Nuclear-Targeting Lipid Pt^IV Prodrug Amphiphile Cooperates with siRNA for Enhanced Cancer Immunochemotherapy by Amplifying Pt-DNA Adducts and Reducing Phosphatidylserine Exposure

Abstract

Patients treated with Pt-based anticancer drugs (Pt II ) often experience severe side effects and are susceptible to cancer recurrence due to the limited bioavailability of Pt II and tumor-induced immunosuppression. The exposure of phosphatidylserine on the cell's outer surface induced by Pt II results in profound immunosuppression through the binding of phosphatidylserine to its receptors on immune cells. Here, we report a novel approach for enhanced cancer chemoimmunotherapy, where a novel nuclear-targeting lipid Pt IV prodrug amphiphile was used to deliver a small interfering RNA (siXkr8) to simultaneously amplify Pt-DNA adducts and reduce the level of exposure of phosphatidylserine. This drug delivery vehicle is engineered by integrating the Pt IV prodrug with self-assembly performance and siXkr8 into a lipid nanoparticle, which shows tumor accumulation, cancer cell nucleus targeting, and activatable in a reduced microenvironment. It is demonstrated that nucleartargeting lipid Pt IV prodrug increases the DNA cross-linking, resulting in increased Pt-DNA adduct formation. The synergistic effects of the Pt IV prodrug and siXkr8 contribute to the improvement of the tumor immune microenvironment. Consequently, the increased Pt-DNA adducts and immunogenicity effectively inhibit primary tumor growth and prevent tumor recurrence. These results underscore the potential of utilizing the nuclear-targeting lipid Pt IV prodrug amphiphile to enhance Pt-DNA adduct formation and employing siXkr8 to alleviate immunosuppression during chemotherapy.

Endowing Pt(IV) with Perfluorocarbon Chains and Human Serum Albumin Encapsulation for Highly Effective Antitumor Chemoimmunotherapy

“…A variety of previous studies have demonstrated that the subcellular localization of a compound inside cancer cells has a drastic effect on its biological effects, including its cytotoxicity, possible interactions with biomolecules, or cell death mechanism. As crucial factors to change the subcellular localization of a compound, researchers have reported on the extension with organelle-targeting moieties, the change of the overall charge or the increase/decrease of the lipophilicity of the compound. , Capitalizing on this, herein, the Pt­(II) anticancer drug cisplatin was modified through axial coordination with aliphatic hydrocarbons or perfluorocarbon carboxylic acids to form Pt­(IV) prodrugs. The axially hydrocarbon carboxylic acid-functionalized metal complexes are followingly referred to as C2–Pt­(IV) , C3–Pt­(IV) , as well as C4–Pt­(IV) and the perfluorocarbon carboxylic acid-functionalized metal complexes are referred to as C2F3–Pt­(IV) , C3F5–Pt­(IV) , as well as C4F7–Pt­(IV) based on the lengths of the extension of the carboxylic acid chain (Figure A).…”

Nanomedomics

“…Chemotherapy is an essential therapy for tumors that can inhibit various types of solid and nonsolid tumors. However, some chemotherapy drugs, such as platinum-based drugs, have defects such as low bioavailability and severe side effects. − To address these deficiencies, many nanomaterials have been utilized as carriers to load platinum drugs. − Despite this, there is still a lack of research on the mechanism of action of these nanomedicines, which adversely affects their further clinical translation. To solve this problem, Wang et al used RNA-seq and metabolomics to study the mechanism of nanobased platinum drugs.…”

A Trisulfide Bond Containing Biodegradable Polymer Delivering Pt(IV) Prodrugs to Deplete Glutathione and Donate H2S to Boost Chemotherapy and Antitumor Immunity

“…Pt­(IV) complexes, commonly exhibiting an octahedral structure, are characterized by their high chemical inertness that results in fewer side effects than Pt­(II) drugs by reducing unfavorable interactions with biomolecules . Upon cellular uptake, inert Pt­(IV) prodrugs can be reduced to highly active Pt­(II) and exhibit cytotoxicity. ,− In the field of cancer therapy, nanodrug delivery systems have garnered significant attention as they endow small-molecule drugs with tumor-targeting properties due to the enhanced permeability and retention (EPR) effect. ,− However, the effectiveness of the EPR effect heavily relies on tumor characteristics, necessitating the implementation of more sophisticated drug delivery strategies, such as reduction-responsive polymers, to improve tumor uptake. − Considering that the concentration of glutathione (GSH) in tumor cells is significantly higher than that in blood and normal cells, − the disulfide bond, which can offer on-demand drug release via fast cleavage in a reducing tumor environment, has been frequently employed in the creation of reduction-responsive polymers. , Recent investigations have revealed that the trisulfide bond, in comparison to the conventional disulfide bond, exhibits improved stability in the presence of low levels of GSH and a blood pool. However, it displays extreme susceptibility to excessive GSH in tumor cells, , thereby demonstrating greater selectivity.…”