Abstract
In this study, poly(N-isopropyl acrylamide-co-methyl acrylic acid) (PLA-g-P(NIPAAm-co-MAAc) graft copolymer with thermal sensitivity, pH sensitivity and biodegradability was synthesized by free radical polymerization from NIPAAm monomers, MAAc monomers and PLA macromonomers. Additionally, poly(2-ethyl-2-oxazoline)-b-poly(D,L- lactide) (PLA-PEOz) diblock copolymer that can be avoided mononuclear phagocyte systems recognition was synthesized by ring opening polymerization. A novel nanostructure, which was called mixed micelle, was prepared from PLA-g-P(NIPAAm-co-MAAc) and PLA-PEOz by a solvent exchange process. This nanostructure not only provide a particle modification technique to hide the inner structure from graft copolymer or to prepare a stealth micelle for avoiding the recognition by the physiological system, but also provide a environmental sensitive core to control the anticancer drug released for application in cancer therapy.This study was divided into two sections. In the first section, the difference of critical micelle concentration (CMC) of each copolymer was used to study the formation mechanism of mixed micelles. From our study, the completely mixed micelle was formed as the CMC of diblock copolymer was lower than or equal to that of graft copolymer. As the CMC of diblock copolymer was higher than that of graft copolymer, otherwise, the mixed micelle and micelles from each copolymer were coexisted. In section two, the hydrophobic anticancer drug, doxorubicin (Dox), was incorporated into mixed micelle for used in cancer therapy. Dialysis method was conducted on the Dox and copolymer solution, and mixed micelles with Dox were formed, exhibiting a uniform particle size of 262.3 nm. From UV/Vis spectrophotometer analysis, drug content of mixed micelle incorporated with Dox was around 25 %. In vitro drug released evaluation was conducted at 37 ℃ with different pH levels. In neutral surrounding, the release of drug form mixed micelles with Dox was less, indicating that the mixed micelle was stabilized and efficiently protect the drug under such surrounding. In contrast, a significant release of Dox was observed in acidic surrounding. That is because of the P(NIPAAm-co-MAAc)s collapsed and aggregated in acidic surroundings, deforming the inner core, causing Dox to be released from the mixed micelles. On the other hand, cytotoxicities of free Dox and mixed micelle with Dox were determined by measurement the inhibition of HeLa cell growth using a tetrazolium dye (MTT) assay. The result exhibited that Dox released from mixed micelle also demonstrated pharmaceutically activity. In summary, this study presents the first example of self-assembly from diblock and graft copolymer, not only involving a particle modification technique to hide the inner structure and to increase the biocompatibility of materials, but also combining the advantages of the two copolymers to exhibit multi-functions for used in drug delivery.