Thermo/pH-sensitive Biodegradable Polymer Micelles For Drug Delivery

In recent years, thermo/pH-sensitive polymeric nano-micelles have been extensively investigated in the field of drug delivery systems (DDS). Polymeric micelles are self-assembled core-shell nanostructures formed in an aqueous solution consisting of amphiphilic polymers. The hydrophobic chains of the polymers form the core of the micelles which have a capacity to accommodate hydrophobic drugs, while the hydrophilic chains of the polymers form the shell of the micelles which stabilize the micellar structure and allow drug-loaded polymeric micelles prolonging circulation in the bloodstream. Chemical modification of polymer structure by introduction of aromatic groups has been demonstrated to effectively reduce the CMC and stabilize the encapsulation of hydrophobic drugs (obviously comprising aromatic groups), which were ascribed to aromatic rigidity and π-π interaction. The dialysis method as well as the solvent evaporation technique is commonly used for the preparation of drug loaded micelles. In most cases, toxic organic solvent was utilized in drug loading process, such as DMSO, CHCl3, and so on. The residue solvent could cause serious problem in vivo. To resolve these problems, in this study, a series of thermo/pH-responsive biodegradable polyaspartamide derivatives bearing aromatic structures were designed and synthesized. The polymeric micelles and drug-loaded micelles were prepared by a quick heating or pH-changing method, which can avoid using toxic organic solvent.In Chapter1, the progress of nano-drug carrier and applications of stimuli-responsive polymer in drug delivery systems were reviewed.In Chapter2, a series of biodegradable and thermosensitive polyaspartamide derivatives bearing pendant aromatic structures (phe-g-PHPA) are designed and synthesized via aminolysis of poly(succinimide) with5-aminopentanol and introduction of aromatic functionalities to the side chains. All the five phe-g-PHPA polymers are soluble in water at low temperature (4℃) and show thermosensitive behaviour. The thermoresponsive behaviour of the resulted phe-g-PHPA polymers can be tuned by adjusting the graft copolymer composition and partial removal of pendant aromatic moieties due to the hydrolytic degradation, which is very useful for controlled instability and controlled drug release. The nanoparticles self-assembled from the biodegradable phe-g-PHPA polymers by a quick heating process were not stable under the physiological condition and hydrophilic long PEG chain will be introduced for drug delivery application.In Chapter3, based on the biodegradable and thermosensitive polymer phe-g-PHPA described in chapter2, hydrophilic long PEG chains were conjugated to the phe-g-PHPA polymers to stabilize the nanoparticles and prevent nonspecific interactions in the blood circulation for drug delivery. The micelles based on thermosensitive and degradable amphiphilic polyaspartamide derivatives containing pendant aromatic structures (phe-g-PHPA-g-mPEG) were prepared by a quick heating method without using toxic organic solvent. Dynamic light scattering results show that the micelles are stable upon dilution under physiological conditions and the destabilization of the micelles is pH-dependent and the phe-g-PHPA-g-mPEG polymers are biodegradable. Paclictaxel (PTX) was loaded into the phe-g-PHPAs-g-mPEG micelles with encapsulation efficiency over90%, resulting in a high drug loading content (up to29%). PTX-loaded micelles had a mean size around70nm with narrow size distribution (PDI<0.1). The PTX-loaded micelles showed sustained drug release and obvious anti-cancer activity similar to Taxol (the commercial paclitaxel formulation) against HepG2cells, while blank micelles were non-toxic. The present results suggest that the thermosensitive and biodegradable phe-g-PHPA-g-mPEG micelles are a promising delivery system for the hydrophobic drugs.In Chapter4, based on the biodegradable and thermosensitive polymers phe-g-PHPA (chapter2) and phe-g-PHPA-mPEG (chapter3), the pH-sensitive groups (tertiary amino groups) were introduced to synthesize double-stimuli (pH/thermo) sensitive degradable copolymers phe/DEAE-g-PHPA-g-mPEG containing pendant aromatic structures. The micelles based on phe/DEAE-g-PHPA-g-mPEG polymer and the anticancer drug-loaded micelles were prepared by a quick pH-changing method without using toxic organic solvent. The obtained polymeric micelles, PTX-loaded micelles and DOX-loaded micelles were stable under physiological conditions. Both the PTX-loaded micelles and the DOX-loaded micelles showed much faster release at pH5than at pH7.4. The DOX-loaded micelles showed obvious and better anti-cancer activity against HepG2cells and HeLa cells than free DOX. Thus these non-toxic, dual thermo-and pH-sensitive and biodegradable phe/DEAE-g-PHPA-g-mPEG micelles may be a promising anti-cancer drug delivery system.In Chapter5, pH-sensitive and degradable polyaspartamide based amphiphilic polymers MNI/DEAE-g-PHPA-g-mPEG bearing2-methyl-5-nitroimidazole groups and ionizable tertiary amino groups were synthesized and investigated for anticancer drug PTX delivery. The micelles based on MNI/DEAE-g-PHPA-g-mPEG polymers and the PTX-loaded micelles were prepared by a quick pH-changing method without using toxic organic solvent. The obtained micelles were stable under physiological conditions. The drug loading content was very high (up to100%) with PTX loading efficiency over95%. The PTX-loaded micelles being stable showed sustained drug release behavior in pH7.4solution, but showed a quick release profile in pH5.0solution. The PTX-loaded micelles demonstrated comparable cytotoxic activity as PTX formulated with Cremophor EL/ethanol (Taxol) against HepG2cells. Thus these non-toxic, pH-sensitive and biodegradable MNI/DEAE-g-PHPA-g-mPEG micelles may be worth further investigation for anti-cancer drug delivery.