pH-responsive micelles composed of poly(ethylene glycol) and cholesterol-modified poly(monomethyl itaconate) as a nanocarrier for controlled and targeted release of piroxicam

Abstract

A novel monomethyl itaconate-based copolymer (PEG-PMMI-CholC(6)) bearing cholesteryl (CholC(6)) and poly(ethylene glycol) (PEG) side chains with specific degrees of side-chain substitution (DSChol=4.85 and DSPEG=16.41) was synthesized by performing a reaction involving cholesterol-containing poly(monomethyl itaconate) (PMMI-CholC(6)) and polyethylene glycol monomethyl ether (PEG, M-W similar to 2000). In aqueous solution, reversible pH-responsive micelle-like aggregates of PMMI-CholC(6) and PEG-PMMI-CholC(6) amphiphilic copolymers formed, with their phase transitions occurring around pH 3.8 and 5.12, respectively. The presence of the PEG groups improved the hydrophilicity of the copolymer and suppressed excessive micelle aggregation. The critical micelle concentration (CMC) of the PEG-PMMI-CholC(6) copolymeric micelles at pH5.12 was about 1 mg/L. DLS and TEM studies revealed that the spherical micelles had mean diameters of <50 nm, which increased in basic solution. On the other hand, upon increasing the pH, the zeta potential decreased from -0.645 to -47.1 due to increased negative charge on the surfaces of the micelles. These pH-responsive micelles were then loaded with piroxicam (PX), a hydrophobic anticancer drug. High drug entrapment efficiencies (>40 %) of the PEG-PMMI-CholC(6) micelles were observed due to the enhanced surface hydrophilicity of these micelles. In vitro release studies performed in buffer solutions at pH 1.2, 4.5, and 7.4 indicated that the PEG-PMMI-CholC(6) delivery system can act as a stable nanocarrier allowing controlled drug release at target sites in the pH range 4.5-7.4. Interestingly, MTT assays indicated that the PEG-PMMI-CholC(6) micelles did not inhibit HeLa cells regrowth, even at high micellar concentrations. These results suggest that PEG-PMMI-CholC(6) micelles have great potential to be safely used in tumor-targeting chemotherapy.