Stimuli-responsive Intelligent Polymeric Micelles For Drug Delivery

During the past decades,various vehicles have been developed as drug delivery carriers and polymeric micelles self-assembled from amphiphilic polymers are extensively reported as drug delivery systems,especially for poorly water soluble anticancer drugs.Polymeric micelles usually have a size around 10-200nm which are advantageous for passive targeting due to the enhanced permeability and retention(EPR)effect.Some of the most important considerations for a drug carrier are the drug incorporation capacity,stability,and biocompatibility.To improve the therapeutic efficiency further,intelligent polymeric micelles have been designed which are stable under physiological conditions but can accelerate 'the drug release in response to the specific signals near tumor sites selectively.In this study,a series of sensitive,functionalized polymers have been designed and synthesized as drug carrers.In Chapter 1,the concept and application of nano-drug carriers are systematically introduced.Various sensitive drug carriers,cross-linking and multifunctional drug carriers are reviewed.In Chapter 2,a thermo-responsive block copolymer bearing pendant disulfide side chain was synthesized by a facile radical polymerization using a macroinitiator.Dynamic light scattering(DLS)results showed this copolymer had a lower critical solution temperature(LCST)around 22?.The reduction-degradable behavior of the polymer was also observed by DLS.The polymer can self-assembly into a stable micelle which can be used for the delivery of anticancer drug in aqueous solution.Doxorubicin(Dox)can be loaded into the micelle with a relative high loading content(up to 8%).The drug can be released faster in the presence of lOmM dithiothreitol(DTT)which mimics the reducing concentrations in intracellular environments.The MTT assays indicated that the blank polymer solutions were nearly nontoxic to HepG2 cells.And the Dox-loaded micelles showed similar anticancer activity to free Dox.Thus this copolymer micelle can be used as a promising carrier for the intracellular release of anticancer drug.In Chapter 3,a dual functional thermo-and pH-responsive block copolymer containing aromatic structure was firstly synthesized by a facile radical polymerization using a macroinitiator.This copolymer displayed a thermo-responsive behavior which had a LCST around 20?.The pH-transition point was around 6.5.Dox can be loaded into the micelle with a relative high loading content(up to 14%).The drug can be released faster at acidic environments.The MTT assays indicated that the blank polymer solutions were nearly nontoxic to HepG2 cells.And the Dox-loaded micelles showed similar anticancer activity to free Dox.These results showed the micelle hold great promise for the delivery of a hydrophobic drug.In Chapter 4,a novel multi-responsive hybrid-brush polymer was prepared by facile aminolysis of poly(succinimide)(PSI)with the amino-disulfide linked poly(ethylene glycol)monomethyl ether(mPEG-SS-NH2),octadecylamine(C18),phenethylamine(PEA),1-(3-aminopropyl)imidazole(API)and 5-aminopentanol(AP).In aqueous solution,the obtained polyaspartamide derivatives can respond to the changes of pH,temperature or both and self-assembly into micelles under physiological conditions.Dox-loaded micelles are stable under the normal physiological conditions and in vitro release profile revealed that intensified Dox release kinetics can be realized at the lower pH(5.0)and the higher reductant concentration(DTT 10 mM)by the synergistic effect of imidazole group protonation with disulfide linkage cleavage.The cytotoxicity assays showed that the blank micelles had low cytotoxicity and the Dox-loaded micelles own similar anticancer activity to free Dox against HeLa cells.The completely new method in this work may be a useful strategy to construct multifunctional micelles for diversified applications such as drug delivery vehicles.In Chapter 5,we firstly reported an amphiphilic graft copolymer based on polyaspartamide derivative which was synthesized via ring opening reaction of poly(succinimide)(PSI)with O-(2-aminoethyl)-O'-methylpoly ethylene glycol(mPEG),2-nitrobenzyloxycarbonylaminocystamine(NB-Cyst),1-(3-aminopropyl)-imidazole(API)and 5-Aminopentanol(AP)step by step.The new type of amphiphilic biodegradable poly(amino acid)derivative can self-assembly into micelles which respond to multiple triggers including temperature,pH and redox potential.The disulfide bond was located in the hydrophobic segments of the polymer which was more stable than the previous polymer in Chapter 4.Moreover,Dox-loaded micelles could exhibit more gentle drug release kinetics which can be realized at the lower pH(5.0)and the higher reductant concentration(DTT 10 mM).The cytotoxicity test indicated the biodegradable polymer was nearly nontoxic to HeLa cells and the Dox-loaded micelles showed enhanced anticancer activity to free Dox.This biocompatible polymer micelle provided a promising vehicle for the controlled release of anticancer drug.In Chapter 6,a blending strategy was used to construct the multiple responsive polymer micelles simply by mixing two functional polymers.One of the polymers(PEG-b-PNIPAM-co-HEMA-BEA-co-IM)had benzene ring structure and displayed thermo-and pH responsive behavior.Another polymer(PEG-b-PNIPAM-co-PyMA)showed thermo-and photo-responses.The double responses of the single micelles and the triplet responses of the heterogenous micelles were evaluated.The drug delivery of the single and heterogenous micelles were assayed.In Chapter 7,we had designed and synthesized a series of multifunctional polymers.BrijS100 terminal hydroxyl groups were functionalized to obtain three functional macromolecules with fluorophores,targeting groups and DTPA with chelated gadolinium for MRI imaging.A pH-sensitive,side-chain modified DTPA macromolecular acid-enhanced contrast agent had been designed,Meanwhile,a pH-sensitive enzyme-crosslinked polymer,pH-sensitive oxidative cross-linked and ionically cross-linked polymer and pH-sensitive reduction-induced cross-linked polymer had been synthesized.Through the corresponding combination of different polymers,we can obtain a series of fluorescence,targeting,MRI imaging,cross-linking,sensitive and stable polymer nanoparticles.Further experiments are needed to verify the polymer properties we designed.