D-α-Tocopherol Polyethylene 1000 Glycol Succinate-based Smart Nanodrugs For The Modification Of Tumor Microenvironment

Objectives: Improving therapeutic efficiency is one of the most important goals in clinical cancer treatment.This work developed two kinds of TPGS-based redox/pH-sensitive nanodrugs to realize self-promoted drug delivery and immunochemotherapy against cancer.Methods: Two kinds of nanodrugs were prepared via solvent-evaporation method.The sizes,zeta potentials,stabilities were measured through DLS.The in vitro drug release,cellular and in vivo drug co-delivery were investigated.The enhanced vascular permeability,blood perfusion,and biodistribution were studied in TSP-TN treated mice using DCE-MRI,ultrasound imaging,and IVIS;the modification of tumor immune microenvironment was studied in PTX@TPC@c-CS treated mice via flow cytometry,immunohistochemical staining,and ELISA.Several tumor-bearing mice models were established to evaluate the in vivo tumor growth/spread inhibition efficacy of TSP-TN and PTX@TPC@c-CS.Results: The sizes of TSP-TNs in different components were ranged from 94~162 nm,while the size of PTX@TPC@c-CS was around 80 nm.The zeta potentials of the nanodrugs were all negative.TSP-TN and PTX@TPC@c-CS were stable in FBS and exhibited redox/pH-triggered drug release properties in vitro.When TSP-TN was endocytosed by tumor cells,NO was released from the hybrid micelles and further diffused outside cells to realize the increased vascular permeability,improved blood perfusion,as well as enhanced tumor PTX distribution.As for PTX@TPC@c-CS,the nanoparticles(NPs)achieved charge conversion and further divided into positive charged PTX@TPC NPs and chitosan(CS).On the one hand,PTX@TPC NPs could realize enhanced cellular uptake,endo/lysosomal escape,and cytotoxicity.On the other hand,CS was capable of inducing neutrophils to tumor matrix,followed by various cytokine releases and activated CTL.These two kinds of nanodrug with good in vivo safety demonstrated excellent tumor growth/spread inhibition and great potential in the clinical transformation.Conclusions: TSP-TN and PTX@TPC@c-CS achieved redox/pH-sensitive drug release,and the released drug could further modify tumor microenvironment.The enhanced blood perfusion promoted the delivery efficacy of chemotherapeutic agents,and the activated immune response was combined with chemotherapy to receive ideal therapeutic efficiency.