Platinum(IV)-Backboned Polymer Prodrug-Functionalized Manganese Oxide Nanoparticles for Enhanced Lung Cancer Chemoimmunotherapy

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The stimulator of interferon genes (STING) pathway shows great potential in reshaping the immunosuppressive tumor microenvironment and initiating anti-tumor immunity. However, effectively activating STING while avoiding toxic side effects from systemic administration remains challenging.

On January 7, 2025, a communication from Li Weimin’s team at Sichuan University was published online in ACS Nano titled “Platinum(IV)-Backboned Polymer Prodrug-Functionalized Manganese Oxide Nanoparticles for Enhanced Lung Cancer Chemoimmunotherapy via Amplifying Stimulator of Interferon Genes Activation” The study developed pH/redox dual-responsive platinum (IV) backbone polymer prodrug-coated manganese oxide nanoparticles (DHP/MnO₂NP), which can precisely release cisplatin and Mn²⁺ to synergistically amplify STING activation.

In in vitro experiments, the authors demonstrated that DHP/MnO₂NP effectively induced DNA damage in tumor cells and penetrated the cytoplasm, synergistically promoting STING activation and upregulating the expression of pro-inflammatory cytokines in conjunction with Mn²⁺. Furthermore, DHP/MnO₂NP can selectively release cisplatin and Mn²⁺ to mediate tumor killing while reducing toxicity to normal cells. In vivo studies showed that DHP/MnO₂NP enhances therapeutic efficacy by activating STING and initiating robust anti-tumor immunity. Specifically, DHP/MnO₂NP skewed tumor-associated macrophages towards a pro-inflammatory phenotype, with pro-inflammatory cytokine expression in tumors upregulated by as much as 99 times compared to the control group, and significant increases in CD8⁺ T cell infiltration. When STING signaling was blocked, the anti-tumor effects and immune-stimulating effects of DHP/MnO₂NP were significantly inhibited. Additionally, DHP/MnO₂NP has advantages in enhancing tumor homing and retention, resulting in stronger and more durable anti-cancer effects. Overall, DHP/MnO₂NP provides a platform for enhancing cancer chemo/immunotherapy and holds promise for achieving precision treatment.

Platinum(IV)-Backboned Polymer Prodrug-Functionalized Manganese Oxide Nanoparticles for Enhanced Lung Cancer Chemoimmunotherapy

Immunotherapy shows great promise in treating lung cancer, especially for advanced patients. The clinical application of immune checkpoint inhibitors has increased the 5-year survival rate of patients with advanced non-small cell lung cancer from 5% to 30%. However, due to the immunosuppressive tumor microenvironment, immunotherapy is only effective for about 20% of patients. Research indicates that the stimulator of interferon genes (STING) has emerged as a potential target for reshaping the tumor immune microenvironment. STING is a cytosolic pattern recognition receptor that acts as an immune sensor for cytosolic DNA. Damage-associated DNA in the cytoplasm is first recognized by cyclic GMP-AMP synthase (cGAS), which then catalyzes the production of 2′,3′-cyclic GMP-AMP (cGAMP). cGAMP, as a second messenger, binds to STING and induces the transcriptional activation of interferon regulatory factor 3 (IRF3) and nuclear factor-κB (NF-κB), ultimately leading to the production of type I interferons and other pro-inflammatory cytokines, thereby initiating effective anti-tumor immunity. Based on this, STING agonists like cyclic dinucleotides (CDN) have been developed to induce anti-tumor immune responses across various types of cancer. Preclinical studies have shown that STING agonists have great potential in tumor therapy. However, due to the drawbacks of STING agonists such as membrane impermeability and metabolic instability, their limited immune-stimulating efficacy and adverse toxicity affect clinical application. Therefore, there is an urgent need to design more effective STING agonists and delivery strategies.

It is known that chemotherapeutic drugs like cisplatin induce tumor cell death by triggering DNA damage, where damage-associated DNA fragments can leak into the cytoplasm and activate the cGAS-STING signaling pathway. Meanwhile, Mn²⁺ plays an amplifying role in cGAS-STING activation induced by cytoplasmic DNA. Specifically, Mn²⁺ can directly bind to cGAS to enhance its enzymatic activity and sensitivity to cytoplasmic DNA, allowing cGAS to catalyze the production of cGAMP even in the presence of low concentrations of DNA. Based on this, the authors hypothesized that the combination of DNA-damaging chemotherapeutic drugs and Mn²⁺ could synergistically improve anti-tumor efficacy by amplifying STING activation, achieving a chemo-immunotherapy synergistic effect. However, these chemotherapeutic drugs and Mn²⁺ have the following drawbacks: (1) short half-lives leading to poor intratumoral accumulation and low bioavailability; (2) non-specific uptake causing systemic toxicity; (3) limited spatiotemporal synergistic effects due to their pharmacokinetic differences. A delivery strategy that can simultaneously increase the accumulation of chemotherapeutic drugs and Mn²⁺ at the tumor site while reducing systemic toxicity is needed.

Figure 1 Schematic of pH/redox dual-responsive DHP/MnO₂NP enhancing cancer chemoimmunotherapy (Adapted from ACS Nano)

Compared to physiological environments (pH ∼ 7.4), the tumor extracellular environment (pH ∼ 6.5) and intracellular endosomes and lysosomes (pH 4-6) are more acidic, with significantly higher concentrations of glutathione (GSH) in the tumor extracellular environment (∼1mM) and cytoplasm (∼10mM) compared to the glutathione (GSH) concentration in physiological environments (∼0.1mM). Therefore, tumor extracellular and intracellular responsive nanomedicines have become potential platforms for combination therapy due to their advantages in improving tumor accumulation, achieving synchronous delivery, and avoiding systemic toxicity. This study developed a novel pH/redox dual-responsive platinum (IV) backbone prodrug-coated manganese oxide (MnO₂) nanoparticles (DHP/MnO₂NP) to achieve the combination of cisplatin and Mn²⁺.

DHP/MnO₂NP can precisely release cisplatin and Mn²⁺ in the tumor microenvironment, synergistically amplifying STING activation and enhancing the effects of tumor chemoimmunotherapy. A one-pot method was used to polymerize and weakly alkaline hydrolyze to synthesize the carboxylated platinum (IV) backbone polymer prodrug P(DHP-PEG). Subsequently, using P(DHP-PEG) as a coating, manganese dioxide nanoparticles were prepared under weakly alkaline conditions. The pH/redox dual-responsive DHP/MnO₂NP has the following advantages that can enhance its anti-cancer efficacy while reducing systemic toxicity: (1) Increased drug accumulation in the tumor due to enhanced permeability and retention (EPR) effect. (2) Surface PEGylation can reduce non-specific uptake by the reticuloendothelial system, achieving prolonged circulation in the blood, further enhancing the tumor EPR effect and reducing drug accumulation in normal organs, thus lowering toxicity. (3) Tumor microenvironment (pH ∼ 6.5, ∼1mM GSH) responsive de-PEGylation and surface charge transition from negative to positive can enhance tumor cell uptake of DHP/MnO₂NP.

References:

https://pubs.acs.org/doi/10.1021/acsnano.4c15115

Platinum(IV)-Backboned Polymer Prodrug-Functionalized Manganese Oxide Nanoparticles for Enhanced Lung Cancer Chemoimmunotherapy

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