Proline Isomerization-Regulated Tumor Microenvironment-Adaptable Self-Assembly of Peptides for Enhanced Therapeutic Efficacy
Proline Isomerization-Regulated Tumor Microenvironment-Adaptable Self-Assembly of Peptides for Enhanced Therapeutic Efficacy
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脯氨酸异构化调节的肿瘤微环境——肽的适应性自组装以增强治疗功效。
DOI：
10.1021/acs.nanolett.9b03136
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发表时间：
2019-11-01
期刊：
影响因子：
10.8
通讯作者：
Yu, Zhilin
中科院分区：
文献类型：
--
作者：
Li, Mingming;Ning, Yashan;Yu, Zhilin
纳米药物由于在药物动力学和靶向递送肿瘤组织方面的优势，已被证明是有前途的癌症治疗策略。然而，创建能够在整个递送过程中内在地和空间地优化药物细胞摄取的递送平台仍然具有挑战性。为了应对这一挑战，在这里，我们报告了肿瘤微环境适应性自组装（TMAS）的五肽调节的pH敏感的顺反异构化的4-氨基-脯氨酸（NH 4）酰胺键，以增强药物输送和光动力治疗（PDT）的功效。我们发现，降低溶液pH值导致顺式-反式异构化的N-二甲酰胺键，从而促进可逆的自组装五肽FF-N-FF（AmpF）成超螺旋和纳米粒子后，交替暴露于中性和弱酸性条件。肽AmpF与其含有光敏剂二氢卟酚e6（AmpF-C）的衍生物的共组装允许产生经历适应细胞摄取途径中存在的pH梯度的形态转变的TMAS系统。离体研究表明，与形态持久性纳米药物相比，TMAS纳米药物延长了动物体内的循环，并改善了肿瘤部位的积累。除了优化的细胞摄取之外，与纳米颗粒对应物相比，TMAS在细胞质中向纳米纤维的形态转变导致细胞内ROS水平提高，从而导致癌细胞的半致死剂量值降低。TMAS的综合优势最终允许体内PDT治疗显著抑制肿瘤生长，从而证明了TMAS系统对新一代纳米医学的改善的药物递送效率和治疗功效。
Nanomedicines have been demonstrated as promising strategies for cancer therapy due to the advantages in pharmacokinetics and drug targeting delivery to tumor tissues. However, creation of delivery platforms able to intrinsically and spatially optimize drug cellular uptake during entire delivering process remain challenging. To address this challenge, here we report on tumor microenvironment-adaptable self-assembly (TMAS) of pentapeptides regulated by the pH-sensitive cis-trans isomerization of 4-amino-proline (Amp) amide bonds for enhanced drug delivery and photodynamic therapeutic (PDT) efficacy. We found that decreasing solution pH led to the cis trans isomerization of Amp amide bonds, thus promoting reversible self-assembly of pentapeptide FF-Amp-FF (AmpF) into superhelices and nanoparticles upon alternating exposure to neutral and mild acidic conditions. Co-assembly of peptide AmpF with its derivative containing a photosensitizer Chlorin e6 (AmpF-C) allows for creation of TMAS systems undergoing a morphological transition adaptable to the pH gradient present in cellular uptake pathway. Ex vivo studies revealed that TMAS nanomedicines prolonged circulation in animal body and improved accumulation at tumor sites compared to morphological persistent nanomedicines. In addition to the optimized cellular uptake, the morphological transition of TMAS into nanofibers in cytoplasm caused an enhanced intracellular ROS level compared to nanoparticle counterparts, thus leading to a lower half lethal dose value for cancer cells. The combined advantages of TMAS eventually allowed in vivo PDT therapy for significant inhibition of tumor growth, thus demonstrating the improved drug delivery efficiency and therapeutic efficacy of TMAS systems towards new-generation nanomedicines.