Enzyme-responsive nano-drug delivery system for combined antitumor therapy.

Efficient drug loading, tumor targeting, intratumoral penetration, and cellular uptake are the main factors affecting the effectiveness of drug delivery systems in oncotherapy. Based on the tumor microenvironment, we proposed to develop Curcumin (Cur)-loaded matrix metalloproteinase (MMP)-responsive nanoparticles (Cur-P-NPs) by static electricity, to enhance tumor targeting, cellular uptake, and drug loading efficiency. These nanoparticles combine the properties of both PEG-peptides (cleaved peptide + penetrating peptide) and star-shaped polyester (DPE-PCL) nanoparticles. Cur-P-NPs displayed good entrapment efficiency, drug loading and biocompatibility. Additionally, they showed an enhanced release rate, cellular uptake, and anti-proliferative activity by activating peptides under the simulated tumor microenvironment. Furthermore, intraperitoneal injection of losartan (LST) successfully enhanced intratumoral drug penetration by collagen I degradation. In vivo studies based on the systematic administration of the synergistic LST + Cur-P-NPs combination to mice confirmed that combined antitumor therapy with LST and Cur-P-NPs could further improve intratumor distribution, enhance anticancer efficacy, and reduce the toxicity and side effects. Therefore, LST + Cur-P-NPs represent a new and efficient system for clinical oncotherapy.