Development, Characterization, and Evaluation of PSMA‐Targeted Glycol Chitosan Micelles for Prostate Cancer Therapy

Jing Xu,Lixin Li,Jianguo Zhao,Jingmou Yu,Yonghua Liu,Liangliang Wang,Ming He,Xiao Xu

doi:10.1155/2014/462356

Abstract

Prostate cancer‐binding peptides‐ (PCP‐) modified polymeric micelles were prepared and used for the treatment of prostate‐specific membrane antigen‐ (PSMA‐) expressing prostate cancer in a target‐specific manner. Cholesterol‐modified glycol chitosan (CHGC) was synthesized. PCP‐conjugated CHGC (PCP‐CHGC) micelles were fabricated and characterized. The degree of substitution was 5.2 PCP groups and 5.8 cholesterol groups per 100 sugar residues of glycol chitosan. The critical aggregation concentration (CAC) of PCP‐CHGC copolymer was 0.0254 mg/mL. Doxorubicin (DOX) was chosen as a model antitumor drug. The DOX‐loaded micelles were prepared by an o/w method. The mean diameter of DOX‐loaded PCP‐CHGC (DOX‐PCP‐CHGC) micelles was 293 nm determined by dynamic light scattering (DLS). DOX released from drug‐loaded micelles was in a biphasic manner. DOX‐PCP‐CHGC micelles exhibited higher cytotoxicity in vitro against PSMA‐expressing LNCaP cells than DOX‐loaded CHGC (DOX‐CHGC) micelles. Moreover, the cellular uptake of DOX‐PCP‐CHGC micelles determined by confocal laser scanning microscopy (CLSM) and flow cytometry was higher than that of DOX‐CHGC micelles in LNCaP cells. Importantly, DOX‐PCP‐CHGC micelles demonstrated stronger antitumor efficacy against LNCaP tumor xenograft models than doxorubicin hydrochloride and DOX‐CHGC micelles. Taken together, this study provides a potential way in developing PSMA‐targeted drug delivery system for prostate cancer therapy.

Highlights

Prostate cancer is one of the most frequently diagnosed cancers among men in the United States and is the second leading cause of male cancer death with 233,000 new cases and an estimated 29,480 deaths in 2014 [1]
Before the PCP modification, the Cholesterol-modified glycol chitosan (CHGC) was synthesized by the reaction between carboxyl group of cholesterol hemisuccinate and amino group of glycol chitosan using ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) as the coupling reagent
The chemical structure of CHGC was confirmed by 1H nuclear magnetic resonance (NMR) spectra (Figure 2)

Summary

Introduction

Prostate cancer is one of the most frequently diagnosed cancers among men in the United States and is the second leading cause of male cancer death with 233,000 new cases and an estimated 29,480 deaths in 2014 [1]. In the early stage of prostate cancer, the surgical or radiation ablation therapies are relatively effective. There is no effective therapy for men with metastatic prostate cancer. The dose and duration of administration of these drugs were limited, due to the systemic toxicity and the lack of sufficient selectivity towards tumor cells. It is an urgent medical need to develop drug delivery systems that selectively transport the antitumor agent into the tumor tissues and cells. Nanosized carriers such as liposomes, micelles, and polymeric nanoparticles have demonstrated improved therapeutic index with minimal side effects [4,5,6]

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