Encapsulating a Hydrophilic Chemotherapeutic into Rod-Like Nanoparticles of a Genetically Encoded Asymmetric Triblock Polypeptide Improves Its Efficacy
Encapsulating a Hydrophilic Chemotherapeutic into Rod-Like Nanoparticles of a Genetically Encoded Asymmetric Triblock Polypeptide Improves Its Efficacy
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DOI：
10.1002/adfm.201605421
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发表时间：
2017-03-24
影响因子：
19
通讯作者：
Chilkoti, Ashutosh
中科院分区：
文献类型：
--
作者：
Bhattacharyya, Jayanta;Weitzhandler, Isaac;Chilkoti, Ashutosh
将亲水性化疗药物包裹到聚合物纳米粒的核心可以通过增加它们的血浆半衰期、肿瘤蓄积和细胞内摄取，以及通过保护它们免受过早降解来提高它们的治疗效果。为了实现这些目标，设计了一种重组不对称三嵌段多肽(ATBP)，它可以自组装成棒状纳米粒子，并可用于将包括化疗药物在内的各种亲水性分子连接到其核心。这些ATBP由三个片段组成：可生物降解的弹性蛋白样多肽、疏水性富含酪氨酸的片段和富含半胱氨酸的短片段，它们自发地自组装成棒状胶束。一组结构不同的亲水性小分子，包括亲水性化疗药物-吉西他滨-与半胱氨酸残基的共价连接也导致在一定范围的ATBP浓度范围内形成纳米颗粒。在小鼠癌症模型中，与游离药物相比，载吉西他滨的ATBP纳米粒具有显著更好的肿瘤消退效果。这种通过与ATBP偶联来包裹亲水性小分子的简单策略可以用于在体内有效地输送一系列水溶性药物和显像剂。
Encapsulating hydrophilic chemotherapeutics into the core of polymeric nanoparticles can improve their therapeutic efficacy by increasing their plasma half-life, tumor accumulation, and intracellular uptake, and by protecting them from premature degradation. To achieve these goals, a recombinant asymmetric triblock polypeptide (ATBP) that self-assembles into rod-shaped nanoparticles, and which can be used to conjugate diverse hydrophilic molecules, including chemotherapeutics, into their core is designed. These ATBPs consist of three segments: a biodegradable elastin-like polypeptide, a hydrophobic tyrosine-rich segment, and a short cysteine-rich segment, that spontaneously self-assemble into rod-shaped micelles. Covalent conjugation of a structurally diverse set of hydrophilic small molecules, including a hydrophilic chemotherapeutic-gemcitabine-to the cysteine residues also leads to formation of nanoparticles over a range of ATBP concentrations. Gemcitabine-loaded ATBP nanoparticles have significantly better tumor regression compared to free drug in a murine cancer model. This simple strategy of encapsulation of hydrophilic small molecules by conjugation to an ATBP can be used to effectively deliver a range of water-soluble drugs and imaging agents in vivo.