Multifunctional System with Camptothecin and [12]aneN3 Units for Effective In Vivo Anti Pancreatic Cancer through Synergistic Chemotherapy, Gene Therapy, and Photodynamic Therapy.

Abstract

Maximizing drug cargo carrying capacity in blood circulation, controlling the in vivo fate of nanoparticles, and precisely drug release to tumor targets are the main aims of multifunctional nanomedicine-based antitumor therapy. Here we combined macrocyclic polyamine di(triazole-[12]aneN3) (M) and chemical drug camptothecin (CPT, C) through photosensitizer 1,1-dicyano-2-phenyl-2-(4-diphenylamino) phenyl-ethylene (DT) containing the cleavable disulfide (S) linkage as an all-in-one theranostic nanoprodrug, MDTSC. The corresponding compound with carbon chain (C) linkage, MDTCC, was also prepared for a comparison study. MDTSC showed the ability to carry plasmids, including the p53 tumor suppressor gene, to form lipoplexes with a size of ∼150 nm. Further addition of DOPE-PEG2k resulted in the hybrid lipoplexes MDTSC/DOPE-PEG2k@DNA, which showed good stability in blood circulation and good biocompatibility to normal cell lines. Experiments demonstrated that the hybrid lipoplexes were able to realize the successful cellular uptake and endosomal escape, to generate ROS under visible light irradiation as well as to trigger the localized release of CPT and the plasmid encoding p53 in tumor cells. In vitro, the hybrid lipoplexes showed better EGFP expression than the commercial Lipo2000, and markedly reduced tumor cell proliferation and migration rate irrespective of whether the BxPC-3 cell lines were grown on plates or 3D tumor spheroids. In vivo, the hybrid lipoplexes showed effective anticancer activity by reducing the BxPC-3 pancreatic tumor growth by 99% through the synergetic combination of chemotherapy, photodynamic therapy, and gene therapy. This research represented the first example of using a cocktail of three therapeutic approaches to achieve cooperative and effective anti pancreatic cancer treatment in vivo and in vitro.