In Vitro and In Vivo Studies on HPMA-Based Polymeric Micelles Loaded with Curcumin

[Image: see text] Curcumin-loaded polymeric micelles composed of poly(ethylene glycol)-b-poly(N-2-benzoyloxypropyl methacrylamide) (mPEG-b-p(HPMA-Bz)) were prepared to solubilize and improve the pharmacokinetics of curcumin. Curcumin-loaded micelles were prepared by a nanoprecipitation method using mPEG(5kDa)-b-p(HPMA-Bz) copolymers with varying molecular weight of the hydrophobic block (5.2, 10.0, and 17.1 kDa). At equal curcumin loading, micelles composed of mPEG(5kDa)-b-p(HPMA-Bz)(17.1kDa) showed better curcumin retention in both phosphate-buffered saline (PBS) and plasma at 37 °C than micelles based on block copolymers with smaller hydrophobic blocks. No change in micelle size was observed during 24 h incubation in plasma using asymmetrical flow field-flow fractionation (AF(4)), attesting to particle stability. However, 22–49% of the curcumin loading was released from the micelles during 24 h from formulations with the highest to the lowest molecular weight p(HPMA-Bz), respectively, in plasma. AF(4) analysis further showed that the released curcumin was subsequently solubilized by albumin. In vitro analyses revealed that the curcumin-loaded mPEG(5kDa)-b-p(HPMA-Bz)(17.1kDa) micelles were internalized by different types of cancer cells, resulting in curcumin-induced cell death. Intravenously administered curcumin-loaded, Cy7-labeled mPEG(5kDa)-b-p(HPMA-Bz)(17.1kDa) micelles in mice at 50 mg curcumin/kg showed a long circulation half-life for the micelles (t(1/2) = 42 h), in line with the AF(4) results. In contrast, the circulation time of curcumin was considerably shorter than that of the micelles (t(1/2α) = 0.11, t(1/2β) = 2.5 h) but ∼5 times longer than has been reported for free curcumin (t(1/2α) = 0.02 h). The faster clearance of curcumin in vivo compared to in vitro studies can be attributed to the interaction of curcumin with blood cells. Despite the excellent solubilizing effect of these micelles, no cytostatic effect was achieved in neuroblastoma-bearing mice, possibly because of the low sensitivity of the Neuro2A cells to curcumin.