Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, 3-25-14 Tonomachi, Kawasaki-ku, Kawasaki, 212-0821, Japan.
Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, 3-25-14 Tonomachi, Kawasaki-ku, Kawasaki, 212-0821, Japan.
Biomaterials. 2021 Jan;267:120463. doi: 10.1016/j.biomaterials.2020.120463. Epub 2020 Oct 23.
The crucial balance of stability in blood-circulation and tumor-specific delivery has been suggested as one of the challenges for effective bench-to-bedside translation of nanomedicines (NMs). Herein, we developed a supramolecularly enabled tumor-extracellular (T) pH-triggered NM that can maintain the micellar structure with the entrapped-drug during systemic circulation and progressively release drug in the tumor by rightly sensing heterogeneous tumor-pH. Desacetylvinblastine hydrazide (DAVBNH), a derivative of potent anticancer drug vinblastine, was conjugated to an aliphatic ketone-functionalized poly(ethylene glycol)-b-poly(amino acid) copolymer and the hydrolytic stability of the derived hydrazone bond was efficiently tailored by exploiting the compartmentalized structure of polymer micelle. We confirmed an effective and safe therapeutic application of T pH-sensitive DAVBNH-loaded micelle (T-micelle) in orthotopic glioblastoma (GBM) models, extending median survival to 1.4 times in GBM xenograft and 2.6 times in GBM syngeneic model, compared to that of the free DAVBNH. The work presented here offers novel chemical insights into the molecular design of smart NMs correctly sensing T-pH via programmed functionalities. The practical engineering strategy based on a clinically relevant NM platform, and the encouraging therapeutic application of T-micelle in GBM, one of the most lethal human cancers, thus suggests the potential clinical translation of this system against other types of common cancers, including GBM.
在纳米医学（NM）从实验室向临床转化的过程中，如何实现血液循环稳定性和肿瘤靶向输送之间的平衡一直是一个巨大的挑战。本文构建了一种基于超分子组装的肿瘤细胞外（T）pH 响应型 NM，该纳米载体在血液循环中能够保持药物包载的胶束结构，并通过正确感知肿瘤的异质性 pH 实现药物的持续释放。我们将具有强抗癌活性的长春碱衍生物去乙酰长春碱腙（DAVBNH）偶联到脂肪族酮功能化的聚乙二醇-聚氨基酸共聚物上，利用聚合物胶束的分隔结构有效调控了腙键的水解稳定性。我们在原位胶质母细胞瘤（GBM）模型中证实了 T pH 敏感型 DAVBNH 载药胶束（T-胶束）具有有效的治疗效果和安全性，与游离 DAVBNH 相比，其在 GBM 异种移植和 GBM 同基因模型中的中位生存期分别延长了 1.4 倍和 2.6 倍。本研究为通过程序功能正确感知 T-pH 的智能 NM 的分子设计提供了新的化学见解。该工作基于一种临床相关 NM 平台的实用工程策略，以及 T-胶束在 GBM 中的令人鼓舞的治疗应用，提示该系统具有针对其他常见癌症（包括 GBM）进行临床转化的潜力。
