Temperature-responsive Nano Drug Delivery System Of Organic Conjugated Polymer For Photothermal-Chemo Synergistic Cancer Therapy

Photothermal-chemo therapy based on nano drug delivery systems can synergically enhance the therapeutic index via improving the accumulation of nanocarriers at tumor site,promoting the penetration of drugs in tumor tissue,triggering drug release at target site and enhancing drug cytotoxic effect.Due to the complex physiological environment,how do nano-carriers used in photothermal-chemo therapy overcome the multiple physiological and pathological barriers,deliver photothermal conversion agents and chemotherapeutic drugs to tumor tissues efficiently,and precisely regulate the drug release behavior at the target sites to achieve the best anti-tumor synergistic effect as well as reduce toxic side effects,are all important issues that urgently need to be resolved in photothermal-chemotherapy.In this paper,two kinds of temperature-responsive smart photothermal nanomaterials,based on organic conjugated nanomaterials with good biocompatibility,have been constructed for safe and efficient synergistic photothermal-chemo therapy.The main research contents and results are as follows:(1)A facile one-step method was firstly developed to fabricate in-situ forming hydrogel drug delivery platform(PPy@PNAs),in which temperature-sensitive triblock polymer polyacrylic acid-b-poly N-isopropylacrylamide-b-polyacrylic acid(PNA),was utilized as the stabilizing agent in the polymerization of pyrrole,and pyrrole monomer was adsorbed onto PNA by acid-base neutralization and self-assembled into pyrrolesolubilized PNA micelles.The strong interaction of ionic bonds together with ?–? stacking interactions resulted in high Dox-loading capacity and photothermal-controlled drug release behavior.D-PPy@PNAs in-situ forming hydrogels showed sensitive sol-gel phase transition behavior at body temperature.After single intratumoral injection,D-PPy@PNAs achieved precisely synergistic effect of photothermal-chemo therapy through NIR-PTT promoted intratumoral drug penetration,enhanced cellular uptake,fast drug release and the chemotherapeutic sensibilization of photothermal effect.Local delivery of drugs directly into the tumor sites,not relying on blood vessels,could significantly improve the targeting efficiency and achieved high synergistic effect of photothermal-chemo therapy.(2)NIR-PTT triggered ligand-presenting Dox@IR-z PEGr NPs were synthesized by applying azo molecule as NIR-PTT switchable active tumor-targeting thermolabile linker.PEGz-IR polymer was synthesized by coupling IR783 and long-chain polyethylene glycol at both ends of the azo molecule.The long-chain polymer,the short-chain polymer r PEG-IR,coupled with the c RGD targeting peptide,and Dox could self-assembled into Dox@IR-z PEGr nanoparticles through the strong interaction of ionic bonds together with?–? stacking interactions.After intravenous administration,Dox@IR-z PEGr nanoparticles showed efficient and long-term retention in tumor sites.The photothermal effects of IR783 under NIR irradiation led to the thermo-responsive cleavage of the azo linkers and the long-chain PEG segment.The previously hidden c RGD peptide was exposed on the surface of nanoparticles,which enhanced cellular uptake of nanoparticles by tumor cells and improved accumulation of Dox at the tumor site.The improved tumor delivery efficiency and enhanced tumor retention of Dox@IR-z PEGr nanoparticles resulted in significant synergistic photothermal-chemo therapeutic effect,which providing a new strategy to overcome the PEG dilemma.(3)Poly(phenyleneethynylene)conjugated macromolecule was used as initiator to synthesize poly(N-isopropylacrylamide)grafted polymer(p NE).p NE nanoparticles were prepared by solvent diffusion method through ?–? stacking interactions between p NE backbone chains,which could efficiently load Dox through ?-? stacking and hydrophobic interaction.Due to the significant fluorescence resonance energy transfer effect between p NE and Dox in the resultant Dox-p NE nanoparticles.The intracellular drug release behavior of Dox-p NE in tumor cells could be monitored in real time by detecting the fluorescence of p NE and Dox.Dox-p NE nanoparticles showed good tumor cell killing effect and could be promising novel self-indicating nano-carriers for monitoring drug intracellular release.In summary,in this paper we have developed injectable in-situ forming hydrogels of thermosensitive polypyrrole nanoplatforms which showed NIR-PTT triggered precise/controllable drug release for precisely synergistic photothermal-chemo therapy,and NIR-PTT triggered ligand-presenting nanoparticles for synergistic photothermalchemo therapy,which both could improve the therapeutic efficacy against tumors.