Enhanced Anticancer Activity of 5'-DFUR-PCL-MPEG Polymeric Prodrug Micelles Encapsulating Chemotherapeutic Drugs.

Alicia Sawdon,Xutu Wang,Ching-An Peng,Jun Zhang

doi:10.3390/nano8121041

Alicia Sawdon, Xutu Wang + Show 2 more

Open Access

https://doi.org/10.3390/nano8121041

Copy DOI

Abstract

The compound 5’-deoxy-5-fluorouridine (5’-DFUR) is a prodrug of the anti-tumor drug 5-fluorouracil (5-FU). Thymidine phosphorylase (TP) is an enzyme that can convert 5’-DFUR to its active form 5-FU and the expression of TP is upregulated in various cancer cells. In this study, 5’-DFUR associated with amphiphilic copolymer poly(ε-caprolactone)-methoxy poly(ethylene glycol) (5’-DFUR-PCL-MPEG) was synthesized, characterized, and self-assembled into functional polymeric micelles. To demonstrate that the prodrug 5’-DFUR could convert into cytotoxic 5-fluorouracil (5-FU) by endogenous TP, HT-29 colorectal cancer cells were treated with 5’-DFUR-PCL-MPEG polymeric micelles for various time periods. Chemotherapeutic drugs doxorubicin (DOX) and 7-ethyl-10-hydroxycamptothecin (SN-38) were also encapsulated separately into 5’-DFUR-PCL-MPEG polymeric micelles to create a dual drug-loaded system. HT-29 cells were treated with DOX or SN-38 encapsulated 5’-DFUR-PCL-MPEG polymeric micelles to examine the efficacy of dual drug-loaded micelles. As a result, HT-29 cells treated with 5’-DFUR-PCL-MPEG polymeric micelles showed up to 40% cell death rate after a 72-h treatment. In contrast, HT-29 cells challenged with DOX or SN-38 encapsulated 5’-DFUR-incorporated polymeric micelles showed 36% and 31% in cell viability after a 72-h treatment, respectively.

Highlights

The compound 5-Fluorouracil (5-FU) is one of the main anti-tumor agents used to treat colon, breast and gastric cancers
thymidine phosphorylase (TP), known as platelet-derived endothelial cell growth factor (PD-ECGF), is an angiogenic enzyme involved in pyrimidine nucleoside metabolism [8]
Tetrahydrofuran (THF), toluene, dichloromethane (DCM), dimethyl sulfoxide (DMSO), deuterated dimethyl sulfoxide (DMSO-d6), CDCl3 with 1% tetramethylsilane (TMS), Sn(Oct)2, hexane, N-Hydroxysuccinimide (NHS), acetone, pyridine, magnesium sulfate, 2-propanol, methanol, hydrochloric acid (HCl), SN-38, DOX, methoxypolyethylene glycol amine (MPEG-NH2; MW = 5000), MPEG (MW = 350), penicillin-streptomycin, 0.25% trypsin/EDTA, RIPA lysis and extraction buffer, protease inhibitor, thymidine, thymine and 5-fluorouracil were all purchased from Sigma-Aldrich

Summary

Introduction

The compound 5-Fluorouracil (5-FU) is one of the main anti-tumor agents used to treat colon, breast and gastric cancers. 5-FU is poorly tumor targeted and its treatment results in several severe adverse side effects in patients including intestinal discomfort, granulocytopenia, neuropathy, and cardiotoxicity [2,3,4]. 5’-deoxy-5-fluorouridine (5’-DFUR), a prodrug of 5-FU, is commonly administered to patients [6]. 5’-DFUR is converted to its active and toxic form 5-FU through metabolic conversion by thymidine phosphorylase (TP), a gene overexpressed in many cancer types [7]. The efficacy of 5’-DFUR is closely related to the level of TP expression and activity in tumor sites [12]. Several groups have exploited the enzyme-prodrug activation model of TP and 5’-DFUR and shown that the killing rate of cancer cell lines transfected with TP gene was augmented by the overexpressed TP level [13,14]

Methods

Results

Conclusion