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A polymeric prodrug of 5-fluorouracil-1-acetic acid using a multi-hydroxyl polyethylene glycol derivative as the drug carrier.

ABSTRACT: Macromolecular prodrugs obtained by covalently conjugating small molecular drugs with polymeric carriers were proven to accomplish controlled and sustained release of the therapeutic agents in vitro and in vivo. Polyethylene glycol (PEG) has been extensively used due to its low toxicity, low immunogenicity and high biocompatibility. However, for linear PEG macromolecules, the number of available hydroxyl groups for drug coupling does not change with the length of polymeric chain, which limits the application of PEG for drug conjugation purposes. To increase the drug loading and prolong the retention time of 5-fluorouracil (5-Fu), a macromolecular prodrug of 5-Fu, 5-fluorouracil-1 acid-PAE derivative (5-FA-PAE) was synthesized and tested for the antitumor activity in vivo.PEG with a molecular weight of 38 kDa was selected to synthesize the multi-hydroxyl polyethylene glycol derivative (PAE) through an addition reaction. 5-fluorouracil-1 acetic acid (5-FA), a 5-Fu derivative was coupled with PEG derivatives via ester bond to form a macromolecular prodrug, 5-FA-PAE. The in vitro drug release, pharmacokinetics, in vivo distribution and antitumor effect of the prodrug were investigated, respectively.The PEG-based prodrug obtained in this study possessed an exceedingly high 5-FA loading efficiency of 10.58%, much higher than the maximum drug loading efficiency of unmodified PEG with the same molecular weight, which was 0.98% theoretically. Furthermore, 5-FA-PAE exhibited suitable sustained release in tumors.This study provides a new approach for the development of the delivery to tumors of anticancer agents with PEG derivatives.

SUBMITTER: Li M

PROVIDER: S-EPMC4229301 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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A polymeric prodrug of 5-fluorouracil-1-acetic acid using a multi-hydroxyl polyethylene glycol derivative as the drug carrier.

Li Man M Liang Zhen Z Sun Xun X Gong Tao T Zhang Zhirong Z

PloS one 20141112 11

<h4>Purpose</h4>Macromolecular prodrugs obtained by covalently conjugating small molecular drugs with polymeric carriers were proven to accomplish controlled and sustained release of the therapeutic agents in vitro and in vivo. Polyethylene glycol (PEG) has been extensively used due to its low toxicity, low immunogenicity and high biocompatibility. However, for linear PEG macromolecules, the number of available hydroxyl groups for drug coupling does not change with the length of polymeric chain, ...[more]

PMID: 25389968

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Project description:Immunotherapy based on checkpoint blockade has been regarded as one of the most promising approaches towards many types of cancers. However, low response rate hinders its application due to insufficient tumor immunogenicity and immunosuppressive tumor microenvironment. To achieve an overall enhanced therapeutic outcome, we developed a dual-functional immuno-stimulatory polymeric prodrug carrier modified with pendent indoximod, an indoleamine 2,3-dioxygenase (IDO) inhibitor that can be used to reverse immune suppression, for co-delivery of Doxorubicin (Dox), a hydrophobic anticancer agent that can promote immunogenic cell death (ICD) and elicit antitumor immunity. The resulted carrier denoted as POEG-b-PVBIND, consisting of poly (oligo (ethylene glycol) methacrylate) (POEG) hydrophilic blocks and indoximod conjugated hydrophobic blocks, is rationally designed to improve immunotherapy by synergistically modulating the tumor microenvironment (TME). Our data showed that Dox-triggered ICD promoted intra-tumoral infiltration of CD8+ T cells and IFN-?-production by CD8+ T cells. Meanwhile, cleaved indoximod significantly increased CD8+ T cell infiltration while reducing the immunosuppressive T regulatory cells (Tregs). More importantly, Dox/POEG-b-PVBIND micelles led to significantly improved tumor regression in an orthotopic murine breast cancer model compared to both Dox-loaded POEG-b-PVB micelles (a control inert carrier) and POEG-b-PVBIND micelles alone, confirming combination effect of indoximod and Dox in improving the overall antitumor activity. STATEMENT OF SIGNIFICANCE: Indoleamine 2,3-dioxygenase (IDO) is an enzyme that can induce immune suppressive microenvironment in tumors. As a well-studied IDO inhibitor, indoximod (IND) represents a promising agent for cancer immunotherapy and could be particularly useful in combination with other chemotherapeutic agents. However, three major problems hinder its application: (1) IND is barely soluble in water; (2) IND delivery efficiency is limited (3) simultaneous delivery of two agents into tumor site is still challenging. Currently, most reports largely focus on improving the pharmacokinetic profile of IND alone via different formulations such as IND prodrug and IND nanocrystal. However, there is limited information about IND based co-delivery systems, especially for delivering hydrophobic chemotherapeutic agents. Here, we developed a new dual-functional polymeric prodrug carrier modified with a number of pendent IND units (denoted as POEG-b-PVBIND). POEG-b-PVBIND shows immunostimulatory and antitumor activities by itself. More importantly, POEG-b-PVBIND polymer is able to self-assemble into nano-sized micelles that are highly effective in formulating and codelivering other hydrophobic agents including doxorubicin (Dox), sunitinib (Sun), and daunorubicin (Dau), which can elicit antitumor immunity via promoting immunogenic cell death (ICD). We have shown that our new combination therapy led to a significantly improved antitumor activity in an aggressive murine breast cancer model (4T1.2).

Dataset Information

A polymeric prodrug of 5-fluorouracil-1-acetic acid using a multi-hydroxyl polyethylene glycol derivative as the drug carrier.

Publications

A polymeric prodrug of 5-fluorouracil-1-acetic acid using a multi-hydroxyl polyethylene glycol derivative as the drug carrier.

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