FOLATE-TARGETED SUPRAMOLECULAR VESICULAR AGGREGATES BASED ON POLYASPARTYL-HYDRAZIDE COPOLYMERS FOR THE SELECTIVE DELIVERY OF ANTITUMORAL DRUGS

Abstract

Supramolecular vesicular aggregates (SVAs) have the advantage of combining the safe and biocompatible properties of colloidal vesicular carriers based on phospholipids with those of polymeric materials, i.e. polyaspartyl-hydrazide (PAHy) copolymers. To provide SVAs with a certain tumour selectivity, folate moieties were chemically conjugated to PAHy copolymers. Physicochemical properties (mean sizes, polydispersity index and zeta potential) of folate-targeted SVAs (FT-SVAs) loaded with gemcitabine were evaluated. The antiproliferative and anticancer activity of gemcitabine-loaded FT-SVAs was evaluated against two cancer cell lines, i.e. MCF-7 cells which over-express the folate receptor and the BxPC-3 cells, which do not over-express this receptor. Gemcitabine-loaded FT-SVAs showed a significantly (p < 0.001) greater and more specific in vitro anticancer activity with respect to both the free drug and the drug-loaded conventional liposomes or untargeted SVAs. Confocal microscopy, flowcytometry analysis and b-scintillation highlighted that FT-SVAswere able to interact with MCF-7 cells after just 3 h and to increase the amount internalization in cells over-expressing the folate receptor. The in vivo biodistribution and pharmacokinetic experiments showed that gemcitabine-loaded SVAs and FT-SVAs were removed from the circulatory system at a slower rate than the native drug and a prolonged gemcitabine plasma concentration was observed for up to 16 h. SVAswere accumulated mainly in the lungs, spleen and kidneys, while FT-SVAswere also up taken by brain. These interesting and stimulating results suggest the existence of a possible in vivo application of SVAs and encourage the use of folate as a targeting agent in anticancer therapy.