Computer Simulations On The Drug Loading And Release Behaviors Of Stimuli-responsive Polymer Micelles

Different types of stimuli-responsive polymers have attracted great attention in the field of drug delivery and gene therapy due to their unique responsiveness.In this thesis,the applications of stimuli-responsive micelles in drug delivery and gene therapy were reviewed.Dissipative particle dynamics?DPD?simulation method was employed to explore the mechanism of drug loading and release from the molecular level,which can provide theoretical guidance for the optimal design of novel drug delivery systems?DDS?,and promote the development of their clinical applications.Firstly,the self-assembled dynamic behavior of zwitterionic polymer docosahexaenoic acid-b-poly??-benzyl-L-glutamate?-b-poly?carboxybetaine methacrylate??DHA-PBLG-PCB?in the aqueous solution and its loading/release mechanism for anti-cancer drug doxorubicin?DOX?were investigated.Simulation results reveal that the zwitterionic DHA-PBLG-PCB system can form a stable core-shell structure under specific polymer concentrations and drug contents.The zwitterionic system presents different morphologies under different polymer concentrations and drug contents.Compared with the traditional PEGylated system,the zwitterionic PCB-based system shows a better stability in vivo.Besides,the DHA-PBLG-PCB system has a pH-responsive feature,drug molecules can be slowly released under the acidic tumor environmet.Secondly,the zwitterionic prodrug system contains PEG-b-dendritic polylysine-CPT?PSB_n-TetraCPT?as the carrier,doxorubicin?DOX?and camptothecine?CPT?as model drugs,the structure-performance relationship and the drug release process of the drug-loaded system were investigated via computer simulations.Simulation results show that both PSB₂₀-TetraCPT and PEG₂₀-TetraCPT can form spherical micelles under a suitable concentration.If DOX continues to be loaded on the above prodrug system,the PSB₂₀-TetraCPT/DOX system has a stronger drug-loading capacity and a better stability.The unique pH-responsiveness of the co-delivery system facilitates the release and targeted therapy of CPT and DOX,aming to provide references for the construction and optimization of the co-delivery system.Finally,the fourth generation of the poly?amido amine??G4 PAMAM?dendrimer as the carrier and the co-delivery of methotrexate?MTX?and single stranded DNA?ssDNA?were explored in detail.Besides,effects of pH and salt concentration on the morphology of G4PAMAM/MTX/ssDNA complex were systematically investigated.Simulation results show that the PAMAM dendrimer has a good encapsulation and compression of MTX and ssDNA at the neutral pH.At low pH,MTX can be slowly released in the body;while ssDNA is also away from the surface of the PAMAM dendrimer.The stability of the G4PAMAM/MTX/ssDNA complex decreased significantly with the increase of salt concentration.This study can provide new ideas for the design and development of PAMAM dendrimer carriers.