AUTHOR=Chen Xinlu , Gong Luyao , Wang Yuanyuan , Ye Chen , Guo Huanhuan , Gao Shen , Chen Jiyuan , Wang Zhuo , Gao Yuan 

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

JOURNAL=Frontiers in Pharmacology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1388613

DOI=10.3389/fphar.2024.1388613

ISSN=1663-9812

ABSTRACT=<p><bold>Introduction:</bold> 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.</p><p><bold>Methods:</bold> 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) <italic>in vitro</italic> and <italic>in vivo</italic>. In addition, RT-qPCR and flow cytometry were used to investigate the related mechanisms of the antitumor effect of LNP@PTEN combined with Apilimod.</p><p><bold>Results:</bold> LNPs exhibited significant tumor-targeting and tumor accumulation capabilities both <italic>in vitro</italic> and <italic>in vivo</italic>, 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<sup>+</sup>/CD4<sup>+</sup> T cell ratio.</p><p><bold>Discussion:</bold> 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.</p>