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Resiquimod for Prostate Cancer Treatment

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Wenfeng Lin,1,* Chaoming Li,1,2,* Naijin Xu,1,3 Masami Watanabe,1,4 Ruizhi Xue,1 Abai Xu,2 Motoo Araki,1 Ruifen Sun,5 Chunxiao Liu,2 Yasutomo Nasu,1 Peng Huang1,2,6

1Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; 2Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 3Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 4Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama, Japan; 5Center for Scientific Research, Yunnan University of Chinese Traditional Medicine, Kunming, People’s Republic of China; 6Okayama Medical Innovation Center, Okayama University, Okayama, Japan

*These authors contributed equally to this work

Correspondence: Peng Huang
Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan
Tel + 81-86-235-7997
Fax +81-86-235-7884
Email [email protected]

Purpose: With the advance of screening techniques, there is a growing number of low-risk or intermediate-risk prostate cancer (PCa) cases, remaining a serious threat to men’s health. To obtain better efficacy, a growing interest has been attracted to develop such emerging treatments as immunotherapy and focal therapy. However, few studies offer guidance on whether and how to combine these modalities against PCa. This study was designed to develop dual-functional nanoparticles (NPs) which combined photothermal therapy (PTT) with immunotherapy and determine the anti-tumor efficacy for PCa treatment.
Methods: By a double emulsion technique, the drug nanocarrier, poly(lactic-co-glycolic acid) or PLGA, was applied for co-loading of a fluorescent dye, indocyanine green (ICG) and a toll-like receptor 7/8 (TLR7/8) agonist resiquimod (R848) to synthesize PLGA-ICG-R848 NPs. Next, we determined their characteristic features and evaluated whether they inhibited the cell viability in multiple PCa cell lines. After treatment with PLGA-ICG-R848, the maturation markers of bone marrow-derived dendritic cells (BMDCs) were detected by flow cytometry. By establishing a subcutaneous xenograft model of mouse PCa, we explored both the anti-tumor effect and immune response following the NPs-based laser ablation.
Results: With a mean diameter of 157.7 nm, PLGA-ICG-R848 exhibited no cytotoxic effect in PCa cells, but they significantly decreased RM9 cell viability to (3.9± 1.0)% after laser irradiation. Moreover, PLGA-ICG-R848 promoted BMDCs maturation with the significantly elevated proportions of CD11c+CD86+ and CD11c+CD80+ cells. Following PLGA-ICG-R848-based laser ablation in vivo, the decreased bioluminescent signals indicated a significant inhibition of PCa growth, while the ratio of splenic natural killer (NK) cells in PLGA-ICG-R848 was (3.96± 1.88)% compared with (0.99± 0.10)% in PBS group, revealing the enhanced immune response against PCa.
Conclusion: The dual-functional PLGA-ICG-R848 NPs under laser irradiation exhibit the anti-tumor efficacy for PCa treatment by combining PTT with immunotherapy.

Keywords: prostate cancer, PLGA, indocyanine green, resiquimod, photothermal therapy, immunotherapy

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