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 H-1 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.