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

Supramolecular vesicular aggregates (SVAs) have the advantage of combining the safe and biocompatibleproperties 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, folatemoieties were chemically conjugated to PAHy copolymers. Physicochemical properties (mean sizes, polydispersityindex 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 againsttwo cancer cell lines, i.e. MCF-7 cells which over-express the folate receptor and the BxPC-3 cells, which donot over-express this receptor. Gemcitabine-loaded FT-SVAs showed a significantly (p < 0.001) greater andmore specific in vitro anticancer activity with respect to both the free drug and the drug-loaded conventionalliposomes or untargeted SVAs. Confocal microscopy, flowcytometry analysis and b-scintillation highlightedthat FT-SVAswere able to interact with MCF-7 cells after just 3 h and to increase the amount internalizationin cells over-expressing the folate receptor. The in vivo biodistribution and pharmacokinetic experimentsshowed that gemcitabine-loaded SVAs and FT-SVAs were removed from the circulatory system at a slowerrate 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 andencourage the use of folate as a targeting agent in anticancer therapy.