<p>A Mansonone Derivative Coupled with Monoclonal Antibody 4D5-Modified Chitosan Inhibit AKR1C3 to Treat Castration-Resistant Prostate Cancer</p>

Abstract

Aldo-ketoreductase (AKR) 1C3 is crucial for testosterone synthesis. Abnormally high expression/activity of AKR1C3 can promote castration-resistant prostate cancer (CRPC). A mansonone derivative and AKR1C3 inhibitor, 6e, was combined with 4D5 (extracellular fragment of the monoclonal antibody of human epidermal growth factor receptor-2)-modified chitosan to achieve a nanodrug-delivery system (CS-4D5/6e) to treat CRPC. Materials and Methods: Morphologies/properties of CS-4D5/6e were characterized by atomic force microscopy, zeta-potential analysis, and Fourier transform-infrared spectroscopy. CS-4D5/6e uptake was measured by immunofluorescence under confocal laser scanning microscopy. Testosterone in LNCaP cells overexpressing human AKR1C3 (LNCaP-AKR1C3) and cell lysates was measured to reflect AKR1C3 activity. Androgen receptor (AR) and prostatespecific antigen (PSA) expression was measured by Western blotting. CS-4D5/6e-based inhibition of AKR1C3 was evaluated in tumor-xenografted mice. Results: CS-4D5/6e was oblate, with a particle size of 200-300 nm and thickness of 1-5 nm. Zeta potential was 1.39±0.248 mV. 6e content in CS-4D5/6e was 7.3±1.4% and was 18±3.6% for 4D5. 6e and CS-4D5/6e inhibited testosterone production significantly in a concentrationdependent manner in LNCaP-AKR1C3 cells, and a decrease in expression of AKR1C3, PSA, and AR was noted. Half-maximal inhibitory concentration of CS-4D5/6e on LNCaP-AKR1C3 cells was significantly lower than that in LNCaP cells (P<0.05). CS-4D5/6e significantly reduced growth of 22Rv1 tumor xenografts by 57.00% compared with that in the vehicle group (P<0.01). Conclusion:We demonstrated the antineoplastic activity of a potent AKR1C3 inhibitor (6e) and its nanodrug-delivery system (CS-4D5/6e). First, CS-4D5/6e targeted HER2-positive CRPC cells. Second, it transferred 6e (an AKR1C3 inhibitor) to achieve a reduction in intratumoral testosterone production. Compared with 6e, CS-4D5/6e showed lower systemic toxicity. CS-4D5/6e inhibited tumor growth effectively in mice implanted with tumor xenografts by downregulating testosterone production mediated by intratumoral AKR1C3. These results showed a promising strategy for treatment of the CRPC that develops invariably in prostate-cancer patients.

Inhibition of castration-resistant prostate cancer growth by genistein through suppression of AKR1C3

“…These compounds may be useful for treatment and/or prevention of CRPC. Meanwhile, Zhou et al ( 25 ) designed a low systemic toxicity and a high targeting drug delivery system (CS-4D5/6e) by combining a mansonone derivative and an AKR1C3 inhibitor, 6e, with 4D5-modified chitosan. The system can effectively combat CRPC via downregulating AKR1C3-mediated testosterone levels in tumors.…”

AKR1C3 in carcinomas: from multifaceted roles to therapeutic strategies

“…Encouragingly, ongoing advancements in anti-tumor drugs and AKR1C3 inhibitors, such as ASP9521 and BAY1128688, are progressing in clinical trials for CRPC treatment (Rizner and Penning, 2020). Nanodrug-delivery systems (NDDS), exemplified by CS-4D5/6e, exhibit enhanced inhibitory potency, leveraging improved pharmacokinetics, tumor-targeting capabilities, and responsive drug release in the tumor microenvironment (Zhou et al, 2020). Despite the promising clinical applications of NDDS, challenges remain, including optimizing drug release and addressing potential drawbacks, such as increased drug accumulation.…”

Functionalized Selenium Nanotherapeutics Synergizes With Zoledronic Acid to Suppress Prostate Cancer Cell Growth Through Induction of Mitochondria-Mediated Apoptosis and Cell Cycle S Phase Arrest

“…According to the recommendations of National Comprehensive Cancer Network guideline, endocrine therapy alone or in combination with radiotherapy have been used in clinical practice for the treatment of PCa with T3–T4 stage in the TNM classification. Such treatment can easily lead to castration-resistant prostate cancer (CRPC) ( 6 , 7 ). Based on the characteristics of high degree of malignancy, short median survival time, high mortality, and insensitivity to a variety of chemotherapeutic drugs, clinicians use endocrine therapy combined with chemotherapy, targeted therapy, or immunotherapy for patients with distant bone metastases supplemented with local treatment and supportive therapy (e.g., nutrition to enhance immunity, pain relief, et al) ( 8 ).…”