Study On The Preparation Of Stimulus Responsive Polymeric Assemblies And Their Application In Drug Delivery

Nanoparticles have particular advantages on deliverying cargoes to tumor. In recent years, using nanoparticles as delivery vehicles are hot research topics in the field of cancer therapy, because they can overcome a serious of biological barriers in vivo, improve drug distribution and reduce side effect. However, the accumulation of nanoparticles in tumor through enhanced permeability and retention (EPR) effect cannot fully meet the requirement of imaging sensitivity and specificity for cancer diagnose and therapy. Preparation of smart assemblies using stimulus sensitive polymers is an important target strategy for delivering anti-cancer drugs. They offer a powerful means for releasing drugs at the tumor sites as the pre-design, resulting in improvement of the theraputic efficacy. Several kinds of stimuli, including pH, redox, temperature, enzyme and light, have been exploited in the design of smart drug delivery systems. Such naoparticles are stable during blood circulation; however, the changes in chemical or physical properties of nanoparticles occur in response to single or multiple stimuli, resulting in that the nanoparticles release the drugs after being internalized. The integration of responsive modules adaptable to microenvironmental stimuli associated with tumor tissues and cells into polymeric assemblies can enhance target efficiency, promote cellular uptake, spontaneously and precisely trigger and optimize drug release at the target disease site, and regulate the intracellular fates of delivered drugs. As a result, the theraputic response is improved and side effects are reduced by the smart drug delivery systems. In this dissertation, we designed a serious of stimulus responsive polymeric assemblies utilizing different kinds of intermolecular interactions. Their formation mechanism, response properties, as well as their drug delivery behaviors in vitro/vivo were investigated in detail. The main contents are described as below:(1) Thermal sensitive hydroxypropyl cellulose-poly(acrylicacid)(HPC-PAA) vesicles, which structure is different from block copolymer vesicles, were self-assembled by the polymerization of AA in the solution of HPC through the hydrogen bond interacions between HPC and PAA. The detailed structure, mophorlogy, permeability and membrane mobility of HPC-PAA vesicles were characterized.(2) The invetigation of formation mechanism showed that HPC-PAA vesicles were spontaneously assembled through a nucleation and growth Pathway. The process includes three stages:nucleation satege, coalescence stage, and re-self-assembly stage. The experimental observation demonstrated that the previous theoretical simulation could also be applied to the vesilces self-assembled from irregular macromolecular amphiphilies. Furthermore, the intermediate states of vesicle formation process were captured by simply controlling the solution temperature.(3) A methacrylated strategy was used to functionalize carboxymethyl cellulose and prepare pH and redox dual-sensitive cellulose nangels by copolymerization with cystamine bisacrylamide (CBA) which contained disulfide bonds. The antitumor effect of DOX loaded nanogels was also evaluated in vitro/vivo. When used to load DOX, a high drug loading content and encapsulation efficiency were achieved. These nanogels were stable during blood circulation but de-integrated in the acidic organelle and cellular reducing environments, resulting in a fast release of encapsulated DOX.(4) PHEMALA-b-PVP diblock copolymer was synthesised by controlled free radical polymerization (ATRP and RAFT) and click chemistry. Redox sensitive PHEMALA-b-PVP micelles were prepared by nano-precipitation method and their hydrophobic inner cores were cross-linked through intermolecular disulfide bonds. The micelles showed a good passive targeting capability to accumulate in tumor region through EPR effect. On another hand, the micelles can not only leak out of tumor vessel and penetrate in interstitial, but also be internalized by cancer cells effectively. Our results deminstrated that the PHEMALA-b-PVP micelles can overcome the biological barriers when severed as a drug delivery vehicles.