Tamoxifen-loaded folate-conjugate poly[(p-nitrophenyl acrylate)-co-(N-isopropylacrylamide)] sub-microgel as antitumoral drug delivery system.

Abstract

Folate-conjugate poly[(p-nitrophenyl acrylate)-co-(N-isopropylacrylamide)] sub-microgel (F-SubMG) was loaded with tamoxifen (TMX) to obtain low (9.0 ± 0.4 μg TMX/mg F-SubMG) and high (112.0 ± 15.0 μg TMX/mg F-SubMG) load TMX-loaded F-SubMGs. Maximum in vitro drug release (77 ± 2% to 90 ± 2% of loaded TMX) took place between 47 and 168 h. The cytotoxicity of unloaded F-SubMGs in MCF-7 and HeLa cells was low; although it increased for high F-SubMG concentration. The administration of 10 μM TMX by TMX-loaded F-SubMGs was effective on both cellular types. Cell uptake of F-SubMGs took place in both cell types, but it was larger in HeLa cells because they are folate receptor positive. After subcutaneous administration (2.8 mg TMX/kg b.w.) in Wistar rats, F-SubMGs were detected at the site of injection under the skin, and a significant amount of them were included inside adipocytes. Signs of rejection were not observed after 60 days of injection. Pharmacokinetic study showed an increase in mean residence time of TMX and 4-hydroxytamoxifen (4-OHTMX), as well as a metabolite ratio (MR = AUC(4OHTMX) /AUC(TMX) ) nine times larger, when TMX was administered by drug-loaded F-SubMGs. Since 4-OHTMX is a more potent (at least 100-fold higher) antiestrogen than TMX, administration of TMX-loaded F-SubMGs can be considered an advantage.