Fluorinated chitosan mediated transepithelial delivery of sanguinarine-loaded platinum (IV) prodrug for intravesical instillation therapy of muscle-invasive bladder cancer

Xinzi Hu; Guangzhi Li; Chenfan Kong; Lisha Liu; Dashi Deng; Guizhong Xin; Jian Pan; Song Wu; Qifang Lei

doi:10.1016/j.jconrel.2024.12.023

Fluorinated chitosan mediated transepithelial delivery of sanguinarine-loaded platinum (IV) prodrug for intravesical instillation therapy of muscle-invasive bladder cancer

J Control Release. 2024 Dec 17:S0168-3659(24)00866-6. doi: 10.1016/j.jconrel.2024.12.023. Online ahead of print.

Authors

Xinzi Hu¹, Guangzhi Li², Chenfan Kong³, Lisha Liu², Dashi Deng², Guizhong Xin⁴, Jian Pan⁵, Song Wu⁶, Qifang Lei⁷

Affiliations

¹ Department of Urology, South China Hospital, Health Science Center, Shenzhen University, Shenzhen 518116, China; Institute of Urology, The Affiliated Luohu Hospital of Shenzhen University, Shenzhen University, Shenzhen 518000, China.
² Institute of Urology, The Affiliated Luohu Hospital of Shenzhen University, Shenzhen University, Shenzhen 518000, China.
³ Department of Urology, South China Hospital, Health Science Center, Shenzhen University, Shenzhen 518116, China; Graduate School, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
⁴ State Key Laboratory of Natural Medicines, Department of Chinese Medicines Analysis, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing, China. Electronic address: xingz@cpu.edu.cn.
⁵ Department of Urology, South China Hospital, Health Science Center, Shenzhen University, Shenzhen 518116, China.
⁶ Department of Urology, South China Hospital, Health Science Center, Shenzhen University, Shenzhen 518116, China; Institute of Urology, The Affiliated Luohu Hospital of Shenzhen University, Shenzhen University, Shenzhen 518000, China; Graduate School, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: wusong@szu.edu.cn.
⁷ Department of Urology, South China Hospital, Health Science Center, Shenzhen University, Shenzhen 518116, China; Institute of Urology, The Affiliated Luohu Hospital of Shenzhen University, Shenzhen University, Shenzhen 518000, China. Electronic address: leiqifang@zxbiomed.org.

PMID: 39701454
DOI: 10.1016/j.jconrel.2024.12.023

Abstract

Cisplatin-based neoadjuvant chemotherapy is first-line strategy to inhibit progression and metastasis of muscle-invasive bladder cancer (MIBC). However, its clinical efficacy is often limited by drug resistance and severe systemic side effects, highlighting the urgent need for innovative therapeutic approaches. Despite advancements in cisplatin-based regimens, research on intravesical cisplatin delivery systems remains scarce. In this study, we developed an amphiphilic platinum(IV) prodrug micellar platform (Pt (IV)-DI-PEG) capable of efficiently encapsulating sanguinarine (San), which was further coated with fluorinated chitosan (FCS) to construct San@Pt(IV)-DI-PEG@FCS nanoparticles (SPFNPs) for intravesical instillation even targeting MIBC. The resulting SPFNPs demonstrated several advantages: the FCS coating facilitated enhanced trans-epithelial drug delivery by regulating bladder epithelial tight junction proteins, enabling efficient intravesical administration; Second, the glutathione (GSH)-responsive reduction of the Pt(IV) prodrug promoted tumor-targeted release of San and localized accumulation of Pt(II), while simultaneously depleting intracellular GSH. Furthermore, the released San induced reactive oxygen species (ROS) production, oxidative cleavage and inhibit the activation and function of poly (ADP-ribose) polymerase, collectively impairing nucleotide-excision repair and preventing the elimination of Pt-DNA adducts, resulting in persistent DNA damage, cell cycle arrest, and apoptosis in tumor cells. The synergistic effects of San and cisplatin were validated in both orthotopic mouse models and patient-derived orthotopic xenograft, demonstrating robust anti-tumor efficacy. This study underscores the potential of intravesical cisplatin formulations as a promising strategy for MIBC treatment, offering a shift from traditional systemic chemotherapy towards localized, targeted drug delivery systems.

Keywords: Intravesical synergized therapy; Muscle-invasive bladder cancer; Pt (IV) prodrug; Pt resistance; Transepithelial delivery.