Nanocarrier Co-delivery Drugs For Tumor Therapy

Tumor is one of the major diseases that threaten human health in the world.At present,the monotherapy of tumors has its limitation while achieving the therapeutic effect.Compared with monotherapy,combination therapy can achieve better treatment effect by combining different drugs and different treatment mechanisms.Nanoparticles can effectively deliver two or more drugs to tumor tissue due to their advantages.They can overcome the strong hydrophobicity of small molecules and poor stability of si RNA drugs and improve the bioavailability of drugs to achieve synergistic antitumor effect.In this paper,we made use of nanoparticles to deliver two different drugs for enhancing antitumor effects.The main content of this paper can be divided into the following two parts:Pancreatic ductal adenocarcinoma?PDAC?has a dense extracellular matrix?ECM?surrounding tumor cells to sequester CD8⁺T cell infiltration and prevent drug penetration.Concomitant inhibition of both TGF-?pathway and the PD-1/PD-L1 checkpoint is a viable strategy to increase T cell infiltration and cytotoxicity.Here,we differentially delivered TGF-?receptor inhibitors?LY2157299?to pancreatic stellate cells?PSCs?in the stroma and si RNA targeting PD-L1?si PD-L1?to tumor cells with a stimuli-responsive clustered nanoparticle(^LYi Cluster_{si PD-L1}).LY2157299 encapsulated in the hydrophobic core of i Cluster can be taken up by PSCs and effectively inhibit the activation of PSCs,resulting in a reduction in type I collagen.si PD-L1 adsorbed on the surface of i Cluster was released with poly?amidoamine??PAMAM?in the acidic tumor extracellular p H?p H_e?and penetrated into the tumors to silence PD-L1 gene expression in tumor cells.Compared to monotherapy,^LYi Cluster_{si PD-L1}significantly increased tumor infiltrating CD8⁺T cells and provoked antitumor immunity to enhance antitumor effect.Simultaneous inhibition of poly ADP-ribose polymerase?PARP?and bromodomain protein 4?BRD4?can inhibit tumor growth through a synergistic lethal effect.In this study,we made use of nanoparticles to deliver si RNA or small molecule inhibitors which targeting PARP and BRD4 to achieve a synergistic killing effect on killing tumor cells.We have confirmed the combination therapy of PARP inhibitor?PARPi?and BRD4 inhibitor?BRD4i?can synergistically kill different tumor cells.Although si RNA targeting PARP1 and BRD4 can knock down the expression of corresponding genes,they can not effectively achieve synergistic lethal effect.However,delivering si RNA targeting BRD4?si BRD4?through cationic lipid assisted nanoparticles?CLAN?,combined with PARPi can achieve synergistic effect on killing tumor cells.