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Antitumor Activity of Doxorubicin Conjugated Stearic Acid-g-chitosan Oligosaccharide Polymeric Micelles

Author: LiuLiNa
Tutor: HuFuQiang
School: Zhejiang University
Course: Pharmacy
Keywords: Chitosan oligosaccharide Glycolipid Stearic acid Polymer micelles Doxorubicin Cis-aconityl linkage Antitumor activity Drug resistance Controlled release
CLC: R96
Type: Master's thesis
Year: 2010
Downloads: 115
Quote: 0
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Abstract


Amphiphilic block copolymer could self-aggregate into micelles in an aqueous medium, which emerged as novel targeting drug delivery system with broad prospect.Chitosan oligosaccharide (CSO) with the molecular weight of 18 KDa was obtained from the enzymatic degradation of Chitosan. Mediated by 1-ethyl-3-(3-dimethylami- nopropyl) carbodiimide (EDC), stearic acid grafted chitosan oligosaccharide (CSO-SA) was synthesized. The degree of amino-substitution for CSO-SA was about 6.47±0.60%. CSO-SA could self-assemble to form micelles, the critical micelle concentration (CMC) of which was about 140μg/mL. The diameter and zeta potential of CSO-SA micelles with the concentration of 1 mg/mL were about 32.7±0.1 nm and 51.5±1.0 mV, respectively.Doxorubicin conjugated stearic acid-g-chitosan oligosaccharide polymeric micelles (DOX-CSO-SA) was synthesized via cis-aconityl bond between the anticancer drug doxorubicin (DOX) and stearic acid grafted chitosan oligosaccharide (CSO-SA). The physicochemical of DOX-CSO-SA was determined. The DOX-CSO-SA micelles indicated pH-dependent DOX release behavior. The release rate of DOX from DOX-CSO-SA micelles increased significantly with the reductions of the pH for release medium. In vitro antitumor activity tests showed the cytotoxicity of DOX-CSO-SA micelles with certain concentration significantly decreased at the culture medium with higher pH. In vitro antitumor activity tests also presented the reversal activity of DOX-CSO-SA micelles against DOX resistance MCF-7 cells (MCF-7/Adr), the reversal power was about 4-10. In vivo tissue distribution results showed that DOX-CSO-SA micelles were largely accumulated to tumor tissue. In vivo antitumor activity results showed that DOX-CSO-SA micelles treatments effectively suppressed the tumor growth and reduced the toxicity against animal body than commercial doxorubicin hydrochloride injection.DOX-CSO-SA micelles were used as drug carrier. Comparing to CSO-SA micelles, DOX-CSO-SA micelles showed better ability of drug loading capacity. The size of DOX loaded DOX-CSO-SA micelles (DOX-CSO-SA/DOX) was smaller than DOX-CSO-SA micelles. In vitro DOX release profiles from DOX-CSO-SA/DOX micelles showed excellent characteristic of drug controlled release. In vitro antitumor activity tests showed the cytotoxicity of DOX-CSO-SA micelles was enhanced by loading DOX drug.

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