In Vitro and In Vivo Studies on HPMA-Based Polymeric Micelles Loaded with Curcumin.
In Vitro and In Vivo Studies on HPMA-Based Polymeric Micelles Loaded with Curcumin.
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DOI：
10.1021/acs.molpharmaceut.0c01114
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发表时间：
2021-03-01
影响因子：
4.9
通讯作者：
Hennink WE
中科院分区：
文献类型：
--
作者：
Bagheri M;Fens MH;Kleijn TG;Capomaccio RB;Mehn D;Krawczyk PM;Scutigliani EM;Gurinov A;Baldus M;van Kronenburg NCH;Kok RJ;Heger M;van Nostrum CF;Hennink WE
以聚乙二醇-b-聚（N-2-苯甲酰氧基丙基甲基丙烯酰胺）（mPEG-b-p（HPMA-Bz））为载体，制备了姜黄素聚合物胶束。姜黄素负载胶束通过纳米沉淀法使用具有不同分子量的疏水嵌段（5.2、10.0和17.1 kDa）的mPEG 5 kDa-b-p（HPMA-Bz）共聚物制备。在相同的姜黄素负载量下，由mPEG 5 kDa-b-p（HPMA-Bz）17. lkDa组成的胶束在37 °C下在磷酸盐缓冲盐水（PBS）和血浆中均显示出比基于具有较小疏水嵌段的嵌段共聚物的胶束更好的姜黄素保留。使用不对称流场流分级（AF 4）在血浆中孵育24 h期间未观察到胶束尺寸变化，证明了颗粒稳定性。然而，22-49%的姜黄素负载在24小时期间从胶束中释放，分别从血浆中具有最高至最低分子量p（HPMA-Bz）的制剂。AF 4分析进一步表明，释放的姜黄素随后被白蛋白溶解。体外分析表明，姜黄素负载的mPEG 5 kDa-b-p（HPMA-Bz）17.1kDa胶束被不同类型的癌细胞内化，导致姜黄素诱导的细胞死亡。在小鼠中以50 mg姜黄素/kg的剂量静脉内施用姜黄素负载的Cy 7标记的mPEG 5 kDa-b-p（HPMA-Bz）17.1kDa胶束显示胶束的长循环半衰期（t1/2 = 42 h），与AF 4结果一致。相反，姜黄素的循环时间比胶束的循环时间短得多（t1/2α = 0.11，t1/2β = 2.5 h），但比已报道的游离姜黄素（t1/2α = 0.02 h）长1.5倍。与体外研究相比，姜黄素在体内的更快清除可归因于姜黄素与血细胞的相互作用。尽管这些胶束具有优异的增溶作用，但在神经母细胞瘤荷瘤小鼠中没有实现细胞抑制作用，这可能是因为Neuro 2A细胞对姜黄素的敏感性低。
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.
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