| The side effects of the tumor chemotherapy to the patient attract considerable attention. In recent years, to reduce the side effect of chemotherapy and enhance its bioavailability of the anticancer drugs, many drug delivery systems were developed. The ideal delivery system should have good biocompatibility and long circulation time in blood, as well as targetability to the tumor cells. Drug delivery technology is the key to the clinical success of many potent drugs. This thesis focuses on two kinds of polymeric drug carrier systems.The second chapter of the thesis describes folate-conjugated crosslinked biodegradable micelles for receptor-mediated delivery of paclitaxel. Firstly, two kinds of functional copolymers were synthesized successfully. One is triblock copolymer poly(ethylene glycol)-b-poly(acryloyl carbonate)-b-poly(D,L-lactide) (PEG-PAC-PLA) which was designed to crosslink micelles at the interface by UV irradiation, and the other is folate-PEG-PLA (FA-PEG-PLA) which was to target at FA-receptor over-expressing cancer cells e.g. KB cells. Micelles with varying amounts of folate ligand were prepared at 0 ~ 20 wt. % of FA-PEG-PLA. These micelles achieved high drug loading efficiencies of 70 ~ 88 % at an initial PTX loading content of 10 wt. %. The resulting micelles, either with or without PTX loading, were readily crosslinked by UV irradiation. The crosslinked micelles had much smaller sizes and better stability as compared to the non-crosslinked controls. The in vitro release studies revealed that crosslinked micelles exhibited significantly inhibited PTX release at low micelle concentrations. MTT assays in KB cells showed that the crosslinked micelles were non-toxic while toxicity of PTX-loaded micelles, either crosslinked or non-crosslinked, increased with increasing folate contents. Remarkably, at 12 h incubation time folate-decorated PTX-loaded crosslinked micelles composed of 20 wt.% of FA-PEG-PLA displayed markedly higher toxicity to KB cells than free PTX (33 % versus 50 % cell viability), which is most likely due to their much more efficient cellular uptake through FA receptor-mediated endocytosis. Flow cytometry studies showed that folate-decorated FITC-labeled crosslinked micelles were much more efficiently taken up by KB cells than controls without folate ligand. These results indicate that ligand-conjugated interfacially crosslinked PEG-PLA micelles have great potential in targeted cancer therapy.The third chapter of the thesis reports on chimearic biodegradable polymersomes with encapsulated doxorobicn hydrochloride in the aqueous interior and anti-MDR anticancer drug curcumin in the membrane for combination therapy of cancers. The triblock copolymer poly (ethylene glycol)-b-poly (ε-caprolactone)-b-poly (acrylic acid) (PEG-PCL-PAA) with different length of PAA were successfully synthesized via RAFT polymerization of AA using PEG-PCL-CPADN as macro RAFT agent and AIBN as radical source. The molecular weight of PEG and PCL are 5 kDa and 18 kDa, respectively, and PAA blocks have molecular weights of 0.8, 3.1 and 6.1 kDa, respectively. Using film hydration method polymersomes with a size of 120 ~ 200 nm (PDI 0.09-0.25) were readily prepared via the self assembly process in aqueous solution. The polymersome structure was confirmed by CLSM technique. Especially, zeta potential measurements suggested that the polymersomes formed have an asymmetric membrane, with short PAA (0.8 and 3.1 kDa) preferably located in the inner side of the polymersome membrane and long PEG on the outter side of the polymersome membrane. Remarkably, the polymersomes could DOX·HCl up to 12.4 wt.% loading content and the DOX·HCl loaded polymersomes are stable in terms of particle size and size distribution in several days. The polymersomes can house curcumin in the hydrophobic membrane with quite high loading content (about 11.8 wt.%). The in vitro release studies revealed that DOX·HCl was released under a controlled manner; especially the release rate was much faster in endosome mimicking conditions than that in extracellular medium mimicking conditions. Therefore, the chimearic biodegradable polymersomes loaded with DOX·HCl and curcumin may overcome the multidrug resistance and exert high cancer killing effect. Considering that the building block for the copolymer PEG, PCL and PAA are all approved by FDA for the use in medical devices, thus the present polymersome systems are very attractive in combination therapy of cancers. |
