A self-healing micellar hydrogel system for controlled release of caffeic acid phenethyl ester and durable inhibition of prostate tumor.

Hydrogel-encapsulation allows slow and stable delivery of drugs with short half-lives, avoiding the undesired side effects of high-dose or frequent administration of drugs. We previously reported that gavage or injection of caffeic acid phenethyl ester (CAPE) at 10-15 mg/kg, 2-3 times per week effectively repressed the tumor growth of human prostate xenografts in nude mice. However, daily oral or injectable delivery of CAPE in prostate cancer (PCa) patients may be impractical due to forgetfulness, physical limitations, or treatment fatigue. To overcome these challenges, we developed a hydrogel-based drug delivery system for sustained and stable release of CAPE, reducing dosing frequency without compromising efficacy. Hydrogel encapsulation enables prolonged release of short half-life drugs, minimizing side effects from high-dose or frequent dosing. We encapsulated hydrophobic CAPE in a self-healing micellar hydrogel (CDP hydrogel), forming a novel drug delivery system (CDP@CAPE) that provides continuous, stable release over two weeks after a single injection. Compared to weekly CAPE injection (60 mg/kg/week), bi-weekly CDP@CAPE (120 mg/kg/2 weeks) extended drug release duration by 1.8-fold and enhanced tumor growth suppression by 2.7-fold in androgen-insensitive PC-3 xenografts. Immunohistochemical staining and Micro-Western Array revealed that CDP@CAPE suppressed Ki67, cyclin B1, NF-κB p65, phospho-MEK Ser298, and phospho-RB Ser780 while inducing P21Cip1 and P27Kip1. The alteration of these cell cycle regulatory proteins contributed to inhibition of tumor growth. In conclusion, the CAPE-loaded self-healing micellar hydrogel represents a reliable, long-lasting, and dose-adjustable delivery system for treating advanced PCa. STATEMENT OF SIGNIFICANCE: We developed a self-healing micellar hydrogel (CDP hydrogel) capable of effectively encapsulating the hydrophobic compound caffeic acid phenethyl ester (CAPE). This novel drug delivery system, termed CDP@CAPE, enabled continuous, stable, and sustained release of CAPE over two weeks following a single injection. Compared to the weekly CAPE injection group (60 mg/kg/week), CDP@CAPE administration (120 mg/kg/2 weeks) was 2.7 times more effective in suppressing the growth of PC-3 xenograft tumors. CDP@CAPE significantly downregulated Ki67, cyclin B1, and NF-κB p65, while upregulating P21Cip1 and P27Kip1 in tumor tissues. These findings demonstrated that CDP@CAPE is a long-lasting, reliable, and dose-adjustable drug delivery platform for cancer therapy.