Novel self-assembling PEG-p-(CL-co-TMC) polymeric micelles as safe and effective delivery system for Paclitaxel

Paclitaxel (PTX) is an effective anti-cancer drug currently used to treat a wide variety of cancers. Unfortunately, nonaqueous vehicle containing Cremophor® EL is associated with serious clinical side effects. This work aimed to evaluate the ability of polymeric micelles to (i) solubilize PTX without Cremophor® EL and to be used as a (ii) safe and (iii) effective delivery system for PTX. Hence, we developed novel self-assembling poly(ethyleneglycol)750-block-poly(ε-caprolactone-co-trimethylenecarbonate) (PEG-p-(CL-co-TMC)) polymeric micelles which form micelles spontaneously in aqueous solution. The solubility of PTX increased up to three orders of magnitude. The PTX-loaded micelles showed a slow release of PTX with no burst effect. The HeLa cells viability assessed by the MTT test was lower for PTX-loaded micelles than for Taxol® (IC50 10.6 vs. 17.6 μg/ml). When solubilized in micelles, PTX induced apoptosis comparable with Taxol®. The maximum tolerated doses (MTD) of PTX-loaded micelles and Taxol® in mice were 80 mg/kg and 13.5 mg/kg, respectively, after intraperitoneal administration; and 45 mg/kg and 13.5 mg/kg, respectively, after intravenous administration. Similar anti-tumor efficacy of PTX-loaded micelles and Taxol® was observed at the dose of 13.5 mg/kg on TLT-tumor-bearing mice, while the body weight loss was only observed in Taxol® group. However, as higher dose was tolerated (80 mg/kg – IP), a higher growth delay was induced with PTX-loaded micelles. These results demonstrated that PTX-loaded self-assembling micelles present a similar anti-tumor efficacy as Taxol®, but significantly reduced the toxicity allowing the increase in the dose for better therapeutic response.