Folate Conjugated Polyethylene Glycol Probe for Tumor-Targeted Drug Delivery of 5-Fluorouracil.

Shabnam Sarwar,Michiel Vanmeert,Rima D Alharthy,Mahmood Ahmed,Muhammad Usman Mirza,Muhammad Abdul Qadir,Saghir Ahmad,Abdul Hameed

doi:10.3390/molecules27061780

Abstract

A targeted delivery system is primarily intended to carry a potent anticancer drug to specific tumor sites within the bodily tissues. In the present study, a carrier system has been designed using folic acid (FA), bis-amine polyethylene glycol (PEG), and an anticancer drug, 5-fluorouracil (5-FU). FA and PEG were joined via an amide bond, and the resulting FA-PEG-NH2 was coupled to 5-FU producing folate-polyethylene glycol conjugated 5-fluorouracil (FA-PEG-5-FU). Spectroscopic techniques (UV-Vis, 1HNMR, FTIR, and HPLC) were used for the characterization of products. Prodrug (FA-PEG-5-FU) was analyzed for drug release profile (in vitro) up to 10 days and compared to a standard anticancer drug (5-FU). Folate conjugate was also analyzed to study its folate receptors (FR) mediated transport and in vitro cytotoxicity assays using HeLa cancer cells/Vero cells, respectively, and antitumor activity in tumor-bearing mice models. Folate conjugate showed steady drug release patterns and improved uptake in the HeLa cancer cells than Vero cells. Folate conjugate treated mice group showed smaller tumor volumes; specifically after the 15th day post-treatment, tumor sizes were decreased significantly compared to the standard drug group (5-FU). Molecular docking findings demonstrated importance of Trp138, Trp140, and Lys136 in the stabilization of flexible loop flanking the active site. The folic acid conjugated probe has shown the potential of targeted drug delivery and sustained release of anticancer drug to tumor lesions with intact antitumor efficacy.

Highlights

Traditional chemotherapy for cancer treatment has encountered a serious problem of no/slight specificity for cancer targets, eventually causing systemic toxicity
In Step 2, 5-FU was activated using formaldehyde in the presence of anhydrous dimethyl sulfoxide (DMSO) to proceed with the reaction
An active methylene group was introduced in the scaffold of 5-FU, which served as a linker among 5-FU and polyethylene glycol (PEG) amino units

Summary

Introduction

Traditional chemotherapy for cancer treatment has encountered a serious problem of no/slight specificity for cancer targets, eventually causing systemic toxicity. A promising method to resolve this issue is to design a specific delivery system to transport small molecules towards their target sites. Drug delivery probes labeled with radionuclides are capable of precisely highlighting the infection/tumor lesion in gamma cameras [3–10]. These tumor-targeting delivery systems have been extensively explored in previous decades, demonstrating that it is a promising methodology with reduced toxicity and selective chemotherapy [11–17]. Popular techniques for designing a cytotoxic agent’s delivery system to target cancer lesions include prodrugs with pH-sensitive polymeric coating or matrix formulations dependent on time [18–21]

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