Shi Yang, van der Meel Roy, Theek Benjamin, Oude Blenke Erik, Pieters Ebel H E, Fens Marcel H A M, Ehling Josef, Schiffelers Raymond M, Storm Gert, van Nostrum Cornelus F, Lammers Twan, Hennink Wim E
†Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht 3584 CG, The Netherlands.
‡Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht 3584 CX, The Netherlands.
ACS Nano. 2015;9(4):3740-52. doi: 10.1021/acsnano.5b00929. Epub 2015 Apr 6.
Treatment of cancer patients with taxane-based chemotherapeutics, such as paclitaxel (PTX), is complicated by their narrow therapeutic index. Polymeric micelles are attractive nanocarriers for tumor-targeted delivery of PTX, as they can be tailored to encapsulate large amounts of hydrophobic drugs and achiv prolonged circulation kinetics. As a result, PTX deposition in tumors is increased, while drug exposure to healthy tissues is reduced. However, many PTX-loaded micelle formulations suffer from low stability and fast drug release in the circulation, limiting their suitability for systemic drug targeting. To overcome these limitations, we have developed PTX-loaded micelles which are stable without chemical cross-linking and covalent drug attachment. These micelles are characterized by excellent loading capacity and strong drug retention, attributed to π-π stacking interaction between PTX and the aromatic groups of the polymer chains in the micellar core. The micelles are based on methoxy poly(ethylene glycol)-b-(N-(2-benzoyloxypropyl)methacrylamide) (mPEG-b-p(HPMAm-Bz)) block copolymers, which improved the pharmacokinetics and the biodistribution of PTX, and substantially increased PTX tumor accumulation (by more than 2000%; as compared to Taxol or control micellar formulations). Improved biodistribution and tumor accumulation were confirmed by hybrid μCT-FMT imaging using near-infrared labeled micelles and payload. The PTX-loaded micelles were well tolerated at different doses, while they induced complete tumor regression in two different xenograft models (i.e., A431 and MDA-MB-468). Our findings consequently indicate that π-π stacking-stabilized polymeric micelles are promising carriers to improve the delivery of highly hydrophobic drugs to tumors and to increase their therapeutic index.
使用基于紫杉烷的化疗药物（如紫杉醇（PTX））治疗癌症患者时，其狭窄的治疗指数会带来复杂性。聚合物胶束是用于PTX肿瘤靶向递送的有吸引力的纳米载体，因为它们可以被定制以封装大量疏水性药物并实现延长的循环动力学。结果，PTX在肿瘤中的沉积增加，而药物对健康组织的暴露减少。然而，许多负载PTX的胶束制剂在循环中稳定性低且药物释放快，限制了它们用于全身药物靶向的适用性。为了克服这些限制，我们开发了无需化学交联和共价药物连接即可稳定的负载PTX的胶束。这些胶束的特点是具有出色的负载能力和强大的药物保留能力，这归因于PTX与胶束核心中聚合物链的芳族基团之间的π-π堆积相互作用。胶束基于甲氧基聚（乙二醇）-b-（N-（2-苯甲酰氧基丙基）甲基丙烯酰胺）（mPEG-b-p（HPMAm-Bz））嵌段共聚物，这改善了PTX的药代动力学和生物分布，并显著增加了PTX在肿瘤中的积累（与紫杉醇或对照胶束制剂相比增加了2000％以上）。使用近红外标记的胶束和有效载荷的混合μCT-FMT成像证实了生物分布和肿瘤积累的改善。负载PTX的胶束在不同剂量下耐受性良好，同时在两种不同的异种移植模型（即A431和MDA-MB-468）中诱导了完全的肿瘤消退。因此，我们的研究结果表明，π-π堆积稳定的聚合物胶束是有前途的载体，可改善高度疏水性药物向肿瘤的递送并提高其治疗指数。
