Modular Coassembly Approach To PH-Sensitive, High-targeting Nanoparticles And Injectable, Thermosensitive Nanoparticles Self-supported Hydrogels

People have been devoting plenty of time to studying ways for cancer therapy.Chemotherapy is the the most fundamental and common method.Traditional chemotherapy faces big challenges such as major side-effects and multidrug resistance caused by frequent dosing.In order to improve drug's efficiency and reduce side effects,a pH-sensitive targeting co-delivery nanoplatform CUR/DOX-h-PCEC@CRGDK nanoparticles(NPs)and multifunctional injectable thermosensitive in situ gel DOX-hPECT@CRGDK were designed in this article.CUR/DOX-h-PCEC@CRGDK NPs were co-assembled by three modules:(1)pHsensitive polymeric prodrug DOX-h-PCEC;(2)targeting polymer CRGDK-PEG-PCL;(3)curcumin(CUR),as a chemosensitizer to work with doxorubicin(DOX).Three modules could be co-assembled to form about 100 nm nanoparticles by different ratios.This nanoplatform were biocompatible and stable in long-circulation.Furthermore,the nanoparticles can be gathered at tumor tissue due to EPR effect.Once arriving at tumor tissues,the pH-sensitive and targeting functions may facilitate NPs entering into cells and releasing drugs.As shown in experiments,NPs could be stable in physiological conditions(pH=7.4)and realized pH-sensitive release in lower pH conditions.The treatment effect of double drug and targeting effect of CRGDK were demonstrated by cell experiments.This NPs could realize stable transport and efficient release at the same time.On the issues of delivery barrier in tumor tissue and intracellular site,cellpenetrating peptide(CPP)mediated thermosensitive nanoparticles self-supported hydrogel local drug delivery system was designed by the gelation ability of DOX-hPECT@CRGDK based on our previous work.Thermosensitive nanoparticles selfsupported hydrogel DOX-h-PECT@CRGDK could form in situ gel at body temperature(37?)and release NPs.Multifunctional DOX-h-PECT@CRGDK NPs can realize intracellular drug release and easily uptake.DOX-conjugated NPs hydrogel maintain its gelation ability by the component design.NPs were proved to release from gels and the drug release in gels was stable and persistent.With the study of cell uptake and cytotoxicity,NPs from hydrogels retain the modified abilities.The receptor-ligand interaction was obviously found between the NPs containing CRGDK and Nrp-1 overexpression cells so that it could promote celluar uptake.This novel drug delivery system combines three functions: hydrogel's located and continuous dosing,CPP mediated NPs' high-efficiency endocytosis and pH-sensitive drug release.It could not only avoid the complications of the blood circulatory system but also possess the ability to overcome the delivery barrier and multidrug resistance of tumor cells.