Synthesis and characterization of a new multifunctional polymeric prodrug paclitaxel–polyphosphoester–folic acid for targeted drug delivery

We report here a strategy that allows the preparation of a novel water-soluble polymeric prodrug, paclitaxel–poly(ethyl ethylene phosphate) conjugated with folic acid molecules (abbreviated as PTX–PEEP–FA). PTX was directly used as an initiator for the ring-opening polymerization (ROP) of 2-ethoxy-2-oxo-1,3,2-dioxaphospholane (EOP) under the catalysis of Sn(Oct)2 to fabricate an amphiphilic PTX–PEEP, followed by covalently conjugating a FA moiety via esterification to obtain the biodegradable and targeted polymeric prodrug PTX–PEEP–FA. The chemical structure of the prodrug was characterized by 1H NMR and MALDI-TOF mass spectroscopy. TEM and DLS measurements showed that these prodrugs could self-assemble in aqueous solution to form micelles with PTX as the core and PEEP–FA as the corona, and the average particle size was less than 130 nm. The hydrophobic PTX core could be further used to load more water-insoluble anti-cancer drugs, such as PTX or doxorubicin (DOX), while the hydrophilic PEEP–FA chain endowed micelles with good stability during systemic circulation and significantly improved controlled-release properties compared to free PTX or DOX. Live cell imaging system was utilized to monitor the cellular uptake process of DOX-loaded PTX–PEEP–FA micelles for HeLa and KB cells, respectively. The results revealed that these drug-loaded micelles with FA on their surface could remarkably improve cell endocytosis. In vitro biological evaluations confirmed that PTX–PEEP–FA, simultaneously acted as both a prodrug and drug delivery carrier, could achieve the aims of increased drug loading efficiency, reduced cytotoxicity, and enhanced targeting efficacy.