Oligo(lactic acid)n-Paclitaxel Prodrugs for Poly(ethylene glycol)-block-poly(lactic acid) Micelles: Loading, Release, and Backbiting Conversion for Anticancer Activity.

Poly(ethylene glycol)-block-poly(d,l-lactic acid) (PEG-b-PLA) micelles are nanocarriers for poorly water-soluble anticancer agents and have advanced paclitaxel (PTX) to humans due to drug solubilization, biocompatibility, and dose escalation. However, PEG-b-PLA micelles rapidly release PTX, resulting in widespread biodistribution and low tumor exposure. To improve delivery of PTX by PEG-b-PLA micelles, monodisperse oligo(l-lactic acid), o(LA)8 or o(LA)16, has been coupled onto PTX at the 7-OH position, forming ester prodrugs: o(LA)8-PTX and o(LA)16-PTX, respectively. As expected, o(LA)n-PTX was more compatible with PEG-b-PLA micelles than PTX, increasing drug loading from 11 to 54%. While in vitro release of PTX was rapid, resulting in precipitation, o(LA)n-PTX release was more gradual: t1/2 = 14 and 26 h for o(LA)8-PTX and o(LA)16-PTX, respectively. Notably, o(LA)8-PTX and o(LA)16-PTX in PEG-b-PLA micelles resisted backbiting chain end scission, based on reverse-phase HPLC analysis. By contrast, o(LA)8-PTX and o(LA)16-PTX degraded substantially in 1:1 acetonitrile:10 mM PBS, pH 7.4, at 37 °C, generating primarily o(LA)2-PTX. The IC50 value of o(LA)2-PTX was ∼2.3 nM for A549 human lung cancer cells, equipotent with PTX in vitro. After weekly IV injections at 20 mg/kg as PEG-b-PLA micelles, o(LA)8-PTX induced tumor regression in A549 tumor-bearing mice, whereas PTX delayed tumor growth. Surprisingly, o(LA)8-PTX caused less toxicity than PTX in terms of change in body weight. In conclusion, o(LA)n acts as a novel promoiety, undergoing backbiting conversion without a reliance on metabolizing enzymes, and o(LA)n-PTX improves PTX delivery by PEG-b-PLA micelles, providing a strong justification for clinical evaluation.