Programmable prodrug micelle with size-shrinkage and charge-reversal for chemotherapy-improved IDO immunotherapy.

IDO blockade-based immunotherapy has been impeded by the activation of antitumor immune response and low delivery efficiency of immunotherapeutic, resulting from natural biological barriers and immune resistance. Herein, a programmable drug delivery nanosystem with enhanced tumor penetration and endocytosis is constructed for chemotherapy-enhanced immunotherapy by loading immune checkpoint IDO inhibitor NLG919 in pH/redox cascade-responsive prodrug micelle. The nanosystem shrinked micelles sizes and converted charge from negative to positive for enhanced tumor penetration and endocytosis in responding to the weakly acidic tumor microenvironment. The endocytosed nanosystem dramatically disassembled and released curcumin and NLG919 in redox-rich cytoplasm. In vitro and in vivo studies demonstrate that the nanosystem not only effectively overcame biological barriers, but also significantly boosted antitumor immune response and reduced immune resistance. It was realized by the combined effects of chemotherapy-enhanced immunogenicity, and NLG919-induced IDO-blockade immunotherapy, consequently inhibiting tumor growth, metastasis and recurrence with high efficiency in vivo. The study offers a nanoplatform with deep tumor penetration, high cellular uptake and effective antitumor immune response for the advance of chemo-immunotherapy.

A pH/ROS Cascade-Responsive Charge-Reversal Nanosystem with Self-Amplified Drug Release for Synergistic Oxidation-Chemotherapy.

Poor cell uptake of drugs is one of the major challenges for anticancer therapy. Moreover, the inability to release adequate drug at tumor sites and inherent multidrug resistance (MDR) may further limit the therapeutic effect. Herein, a delivery nanosystem with a charge-reversal capability and self-amplifiable drug release pattern is constructed by encapsulating ß-lapachone in pH/ROS cascade-responsive polymeric prodrug micelle. The surface charge of this micellar system would be converted from negative to positive for enhanced tumor cell uptake in response to the weakly acidic tumor microenvironment. Subsequently, the cascade-responsive micellar system could be dissociated in a reactive oxygen species (ROS)-rich intracellular environment, resulting in cytoplasmic release of ß-lapachone and camptothecin (CPT). Furthermore, the released ß-lapachone is capable of producing ROS under the catalysis of nicotinamide adenine dinucleotide (NAD)(P)H:quinone oxidoreductase-1 (NQO1), which induces the self-amplifiable disassembly of the micelles and drug release to consume adenosine triphosphate (ATP) and downregulate P-glycoprotein (P-gp), eventually overcoming MDR. Moreover, the excessive ROS produced from ß-lapachone could synergize with CPT and further propagate tumor cell apoptosis. The studies in vitro and in vivo consistently demonstrate that the combination of the pH-responsive charge-reversal, upregulation of tumoral ROS level, and self-amplifying ROS-responsive drug release achieves potent antitumor efficacy via the synergistic oxidation-chemotherapy.