Two-in-One Polymeric NO-Donor Prodrugs Mediate Precision and Synergistic Prostate Cancer Treatment.

Abstract

Chemotherapy predominates in clinical treatment of prostate cancer (PCa), while irreversible resistance to chemotherapeutics and severe side effects hinder the therapeutic efficacy, especially in castration-resistant PCa (CRPC). Herein, a bombesin (BBN)-decorated two-in-one prodrug (T-NO/E2-PMs) incorporating a polymeric nitric oxide (NO) donor and acetal-linked 17β-estradiol (E2) in one backbone is developed, aiming to inhibit androgen receptor (AR) expression, reprogram the tumor microenvironment of CRPC, and enhance estradiol-mediated hypoxic CRPC therapy. Following efficient internalization mediated by BBN, T-NO/E2-PMs releases estradiol and NO in response to the unique intracellular environments. Both in vitro and in vivo studies demonstrate that the T-NO/E2-PMs nano-prodrug along with NO release potently downregulates AR levels to reverse CRPC and further enhances the chemo-sensitization of estradiol to PCa PC-3 cell apoptosis and the inhibition of metastasis. Collectively, this two-in-one nano-prodrug strategy offers a promising platform for construction of advanced nanomedicine to boost the therapeutic efficacy.

• Authors: Bingbing Zhao, Yuqing Wan, Xiang Zhou, Junmei Zhang, Jiaxin Chen, Jiachen Yang, Yunzhu Liu, Wei Chen, Yinan Zhong, Hongliang Qian
• Journal: ACS applied materials & interfaces (ACS Appl Mater Interfaces) Vol. 15 Issue 28 Pg. 33309-33321 (Jul 19 2023) ISSN: 1944-8252 [Electronic] United States
• PMID: 37408134 (Publication Type: Journal Article)

Chemical References

• Prodrugs
• Nitric Oxide Donors
• Estradiol
• Nitric Oxide

Topics

• Male
• Humans
• Prostatic Neoplasms, Castration-Resistant (drug therapy, metabolism, pathology)
• Prodrugs (pharmacology, therapeutic use)
• Nitric Oxide Donors (pharmacology, therapeutic use)
• Prostate (pathology)
• Estradiol
• Nitric Oxide (therapeutic use)
• Cell Line, Tumor
• Tumor Microenvironment