Study On Dual-targeting To Cancer Cells And M2 Macrophages Of Albumin Nanoparticulate System For Drug-resistant Colon Cancer Therapy

Multidrug resistance(MDR)is one of the major bottlenecks to cancer chemotherapy.Multidrug resistance(MDR)is an issue that is not only related to cancer cells but also associated with the tumor microenvironments.MDR involves the complicated cancer cellular events and the crosstalk between cancer cells and their surroundings.Ideally,an effective system should take action on both cancer cells and tumor microenvironments for overcoming MDR tumor and thus achieve the improved therapeutic effect.A nanoparticulate codelivery system was developed for targeting the tumor overexpressed nutrient transporters(SPARC and GLUT-1)for MDR cancer therapy.Combination therapy is an important method to overcoming MDR.In this studies the combination of disulfiram/copper complex(DSF/Cu)and regorafenib(Rego)was found to be able to effectively inhibit the growth of MDR tumors.Interestingly,the HCT8/ADR cells was found with mannose receptor(MR)overexpression.Therefore,the mannosylated albumin nanoparticles(Man-BSA NPs)co-loaded with DSF/Cu and Rego were prepared using the NaBH4-H2NCONH2 reduction and denaturation method developed by our lab.The biomimetic codelivery system of Man-BSA NPs can target the tumor via albumin transport receptors(termed albumin-binding proteins,e.g.,SPARC)and mannose receptor(MR).In the studies the ability of intracellular uptake and tumor penetration(e.g.,in vitro tumor spheroid infiltration,and in vivo diffusion in tumor tissue)was examined.The antitumor mechanisms were investigated,and the in vivo pharmacodynamics study was conducted on the HCT8/ADR subcutaneous xenografts mice.The Man-BSA NPs about 140 nm were prepared,displaying efficient intracellular uptake by the HCT8/ADR cells and enhanced cytotoxicity.The Man-BSA NP could accumulate in the tumor by EPR effect.Moreover,the active targeting to the SPARC and MR receptors that were highly expressed by drug-resistant colorectal cancer was the important mechanism for tumor delivery ofthe nanoparticles.The results revealed that th Man-BSA NP penetrated deep into the tumor,thereby exhibiting improved antitumor activity.The therapeutic mechanisms were associated with the increased level of intracellular ROS,enhanced apoptosis and autophagy,and antiangiogenesis.In addition,it was found that the pro-tumor phenotype M2 macrophages also overexpressed both SPARC and MR.Therefore,it provided a useful pathway to target M2 macrophages in the tumor microenvironments.The results showed that the Man-BSA NP could target M2 macrophages via the pathway of SPARC and MR,and the co-loaded drugs Rego and DSF/Cu “re-educated” the M2 macrophages in TME,inhibiting the M2 polaration.This indicated that the nanoparticles had the function of regulating the tumor microenvironments.Therefore,the mannosylated albumin nanoparticles can simultaneously target the colon cancer cells and M2 macrophages with expression of SPARC and MR receptors.the therapeutic mechanisms were associated with increased level of ROS in tumor cells,enhanced apoptosis and autophagy,antiangiogenesis,and tumor microenvironment regulation.Moreover,the nanoparticles were biocompatible with reduced side effects.The studies revealed the potential application of dual-targeting strategies for drug delivery via SPARC and MR,with dual action on both MDR colon cancer cells and M2 macrophages.It thereby provideed a novel way to overcome MDR tumor.