Design And Preparation Of Star Polymeric Micelles Drug/Gene Delivery Systems

Star polymers have received significant attention and have been widely exploited in the prospective applications of drug/gene delivery,cancer imaging and molecular diagnosis owing to topological strtucture and unique physi-chemical characteristics.The star polymeric micelles delivery system is very complex as a multi-phase and multi-component drug/gene delivery system,which properties are not only determined by the micro-structures of polymer,but also closely related to the micro-and meso-structures of nanoplatforms and drugs/genes.Through the combination of experiment,theoretical analysis and dissipative particle dynamics?DPD?simulation,based on the key idea of “microscale-mesoscale-macroscale”,we designed and prepared star polymeric micelles drug/gene delivery systems with well-defined structures,pH-responsiveness,and good biocompatibility.Multi-scale research on the relationships of molecular microstructure,micellar mesostructure and macroscopic release performances along with the inherent structure and formation mechanism of micelles under micro-and mesoscales etc.were further investgated.According to the pH difference between the normal tissues and the tumor tissues,the novel pH-sensitive 6/4 miktoarm star polymers?PCL?₃?PDEAEMA-b-PPEGMA?₃ and?PCL?₂?PDEAEMA-b-PPEGMA?₂ were built and synthesized.Anticancer drug doxorubicin?DOX?was used as a model drug and wrapped into the micelles by dialysis method.Biocompatible PCL was designed as the hydrophobic micellar core and hosted anticancer drugs.PEGMA was designed as the hydrophilic shell to provide a compact sterically protective layer to maintain the stability of micelles during biological circulation.PDEAEMA was as the mesosphere layer to confer pH-sensitivity and control drug release from the micellar carrier.Many properties of the micelles,such as pH-responsiveness,particle size,zeta-potential,drug loading content,entrapment efficiency and in vitro release behavior etc.were measured by a variety of experimental techniques.DPD simulation was conducted to study the effects of the compositions of the polymers,the block length of PDEAEMA,and pH values on the?PCL?₂?PDEAEMA-b-PPEGMA?₂ micellar meso-structure and drug release performance.Both DOX-loaded?PCL?₃?PDEAEMA-b-PPEGMA?₃ and?PCL?₂?PDEAEMA-b-PPEGMA?₂ micelles were stable in the normal physiological environment,while releasing DOX rapidly under tumoral weakly acidic conditions owing to the protonation of the pH-responsive PDEAEMA block.Both cell viability and CLSM experiments demonstrated that the two DOX-loaded micelles exhibited good antitumor efficacy to HepG2 cells.Various nanoplatforms as integrated theranostic vehicles have provided comprehensive therapeutic approaches including lower toxicity and an enhanced therapeutic efficacy.21-Arm star like polymer ?-CD-?PCL-b-PAEMA-b-PPEGMA?₂₁ was first built and synthesized for dual encapsulation of DOX and CT contrast agent gold nanoparticles.The preparation and characterization of polymer,unimolecular micelles and gold nanoparticles as well as drug release performance etc.were then investigated.The unimolecular micelles displayed a core-mesosphere-shell three-layer structure with sizes around 10.5 nm.The PAEMA mesosphere with amine group had two function.On the one hand,it ensured the in situ preapreation of gold nanoparticles.On the other hand,it acted as pH-responsive block to accelerate drug accelerately release when in tumoral conditions due to the protonation.Both in vitro and in vivo experiment demonstrated that ?-CD-?PCL-b-PAEMA-b-PPEGMA?₂₁/Au/DOX exhibited similar antitumor activities to free DOX and owned effective CT imaging performance.Taking advantage of DPD simulation,the formation process of unimolecular micelles,the morphologies and distribution of gold nanoparticles and DOX were further explored,expecting to make a deeper understanding of structure-properties relationships for cancer theranostic application.Co-delivery of antigen-encoding plasmid DNA?pDNA?and immune-modulatory molecules has importance in advancing gene-based immunotherapy and vaccines.Star polymer nanocarriers ?-CD-?PCL-b-PAEMA-b-PPEGMA?₂₁ and ?-CD-?PCL-b-PAEMA?₂1were developed for co-delivery of pDNA and imiquimod?IMQ?,a poorly soluble small-molecule adjuvant,to dendritic cells.Bearing primary amines in its side chains,PAEMA is a chemically simple yet effective delivery vehicle for pDNA and released IMQ fastly in response to intracellular pH of the endo-lysosome.These star polymers were evaluated for their capacities of loading and releasing IMQ under physiological and endosomal pHs and for binding and condensing pDNA.Cytotoxicity and the impact of IMQ loading on gene transfection efficiency in dendritic cells were also determined.It was found that the binding ability and transfection efficiency were much greater in ?-CD-?PCL-b-PAEMA?₂1 micelles than in ?-CD-?PCL-b-PAEMA-b-PPEGMA?₂₁ micelles.Importantly,IMQ-loaded micelle/pDNA complexes displayed much enhanced transfection efficiency than IMQ-free complexes.Based on the above results,we further regulated chemical structure and hydrophobic/hydrophilic ratios of ?-cyclodextrin-core star polymer and prepared ?-CD-?PLA-b-PDMAEMA-b-PEtOxMA?₂1 to achieve higher efficiency of gene binding and transfection.Currently,experimental research,theoretical analysis,and DPD simulation were carried out and provided microscopic,mesoscopic and macroscopic insight into the exploration of structure-properties relationship between polymer microstructure,micellar mesostructure and macroscopic delivery performance of pH-responsive star polymeric micelles drug/gene delivery systems.The results were also useful for the development and optimization of polymer microstructure and micellar mesostructure,provided roadmap and technical base for versatile drug/gene delivery systems systematicallly.