TY - JOUR
T1 - In Vitro and in Vivo Studies on HPMA-Based Polymeric Micelles Loaded with Curcumin
AU - Bagheri, Mahsa
AU - Fens, Marcel H.
AU - Kleijn, Tony G.
AU - Capomaccio, Robin B.
AU - Mehn, Dora
AU - Krawczyk, Przemek M.
AU - Scutigliani, Enzo M.
AU - Gurinov, Andrei
AU - Baldus, Marc
AU - van Kronenburg, Nicky C. H.
AU - Kok, Robbert J.
AU - Heger, Michal
AU - van Nostrum, Cornelus F.
AU - Hennink, Wim E.
N1 - Funding Information: This work was funded by the European Union’s Horizon 2020 research and innovation program Marie Sklodowska-Curie Innovative Training Networks (ITN) under grant no. 676137. Michal Heger is currently supported by grants from the Dutch Cancer Foundation (KWF project # 10666), National Natural Science Foundation of China (#81872220), a Zhejiang Provincial Foreign Expert Program Grant, Zhejiang Provincial Key Natural Science Foundation of China (#Z20H160031), and a grant for the establishment of the Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics. The SK-ChA-1, Mz-ChA-1 cell lines were kindly received under a license agreement to Michal Heger from Alexander Knuth and Claudia Matter (University Hospital Zurich, Switzerland). The AF data used in this research were generated through access to the Nanobiotechnology Laboratory under the Framework of access to the Joint Research Centre Physical Research Infrastructures of the European Commission (Stability of polymeric micelles in serum, MicStab, Research Infrastructure Access Agreement RIAA 35050/7). 4 Publisher Copyright: © Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/3/1
Y1 - 2021/3/1
N2 - 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 mPEG5kDa-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 mPEG5kDa-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 (AF4), 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. AF4 analysis further showed that the released curcumin was subsequently solubilized by albumin. In vitro analyses revealed that the curcumin-loaded mPEG5kDa-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 mPEG5kDa-b-p(HPMA-Bz)17.1kDa micelles in mice at 50 mg curcumin/kg showed a long circulation half-life for the micelles (t1/2 = 42 h), in line with the AF4 results. In contrast, the circulation time of curcumin was considerably shorter than that of the micelles (t1/2α = 0.11, t1/2β = 2.5 h) but ∼5 times longer than has been reported for free curcumin (t1/2α = 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.
AB - 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 mPEG5kDa-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 mPEG5kDa-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 (AF4), 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. AF4 analysis further showed that the released curcumin was subsequently solubilized by albumin. In vitro analyses revealed that the curcumin-loaded mPEG5kDa-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 mPEG5kDa-b-p(HPMA-Bz)17.1kDa micelles in mice at 50 mg curcumin/kg showed a long circulation half-life for the micelles (t1/2 = 42 h), in line with the AF4 results. In contrast, the circulation time of curcumin was considerably shorter than that of the micelles (t1/2α = 0.11, t1/2β = 2.5 h) but ∼5 times longer than has been reported for free curcumin (t1/2α = 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.
KW - human neuroblastoma xenograft model
KW - in vitro uptake and localization
KW - nanomedicine
KW - pHPMA
KW - pharmacodynamics
KW - pharmacokinetics parameters
UR - http://www.scopus.com/inward/record.url?scp=85100230842&partnerID=8YFLogxK
U2 - https://doi.org/10.1021/acs.molpharmaceut.0c01114
DO - https://doi.org/10.1021/acs.molpharmaceut.0c01114
M3 - Article
C2 - 33464911
SN - 1543-8384
VL - 18
SP - 1247
EP - 1263
JO - Molecular pharmaceutics
JF - Molecular pharmaceutics
IS - 3
ER -