Preparation And Structure-performance Relationship Of PH-Sensitive Polymers And Their Self-Assembled Micelle Drug Delivery System

Nanoscopic core-shell pH-responsive micelles, self-assembled from amphiphiliccopolymers, demonstrate a series of attractive properties such as can improve thebioavailability of poorly water soluble drugs, facilitate surface functionalization and realizethe target delivery of anticancer drugs, and has been one of the most prospective drug deliverysystems (DDS). However, polymeric micelles are still faced with some of great challenges,such as how to maintain high drug entrapment, decrease the burst release effectively, controlthe site-specific drug release responding to the pH change, etc. The polymeric micelles arevery complex as a multiphase and polydispersity drug delivery system and their drug deliveryperformances are not only determined by the properties of polymer materials, but also closelyrelated to the micro-structure and compatibility of carriers and drugs. By combination ofexperiment, molecular/mesoscale simulation and theoretical analysis, multi-scale research onthe relationships of molecular microstructure, micellar mesostructure and macroscopic releaseperformance was implemented in the current work.According to the properties of hydrophobic drugs and the pH gradients between stomachand intestine after oral administration, three pH-responsive amphiphilic copolymer brusheswere designed using poly (methacrylic acid)(PMAA) as the pH responsive block,poly(polylactide)(PLA) or poly(methyl methacrylate)(PMMA) as the hydrophobic block andpoly(poly-(ethylene glycol) methyl ether monomethacrylate)(PPEGMA) as hydrophilic block.â‘ PLA-b-PMAA-b-PPEGMA: PLA, PMAA and PPEGMA were designed as a triblockstructure. After PLA-b-PMAA-b-PPEGMA self-assembled to micelle, the PMAA layerdistributed on the surface of the PLA core, maintained the micellar structure stable in thestomach and promoted drug release in the intestinal pH.â‘¡P(MMA-co-MAA)-b-PPEGMA:The hydrophobic PMMA and pH-sensitive MAA were designed to be a random copolymerstructure which could spread the pH-sensitive area of micelles and make the core moresensitive to the pH change of the environment, and provide a fast drug release rate in theintestinal tract.â‘¢P(PLAMA-co-MAA)-b-PPEGMA: The graft copolymerized hydrophobicPLA and MAA was designed to be a random copolymer structure, then formed a diblockcoplymer brush with PPEGMA. The graft PLA chain could spread the pH sensitive area ofmicelles, diminish the burst release behavior on the premise of maintaining high drug loadingcontent and control the drug release rate and efficiency by tuning the content of MAA in thebrush. The copolymer brushes were synthesized using one or the combination of atom transferradical polymerization (ATRP), activators regenerated by electron transfer atom transfer radical polymerization (ARGET ATRP) and ring opening polymerization (ROP). Themolecular structures and characteristics of the polymers were confirmed by1H NMR, FT-IR,and GPC. The pH-responsive self-assembly behavior of the copolymers in aqueous solutionand the pH-dependent drug release process were investigated by dynamic light scattering(DLS), transmission electron microscopy (TEM) and scanning electron microscopy (SEM).By a combination of mesoscopic simulation, the mechanism of drug release wasinvestigated using mathematical modeling. The qualitative rule and model between themolecular microstructure (block/random/graft, block number and length), micellarmesostructure (size, morphology, zeta potential, pH-responsivity) and macroscopic releaseperformance (burst release, stability in stomach, release rate and mechanism in intestinal tract)were explored in the current work.Dissipative particle dynamics (DPD) and mesoscopic dynamics (MesoDyn) wereperformed to study the aggregation mechanism and microstructure of the pH-sensitivemicelles. The effects of the compositions and topological structure of the polymers, the blocklength of PMAA, the polymer and drug proportion, pH value on the micellar structure anddrug release performance were investigated. A multi-scale understanding of polymermolecular microstructure, micellar mesostructure, and macroscopic drug-loading and releaseperformance can be achieved.According to the pH difference between the normal tissues and the tumorous tissues, thenovel amphiphilic multiarm star triblock pH-sensitive copolymers based onpoly(-caprolactone)(PCL), poly(diethylamino)ethyl methacrylate (PDEAEMA) andPPEGMA were designed and synthesized by a combination of ROP and continuous ARGETATRP for controlled anticancer drug delivery. Doxorubicin (DOX) was used as a model drugand encapsulated into the star copolymers self-assembled three-layer micelles. ThepH-responsive PDEAEMA layer is hydrophobic and collapses on the core at the physiologicalpH (7.4), which can prevent the premature burst drug release, but it became highly positivelycharged by protonation of the pendant tertiary amine groups and led the micelles to beendocytosed by tumor cells. Once internalized and transferred to a lysosome, the furthercharged PDEAEMA leads to faster release of the entrapped drug into the cytoplasm andnucleus. The influences of the PCL and PDEAEMA contents,4-or6-arm topologicalstructures on the micellar physicochemical properties, release performance, as well as thefinal anticancer activity were explored in depth.In the current work, experimental research, computer simulation, and theoretical analysiswere employed to investigate the relationship between the molecular microstructure, micellar mesostructure and macroscopic release performance of pH-responsive micellar DDS. Bydesigning polymeric molecular structure and micellar structure and exploring the general ruleaccording to the target demand, the present work provided some guidelines to thedevelopment of novel functional carrier materials, and established the theoretical andtechnological foundation of the development and clinical application of novel drug deliverysystem.