid isolated from Taxus brevifolia, used clinically for treatment of ovarian and breast cancer. Due to its aqueous insolubility it is administered as a formulated solution in ethanol and Cremophore EL(polyethoxylated caster oil), which has serious side effects. Water soluble cyclotriphosphazene derivatives have been studied in order to improve water solubility and the chemotherapeutical potency of paclitaxel. Cyclotriphosphazene derivatives were synthesized by stepwise nucleophilic substitutions of hexachlorocyclotriphosphazene with a hydrophilic poly(ethylene glycol) as a solubilizing group and Glycyl lysine methyl ester as a spacer group. They were found to form a micelle in the presence of 2′-succinyl taxol. It is presumed that the cyclic trimer may form an ion pair adduct with carboxylic acid of 2′-succinyl taxol through the epsilon-amine group of lysine. We also synthesized water soluble cyclotriphosphazene-taxol conjugates by conjugating succinyl taxol to glycyl lysine spacer group through amide linkage bonding. The conjugate was found to undergo hydrolytic degradation in PBS solution and exhibited lower but reasonably good cytotoxicity compared with free taxol. The conjugate was found to enter the cell by endocytosis mechanism and to induce very efficient apoptosis by stopping the G2/M step in the cell cycle. The biodistribution experiment did not show high tumor selectivity of the conjugate, but the conjugate has shown organ selectivity to lung.	-
dc.description.tableofcontents	Chapter Ⅰ Introduction 1 1.1. Polymeric drug delivery systems 2 1.2. Biodegradable Polymers 4 1.3. Polyphosphazenes 6 1.3.1. Introduction 6 1.3.2. Cyclotriphosphazene의 특성 7 1.3.3. Poly(organophosphazene)의 특성 10 1.4. Taxol as an anticancer agent 13 1.4.1. History of the development of taxol 13 1.4.2. The Mechanism of taxol's activity 15 1.4.3. Toxicity and side-effects 17 1.4.4. Structure activity relationships (SAR) of taxol analogs 18 1.5. Goals of this study 20 1.6. References 22 Chapter Ⅱ Syntesis and Characterization of Cyclotriphospazene- paclitaxel conjugates 26 2.1 Introduction 27 2.2. Experimental Section 30 2.2.1. Materials 30 2.2.2. Instruments 30 2.2.3. Synthesis and characterization 31 (가) HCl Gly-CbzLysine methylester의 합성 31 (1) Boc-Lys(Z)-OCH3의 합성 31 (2) Lys(Z)-OCH3의 합성 32 (3) BocGlyLys(Z)-OCH3 의 합성 32 (4) HCl·GlyLys(Z)-OCH3 의 합성 33 (나) [NP(MPEG350)GlyLysMe]3 의 합성 34 (다) 2'-Succinyltaxol 35 (라) {[NP(MPEG350)(GlyLysMe-2’-succinylTaxol]1 [NP(MPEG350)(GlyLys- Me)]2} 의 합성 35 (마) {[NP(MPEG550)(GlyLysMe-2’-succinylTaxol]₁ [NP(MPEG550)(GlyLys- Me)]2} 의 합성 37 (바) {[NP(MPEG350)(GlyLysMe-2’-succinylTaxol]₁[NP(MPEG350) (GlyLys- Me)-FITC]2} 의 합성 37 2.2.4. Micelle size and size distribution 38 2.2.5. Determination of critical micelle concentration 38 2.2.6. in vitro Drug Releasing study 39 2.2.7. in vitro Cytotoxicity data 39 2.2.8. cell cycling 40 2.2.9. Paramacokmetic study 40 2.2.10 Bio distibution 42 2.2.11 Viscosity 42 2.3. Result and discussion 43 2.3.1. Synthesis and characterization 43 2.3.4. Critical micelle concentration(CMC) 49 2.3.5. Size disribution 52 2.3.6. in vitro Drug Releasing study 54 2.3.7. in vitro Cytotoxicity data 55 2.3.8. cell cycling data 57 2.3.9. Paramacokmetic study 59 2.3.10 Bio Distribution 61 2.3.12 Viscosity 62 2.4. Conclusions 63 2.5. Reference 64 Chapter Ⅲ Synthesis and Characterization of Cyclotriphosphazene -paclitaxel ion pair adduct 67 3.1. Introduction 68 3.2. Experimental section 72 3.2.1. Materials 72 3.2.2. Instruments 72 3.2.3. Synthesis and characterization 73 3.2.4. Determination of critical micelle concentration 74 3.2.5. Micelle size and size distribution 74 3.2.6. Zeta potential 74 3.3 Result and Discussion 75 3.3.1. Synthesis and characterization 75 3.3.2. Determination of critical micelle concentration 76 3.3.3. Micelle size and size distribution 78 3.3.4. Zeta potential 80 3.3 Conclusion 83 3.4 Reference 84 Abstract 87	-
dc.format	application/pdf	-
dc.format.extent	5550216 bytes	-
dc.language	kor	-
dc.publisher	이화여자대학교 대학원	-
dc.title	Synthesis and Physico-Chemical Properties of Cyclotriphosphazene-Paclitaxel Conjugate	-
dc.type	Master's Thesis	-
dc.creator.othername	JI, DA EUN	-
dc.format.page	x, 88 p.	-
dc.identifier.thesisdegree	Master	-
dc.identifier.major	대학원 나노과학부	-
dc.date.awarded	2007. 2	-