Preparation Of Stimuli-responsive Nanomicelles And Their Applications In Drug Delivery

Amphiphilic polymer is capable of self-assembly to micelles in aqueous solution, which can be applied to load the medicine such as anticancer drugs, protein, DNA via physical or chemical methods. These micelles delivery the drugs to a specific site, thus to improve the efficacy of cancer therapy. However, the design and preparation of stimuli-responsive biological polymeric materials for the the construction of smart drug delivery system has been a great challenge. This dissertation has been designed and synthesized functionalized, biocompatible amphiphilic polymers. We used these polymeric micelles to delivery protein and hydrophobic drug and studied the vitro release effect. The main contents and conclutions of this dissertation are summarized in the following aspects:(1) The amphiphilic block copolymers PEG11 3-b-PMPCn were synthesized via the organic catalysis ring-opening polymerization, which were characterized by NMR and GPC. These polymers are capable of forming stable spherical micelles in water. The hydrophobic core in the micelle can load a hydrophobic fluorescent dye such as Nile red. The polymeric critical micelle concentration(CMC) was determined by the fluorescence spectroscopy method and studied the effect of different hydrophobic segment lengths on the micelles. It is found that the hydrophobic segment is too short to form the stable micelles in water.(2) Photoresponsive amphiphilic block copolymers PMPC-Azo were synthesized by azide-alkyne click chemistry, which can self-assemble to spherical micelles with an average diameter of 150 nm in aqueous solution. The micelle will be collapsed and re-assemble under the UV and visible light irradiation. This whole process is monitored using DLS, TEM and UV-vis spectra. Azobenzene photoisomerization changes the polymeric micelles hydrophilic and hydrophobic balance, leading to the disintegration and re-assembled micelles and this irreversible process can be repeated many times. Nile red was used as a hydrophobic model drug in the released experiments. The drug can be released from the drug-loaded micelles quickly under the 365 nm UV irradiation; when irradiated under the 450 nm visible light, the dissociation segment is re-assembled and re-loaded the drugs. This study provides a convenient method to construct smart nanocarriers for controlled release and re-encapsulation of hydrophobic drugs.(3) A series of Light-responsive poly(carbonate)s PEG113-b-PMPCn-SP were synthesized via copper catalyzed azide-alkyne cycloaddition reaction between azide-modified spiropyran(SP-N3) and amphiphilic copolymer PEG113-b-PMPCn. These polymers can self-assemble to biocompatible spherical micelles with an average diameter from 100 nm to 150 nm in aqueo us solution. The changed process was investigated via DLS, TEM and UV-vis spectrometer to study the polymeric micelle disassembly and reassembly behavior under the different wavelengths light irradiation. The spiropyran SP in the hydrophobic unite will be gradually transformed into a hydrophilic merocyanine MC under the UV irradiation, which breaks the balance between the polymeric hydrophilicity and hydrophobicity, resulting in the collapse of the micelles.Then under the visible light irradiation, the merocyanine structure will gradually turn into hydrophobic spiropyran, recovering the hydrophilic and hydrophobic balance, prompting photoresponsive amphiphilic polymer reassembled into micelles. Coumarin 102 was used as a hydrophobic model drug in the released experiments. The drug can be released from the drug-loaded micelles quickly under the 365 nm UV irradiation; when irradiated under the 620 nm visible light, the dissociation segment is re-assembled and re-encapsulated the drugs. These reversible photoresponsive biocompatible polymer micelles possess great potential in the field of controlled drug release.(4) Amphiphilic copolymers p(PDSMAx-co-PEGMAy) were prepared via rversible addition-fragmentation chain transfer radical polymerization(RAFT). The effect of different hydrophobic segment length on the micelles was studied. With post-polymerization modified method, a se ries of reduction-responsive selfimmolative amphiphilic polymers were synthesized. It is found that the hydrophobic section in the polymer is too big to form the stable micelles in aqueous solution. The lysozyme is conjugated with the polymer via amide bond, which can self-assembly to micelles in water. The polyethylene glycol diamine or ethylene diamine was used as the crosslinking reagent to form more stable micelles. The protein activity is masked in the encapsulated form. When the conjugates are in the reduction environment, the protein will be released and the protein activity will be recovered.