Polyacetal‐Based Combination Therapy for the Treatment of Prostate Cancer

Abstract

The high incidence of prostate carcinogenesis has prompted the search for novel effective treatment approaches. We have employed curcumin (Curc) and diethylstilbestrol (DES) to synthesize a series of polyacetal (PA)-based combination conjugates for prostate cancer (PCa) treatment. Given their bihydroxyl functionalities, Curc and DES molecules were incorporated into a PA mainchain using a one-pot reaction between diols and divinyl ethers. The PA-conjugates released both drugs under acidic conditions, such as those found in the tumor microenvironment, endosomes, or lysosomes, while remaining stable at neutral pH 7.4. The drug ratio was optimized to achieve anticancer drug synergism with elevated cytotoxicity against LNCaP-hormone-dependent human PCa cells conferred via the induction of S phase cell cycle arrest by the upregulation of p53 and CDK inhibitors p21Waf/CIP1 and downregulation of cyclin D1. The application of rationally designed PA-Curc-DES combination conjugates represents a potentially exciting new treatment for prostate cancer.

Nanomedicine for the Treatment of Advanced Prostate Cancer

“…[ 125 ] We developed this strategy into a synergistic combinatorial treatment approach by creating a polyacetal conjugate of DES and the anti‐tumor agent curcumin at an optimized ratio that displayed potent anti‐tumor effects. [ 126 ]…”

“…[125] We developed this strategy into a synergistic combinatorial treatment approach by creating a polyacetal conjugate of DES and the antitumor agent curcumin at an optimized ratio that displayed potent anti-tumor effects. [126] Further preclinical examples include the development of PLGA nanoparticles loaded with nimesulide, a cyclooxygenase-2 (COX-2) inhibitor that generally presents with poor solubility, [127] and the encapsulation of EGCG in chitosan polysaccharide nanoparticle, which exhibited enhanced anti-tumoral activity and Table 2. Selected examples of passively-targeted nanomedicines for PCa treatment.…”

“…PEGylated liposomal [116][117][118] Doxorubicin/Radiotherapy PEGylated liposomal [119] Doxorubicin/Ultrasound PEGylated liposomal [120] Paclitaxel PGA [55,116] Diethylstilbestrol Polyacetal [125] Curcumin/diethylstilbestrol Polyacetal [126] Nimesulide PEGylated nanoparticle [127] Epigallocatechin-3-gallate Chitosan [128] siRNA Chitosan [139] pDNA/Cisplatin PAMAM dendrimer [141] siRNA PEGylated nanoparticle [146][147][148] siRNA Template lipoprotein particles [149] PGA: poly-L-glutamic acid. PEG: Poly (ethylene glycol).…”

“…There exist examples of nanomedicine-based combination therapies with promising results in preclinical PCa studies, as described in previous sections. [61,62,63,90,91,116,126] We believe that a more in-depth exploration of this strategy may provide exciting advances, and we hope to provide a brief overview of the opportunities and challenges to their implementation that may allow for the generation of efficient combination-based nanomedicines for PCa treatment.…”

A multifunctional biodegradable brush polymer-drug conjugate for paclitaxel/gemcitabine co-delivery and tumor imaging

“…14 Recent studies have also revealed the promising application potential of polymer-drug conjugates (PDCs) as combination nanomedicines. [15][16][17][18][19][20][21][22] Compared with separate administration of PTX and GEM, integrated single nanomedicine formulations for co-delivery of PTX and GEM can simplify the cancer treatment process. 23 However, there is a vast difference in hydrophobicity between PTX and GEM.…”