IL-23 inhibitor enhances the effects of PTEN DNA-loaded lipid nanoparticles for metastatic CRPC therapy

TL;DR

This study shows that combining PTEN DNA-loaded nanoparticles with an IL-23 inhibitor improves treatment for advanced prostate cancer by boosting immune response and reducing tumor spread.

Contribution

A novel combination therapy using PTEN DNA-loaded lipid nanoparticles and an IL-23 inhibitor is proposed for treating metastatic prostate cancer.

Findings

LNPs effectively delivered PTEN DNA to tumor sites, restoring PTEN function and enhancing therapeutic effects.

Combining LNP@PTEN with Apilimod significantly reduced tumor growth, metastasis, and improved survival in mice.

The treatment reversed immune suppression by reducing MDSCs and increasing CD8+/CD4+ T cell ratios.

Abstract

Introduction: Metastatic castration-resistant prostate cancer (mCRPC) patients face challenges due to limited treatment options. About 50% of patients with mCRPC have a functional loss of phosphatase and tensin homology deleted on chromosome 10 (PTEN), leading to tumor progression, metastasis, and immune suppression. Moreover, elevated IL-23 produced by myeloid-derived suppressor cells (MDSCs) is found in CRPC patients, driving tumor progression. Therefore, a combination strategy based on PTEN restoration and IL-23 inhibition may block CRPC progression and metastasis.

Methods: The antitumor effect of restoring PTEN expression combined with the IL-23 inhibitor Apilimod was studied in a mouse model of bone metastasis CRPC and mouse prostate cancer RM-1 cells. To verify the targeting ability of PTEN DNA coated with lipid nanoparticles (LNP@PTEN) in vitro and in vivo. In addition, RT-qPCR and flow cytometry were used to investigate the related mechanisms of the antitumor effect of LNP@PTEN combined with Apilimod.

Results: LNPs exhibited significant tumor-targeting and tumor accumulation capabilities both in vitro and in vivo, enhancing PTEN expression and therapeutic efficacy. Additionally, the combination of LNP@PTEN with the IL-23 inhibitor Apilimod demonstrated enhanced inhibition of tumor growth, invasion, and metastasis (particularly secondary organ metastasis) compared to other groups, and extended the survival of mice to 41 days, providing a degree of bone protection. These effects may be attributed to the PTEN function restoration combined with IL-23 inhibition, which help reverse immune suppression in the tumor microenvironment by reducing MDSCs recruitment and increasing the CD8+/CD4+ T cell ratio.

Discussion: In summary, these findings highlight the potential of LNPs for delivering gene therapeutic agents. And the combination of LNP@PTEN with Apilimod could achieve anti-tumor effects and improve tumor microenvironment. This combinational strategy opens new avenues for the treatment of mCRPC.

Cationic lipids, β-sitosterol, phospholipids and PEG-lipids self-assemble in aqueous solution to form cationic lipid nanoparticles (LNPs), which could encapsulate PTEN DNA through electrostatic adsorption to generate LNP@PTEN. This formulation could be delivered to prostate cancer bone metastatic sites. LNP@PTEN combined with the IL-23 inhibitor Apilimod showed enhanced anti-tumor effects by inhibiting tumor proliferation and metastasis, and reactivating anti-tumor immunity with good safety (Created with BioRender.com).

Cationic lipids, β-sitosterol, phospholipids and PEG-lipids self-assemble in aqueous solution to form cationic lipid nanoparticles (LNPs), which could encapsulate PTEN DNA through electrostatic adsorption to generate LNP@PTEN. This formulation could be delivered to prostate cancer bone metastatic sites. LNP@PTEN combined with the IL-23 inhibitor Apilimod showed enhanced anti-tumor effects by inhibiting tumor proliferation and metastasis, and reactivating anti-tumor immunity with good safety (Created with BioRender.com).

Figures