Carrier-free nanodrugs with efficient drug delivery and release for cancer therapy: From intrinsic physicochemical properties to external modification.

Carrier-free nanodrugs with efficient drug delivery and release for cancer therapy: From intrinsic physicochemical properties to external modification

Blocking energy metabolism of cancer cells and simultaneously stimulating the immune system to perform immune attack are significant for cancer treatment. However, how to potently deliver different drugs with these functions remains a challenge. Herein, we synthesized a nanoprodrug formed by a F127-coated drug dimer to inhibit glycolysis of cancer cells and alleviate the immunosuppressive microenvironment. The dimer was delicately constructed to connect lonidamine (LND) and NLG919 by a disulfide bond which can be cleaved by excess GSH to release two drugs. LND can decrease the expression of hexokinase II and destroy mitochondria to restrain glycolysis for energy supply. NLG919 can reduce the accumulation of kynurenine and the number of regulatory T cells, thus alleviating the immunosuppressive microenvironment. Notably, the consumption of GSH by disulfide bond increased the intracellular oxidative stress and triggered immunogenic cell death of cancer cells. This strategy can offer more possibilities to explore dimeric prodrugs for synergistic cancer therapy.

GSH-Responsive Nanoprodrug to Inhibit Glycolysis and Alleviate Immunosuppression for Cancer Therapy.

Smart transformable nanomedicines for cancer therapy.

The ability of nanomotors to promote the deep penetration of themselves and the loaded drugs in diseased tissues has been proposed and confirmed. However, whether such motion behavior of the nanomotors can also promote deep penetration of micrometer-sized immune cells in the diseased microenvironment, which is important for the immunotherapy of some diseases, has not been mentioned. Herein, we construct a nitric oxide (NO)-driven nanomotor that can move in the tumor microenvironment, focusing on its motion behavior and the role of NO, the beneficial product released during movement from this kind of nanomotor, in regulating the infiltration behavior and activity of immune cells. It can be found that the drug-loaded nanomotors with both NO-releasing ability and motility can promote the normalization of the tumor vasculature system and the degradation of the intrinsic extracellular matrix (ECM), which can significantly improve the tumor infiltration ability of T cells in vivo. The efficiency of T-cell infiltration in tumor tissue in vivo increased from 2.1 to 28.2%. Both subcutaneous and intraperitoneal implantation tumor models can validate the excellent antitumor effect of drug-loaded NO-driven nanomotors. This combination of motility of the power source from nanomotors and their physiological function offers a design idea for therapeutic agents for the future immunotherapy of many diseases.

Deep Penetration of Nanolevel Drugs and Micrometer-Level T Cells Promoted by Nanomotors for Cancer Immunochemotherapy.

Nanoparticle-based drug delivery faces challenges from the imprecise targeted delivery and the low bioavailability of drugs due to complex biological barriers. Here, we designed cascade-targeting, dual drug-loaded, core-shell nanoparticles (DLTPT) consisting of CD44-targeting hyaluronic acid shells decorated with doxorubicin (HA-DOX) and mitochondria-targeting triphenylphosphonium derivative nanoparticle cores loaded with lonidamine (LND) dimers (LTPT). DLTPT displayed prolonged blood circulation time and efficiently accumulated at the tumor site due to the tumor-homing effect and negatively charged hyaluronic acid. Subsequently, the HA-DOX shell was degraded by extracellular hyaluronidase, resulting in decreased particle size and negative-to-positive charge reversal, which would increase tumor penetration and internalization. The degradation of HA-DOX further accelerated the release of DOX and exposed the positively charged LTPT core for rapid endosomal escape and mitochondria-targeted delivery of LND. Notably, when DLTPT was used in combination with anti-PD-L1, the tumor growth was inhibited, which induced immune response against tumor metastasis.

Lei Lei

Papers

A combinational chemo-immune therapy using an enzyme-sensitive nanoplatform for dual-drug delivery to specific sites by cascade targeting.