Abstract
PurposeMacromolecular 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.MethodsPEG 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.ResultsThe 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.ConclusionThis study provides a new approach for the development of the delivery to tumors of anticancer agents with PEG derivatives.
Highlights
Cancer is one of the most life-threatening diseases worldwide, which seriously endangers human health and survival [1,2]
This study provides a new approach for the development of the delivery to tumors of anticancer agents with Polyethylene glycol (PEG) derivatives
Synthesis and characterization of 5-fluorouracil-1 acetic acid (5-FA)-polyethylene glycol derivative (PAE) prodrug As a polyether macromolecule, PEG is widely used for its suitable solubility and bioavailability in developing drug delivery systems [50,51,52,53]
Summary
Cancer is one of the most life-threatening diseases worldwide, which seriously endangers human health and survival [1,2]. 5-fluorouracil (5-Fu) is one of the most widely used antimetabolites in clinic [10], which shows significant inhibitory effect against a broad spectrum of solid tumors [11,12,13]. Traditional chemotherapies such as 5-Fu are cytotoxic agents that inhibit rapidly proliferating cancer cells. Due to its low specificity, side effects such as myelosuppression, mucositis, dermatitis and diarrhea are commonly observed during the clinical application of 5-Fu [14,15,16]. The irregular oral absorption and the low bioavailability often results in poor clinical therapeutic outcome [17,18,19]
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