Molecular design of a high-performance polymeric carrier for delivery of a variety of boronic acid-containing drugs
Molecular design of a high-performance polymeric carrier for delivery of a variety of boronic acid-containing drugs
复制标题
DOI：
10.1016/j.actbio.2020.12.015
复制
发表时间：
2021-01-27
影响因子：
9.7
通讯作者：
Nagasaki, Yukio
中科院分区：
文献类型：
--
作者：
Kim, Ahram;Suzuki, Yuya;Nagasaki, Yukio
由于其许多有用和独特的性质，硼酸非常适合于生物医学应用，如抗肿瘤化疗和硼中子捕获治疗（BNCT）。硼替佐米是一种硼酸衍生物，作为一种有效的蛋白酶体抑制剂引起了人们的广泛关注。然而，由于快速排泄和脱靶效应，含硼酸药物的临床转化受到限制。为此，我们采用聚合物载体来稳定地封装含硼酸的药物，并实现具有靶向药物释放能力的上级药代动力学。因此，为了构建超分子聚合物纳米颗粒，我们利用硼酸和二乙醇胺安装的聚合物载体之间的容易、稳定和pH敏感的缀合。我们通过生成硼替佐米负载的纳米颗粒并将其应用于皮下荷瘤小鼠模型来证明我们的分子设计的可行性。硼替佐米的稳定包封和pH敏感性释放促进了抗肿瘤功效并减轻了肝毒性。我们还验证了我们的方法的多功能性，通过生物学评价的纳米粒子封装苯并（B）噻吩-2-硼酸，苯基硼酸，和对亚苯基二硼酸。声明的重要性几项研究概念化的药物输送系统硼替佐米。然而，大多数这些研究通过物理截留或不可裂解的缀合来包封硼替佐米。前者容易导致硼替佐米过早泄漏，而后者则可能损害硼替佐米的活性。为此，为了实现硼替佐米的稳定包封和控制释放，我们开发了一种新型的聚合物载体。因为我们利用硼酸和二乙醇胺安装的聚合物载体之间的简便、可逆和pH敏感的缀合，我们的分子设计不仅能够包封硼替佐米，而且能够包封各种含硼酸的药物。值得注意的是，聚合物载体的两亲性通过药物的包封和pH敏感性释放来调节，分别诱导纳米颗粒的自组装和塌陷。(c)2020 Acta Materialia Inc.由爱思唯尔有限公司出版。保留所有权利。
Because of their many useful and unique properties, boronic acids are well suited for biomedical applications such as antitumor chemotherapy and boron neutron capture therapy (BNCT). Bortezomib, a boronic acid derivative, has drawn a lot of attention as a potent proteasome inhibitor. Nevertheless, because of rapid excretion and off-target effects, the clinical translation of boronic acid containing drugs is limited. To this end, we employed a polymeric carrier to stably encapsulate boronic acid-containing drugs and achieve superior pharmacokinetics with an on-target drug release capability. Accordingly, to construct a supramolecular polymeric nanoparticle, we took advantage of the facile, stable, and pH-sensitive conjugation between boronic acids and diethanolamine-installed polymeric carriers. We demonstrated the feasibility of our molecular design by generating and applying bortezomib-loaded nanoparticles to a subcutaneous tumor-bearing mouse model. Stable encapsulation and pH-sensitive release of bortezomib facilitated antitumor efficacy and alleviated hepatotoxicity. We also verified the versatility of our approach through biological evaluations of the nanoparticles encapsulating benzo(b)thiophene-2-boronic acid, phenylboronic acid, and p-phenylene-diboronic acid.Statement of significanceSeveral studies conceptualized drug delivery systems for bortezomib. However, most of these studies encapsulate bortezomib by physical entrapment or non-cleavable conjugations. The former is prone to premature leakage of bortezomib, and the latter is likely to compromise the activity of bortezomib. To this end, to achieve stable encapsulation and controlled release of bortezomib, we developed a novel polymeric carrier. Because we took advantage of facile, reversible, and pH-sensitive conjugation between boronic acid and diethanolamine-installed polymeric carrier, our molecular design is capable of encapsulating not only bortezomib but also a variety of boronic acid-containing drugs. Notably, the amphiphilicity of the polymeric carrier is regulated by encapsulation and pH-sensitive release of drugs, respectively inducing self-assembly and collapse of the nanoparticles.(c) 2020 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.