Stimui-responsive Multifuncitonal Gene And Drug Delivery Systems For Cancer Therapy

Part 1. A modular design rationale of integrating multi-function via host-guest interaction toward cell-targeting multifunctional cationic gene delivery systemObjective:Develop a modular approach for fabricating multi-functional gene delivery system using the building blocks with pre-built-in functions.Methods:We have generated a multi-functional gene carrier system. By atom transfer radical polymerization (ATRP), the host module has been synthesized to be the reducible brush-shaped PDMAEMA derivatives (PCD-SS-PDMAEMA), which contain poly(?-cyclodextrin) as the backbone and disulfide-linked PDMAEMA as the arms. The host PCD-SS-PDMAEMA and the guest Ad-PEG-FA are self-assembled to be a supramolecular pseudo-copolymer (PCD-SS-PDMAEMA/Ad-PEG-FA).Results:The host PCD-SS-PDMAEMA and the guest Ad-PEG-FA could be self-assembled to be a supramolecular pseudo-copolymer (PCD-SS-PDMAEMA/Ad-PEG-FA), which binds DNA/RNA forming a nano-sized polyplexes. The comprehensive physical, chemical and biomedical characterizations demonstrate that this gene carrier system possesses high gene condensation capability, reducible sensitivity, low cytotoxicity, specific cellular uptake and high transfection efficacy.Conclusion:This supramolecular modular approach might be a promising way of customizing a versatile gene delivery system for biomedical applications.Part 2. Combined Chemo-photothermal therapy to Overcome Drug Resistance in Cancer by a Novel Au-dispersed and Hyaluronic acid-coated Hollow Carbon NanosphereObjective:Combine the high NIR-thermal conversion efficiency of gold and advantages of hollow carbon nanospheres, forming a nanomedicine that combines PTT, PDT and chemotherapy for the treatment of drug resistant cancers.Methods:We choose poly-dopamine (PDA) as a carbon precursor, which is possible for in situ deposition of metallic nanoparticles to fabricated N-doped hollow carbon nanospheres with highly dispersed Au nanoparticles on the surface (AuC nanospheres). DOX was absorbed by the AuC nanocarrier and the DOX@AuC nanospheres were further functionalized with dopamine modified hyaluronic acid (HA) to acquire enhanced solubility and stability in physiological environments and tumor cell targeting ability.Results:In vitro results confirmed the CD44 targeting ability, multi-sensitive drug release behavior of DOX@AuC@HA, the uptake and release of DOX could be greatly promoted and accelerated in DOX-resistant MCF-7/ADR cells. We had measured the changes of cellular ROS level in MCF-7/ADR cells after treated with AuC@HA and NIR and observed a significant inhibition of drug resistance. In vivo experiments were also performed, The DOX@AuC@HA nanospheres showed excellent anti-tumor efficiency in the combination of PTT, PDT and chemotherapy, as well as satisfactory in vivo biocompatibility.Conclusion:This multifunctional nanomedicine might be a promising way of overcome drug resisitance cancers.