Abstract
Folate-targeted poly[(p-nitrophenyl acrylate)-co-(N-isopropylacrylamide)] nanohydrogel (F-SubMG) was loaded with 5-fluorouracil (5-FU) to obtain low (16.3 ± 1.9 μg 5-FU/mg F-SubMG) and high (46.8 ± 3.8 μg 5-FU/mg F-SubMG) load 5-FU-loaded F-SubMGs. The complete in vitro drug release took place in 8 h. The cytotoxicity of unloaded F-SubMGs in MCF7 and HeLa cells was low; although it increased for high F-SubMG concentration. The administration of 10 μM 5-FU by 5-FU-loaded F-SubMGs was effective on both cellular types. Cell uptake of F-SubMGs took place in both cell types, but it was higher in HeLa cells because they are folate receptor positive. After subcutaneous administration (28 mg 5-FU/kg b.w.) in Wistar rats, F-SubMGs were detected at the site of injection under the skin. Histological studies indicated that the F-SubMGs were surrounded by connective tissue, without any signs of rejections, even 60 days after injection. Pharmacokinetic study showed an increase in MRT (mean residence time) of 5-FU when the drug was administered by drug-loaded F-SubMGs.
Highlights
A quick release of the most external 5-FU from F-SubMGs were observed during the first min, which took place at a rate of 12.6 μg 5-FU/h per mg F-SubMGs (r2 = 0.97)
The over expression of folate receptors (FR) in many cancer cells [14,19] has been considered to target anticancer drug-loaded nanocarriers by binding folate molecules in the surface of such nanosystems, which can be transported via receptor mediated endocytosis
Human breast adenocarcinoma (MCF7) cells were obtained from von Kobbe and human cervical cancer (HeLa) cells were obtained from Dr Tierrez
Summary
5-Fluorouracil (5-FU) is one of the chemotherapeutic compounds most used for the treatment of a great variety of tumors [1], such as colorectal cancer [2,3,4], breast cancer [5], pancreatic cancer [6], or gastric cancer [7] It is an antimetabolite of pyrimidine analogue type that acts mainly through the inhibition of synthesis of DNA and RNA during the S-phase of the cell cycle. Many nano-size drug delivery systems (liposomes, liquid-core nanocapsules, dendrimers, polymer-drug conjugates, nanoparticles, polymeric micelles and polymeric nanogels) have been developed [14,15] for the treatment of pathologies as cancer [16,17] Due to their size, nanocarries can penetrate within even small capillaries, and they can be taken up, in many cases, very efficiently by cells, internalized and stored into cytoplasm or different organelles [18]. Administration of 5-FU by drug-loaded folate-conjugate submicrogels can be an approach to achieve high concentrations of the antineoplastic drug near to the target site for a given period of time, increasing its therapeutic effect
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