Antitumor Efficacy and Toxicity of 5-Fluorouracil-Loaded Poly(Lactide Co-glycolide) Pellets

Abstract

The aim of this study was to formulate a biodegradable implant capable of imparting local antitumor activity through the sustained release of the chemotherapeutic agent, 5-fluorouracil (5-FU). Thus, injectable pellets (<1.2 mm diameter) made from poly(lactide co-glycolide) (PLGA) and loaded with 5-FU at varying drug:polymer ratios were fabricated using hot-melt extrusion and tested for their ability to provide sustained release of 5-FU in in vitro and in vivo settings. In addition, these formulations were compared against soluble 5-FU for their antitumor activity in vivo as well as for their toxicity. It was demonstrated that the release rate of 5-FU from PLGA pellets was directly related to the percentage of 5-FU in the pellets. PLGA pellets loaded with 50% w/w 5-FU exhibited comparable, and significantly enhanced, antitumor activity (as measured by tumor volumes and survival) in vivo in a thymoma and colon cancer model, respectively, when compared to an equivalent bolus dose (120 mg/kg) of soluble 5-FU. We concluded that 5-FU-loaded PLGA pellets were more effective and specifically less erythrotoxic than 5-FU bolus injections and therefore may prove to be of benefit as an intraoperative adjunct therapy for patients with cancers that are sensitive to 5-FU and who are undergoing tumor resection.

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“…[2][3][4][5] The anticancer drug 5-fluorouracil (5FU) is one of the most commonly used drugs for treating breast cancer, and various folate (FA)-based controlled drug delivery systems (DDSs) have been developed to deliver 5FU to MCF-7 breast cancer cells. 6,7 Several biodegradable polymer-based materials, including gellan gum, 8 poly(D,Llactic-co-glycolic acid), 9 polycaprolactone, 10 and L-lysinemodified hyperbranched polyester, 11 have been developed as 5FU delivery platforms to enhance the anticancer activity of 5FU. However, the size of these polymeric platforms is a major concern with regard to cell internalization of drugincorporated carriers.…”

Gastrointestinal tumor-related perihepatic fluorouracil encapsulated lesions and liver metastases: a diagnostic imaging study based on contrast-enhanced computed tomography and magnetic resonance imaging

“…Intraperitoneal chemotherapy, which was proposed in the early 1990s, involves the encapsulation of antitumor drugs in preparation to achieve sustained and efficient drug concentration in local tissues, thereby reducing systemic adverse reactions. Many studies had been devoted to the preparation of FU loading materials to achieve better therapeutic effect ( 17 - 19 ). Leelakanok et al formulated injectable pellets made from poly (lactide co-glycolide) (PLGA) and achieved the sustained release of 5-FU in vitro and in vivo settings for 1 month, concluding that 5-FU-loaded PLGA pellets were more effective and specifically less erythrotoxic than 5-FU bolus injections ( 19 ).…”

“…Many studies had been devoted to the preparation of FU loading materials to achieve better therapeutic effect ( 17 - 19 ). Leelakanok et al formulated injectable pellets made from poly (lactide co-glycolide) (PLGA) and achieved the sustained release of 5-FU in vitro and in vivo settings for 1 month, concluding that 5-FU-loaded PLGA pellets were more effective and specifically less erythrotoxic than 5-FU bolus injections ( 19 ). Some physicians thus wrap FU with biodegradable adhesion membrane in suspected areas during surgery.…”

Theoretical Investigation of Chitosan-Assisted Controlled Release of Digestive System Antitumor Drug Fluorouracil

“…5-Fluorouracil (5-FU or 5-fluoro-2,4-pyrimidinedione) has been applied to treat pancreatic cancer, which is one of the most common types of digestive system tumors. [1][2][3] As a chemotherapeutic agent, 5-FU acts by interfering with nucleosides, leading to cytotoxicity and cell death. Maintaining a therapeutic serum concentration requires continuous administration of high doses due to the high metabolism rate of 5-FU.…”