具有高亲和力的靶向金纳米团簇的合理设计用于整合性癌症治疗，靶向整合素αvβ3

Rational Design of Targeted Gold Nanoclusters with High Affinity to Integrin αvβ3 for Combination Cancer Therapy

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BIOCONJUGATE CHEMISTRY

影响因子:3.9

分区:化学2区 / 生化研究方法2区有机化学2区生化与分子生物学3区化学：综合3区

发表日期:2024 Jul 15

作者: María Francisca Matus, Hannu Häkkinen

DOI: 10.1021/acs.bioconjchem.4c00248

摘要

靶向纳米药物递送系统（TNDDS）相较于传统癌症治疗具有抑制非目标效应的独特优势，因此成为癌症治疗中最有潜力的方案之一。有研究表明，表面结合配体的密度是实现TNDDS预期治疗效果的关键因素，但在常规纳米材料中难以精确控制。在此背景下，配体保护的金纳米团簇（AuNCs）因其表面功能的可控性而成为开发新型TNDDS的理想候选，有助于实现更优的递送性能。本研究采用分子动力学模拟和伞状采样法，研究了十种不同功能化的Au144(SR)60（SR为硫醇配体）纳米团簇与整合素αvβ3的相互作用与结合自由能，以优化配方。这些AuNCs被功能化以携带抗癌药物（5-氟尿嘧啶或信号通路抑制剂，如capivasertib、linifanib、tanespimycin和taselisib）以及整合素靶向肽（RGD4C或QS13），我们筛选出最优的混合配体层以增强其与癌细胞受体的结合亲和力。结果显示，改变AuNCs表面相同类型配体的比例，导致结合自由能计算值差异高达38 kcal/mol。以RGD4C作为靶向肽的配方显示出更高的αvβ3亲和力，在大多数研究的配方中，所需药物量多于肽。极性和带电残基（如Ser123、Asp150、Tyr178、Arg214和Asp251）在AuNC的结合中发挥重要作用。模拟还揭示，Mn2+阳离子对于稳定αvβ3-AuNC复合物至关重要。这些发现表明，精心设计TNDDS的表面组成，有望优化其靶向亲和力和特异性，提升治疗效果。

Abstract

The unique attributes of targeted nano-drug delivery systems (TNDDSs) over conventional cancer therapies in suppressing off-target effects make them one of the most promising options for cancer treatment. There is evidence that the density of surface-conjugated ligands is a crucial factor in achieving the desired therapeutic efficacy of TNDDSs, but this is hardly manageable in conventional nanomaterials. In this context, ligand-protected gold nanoclusters (AuNCs) are excellent candidates for developing new TNDDSs with a unique control on their surface functionalities, thus helping to achieve enhanced delivery performance. Here, we study the interactions and binding free energies between ten different functionalized Au144(SR)60 (SR = thiolate ligand) nanoclusters and integrin αvβ3 using molecular dynamics simulations and the umbrella sampling method to obtain the optimal formulations. The AuNCs were functionalized with anticancer drugs (5-fluorouracil or signaling pathways inhibitors, such as capivasertib, linifanib, tanespimycin, and taselisib) and integrin-targeting peptides (RGD4C or QS13), and we identified the optimal mixed ligand layer to enhance their binding affinity to the cancer cell receptor. The results showed that changing the proportions of the same type of ligands on the surface of AuNCs led to differences of up to 38 kcal/mol in computed binding free energies. RGD4C as the targeting peptide resulted in greater affinity for αvβ3, and in most formulations studied, a higher amount of drug than peptide was needed. Polar and charged residues, such as Ser123, Asp150, Tyr178, Arg214, and Asp251 were found to play a significant role in AuNC binding. Our simulations also revealed that Mn2+ cations are crucial for stabilizing the αvβ3-AuNC complex. These findings demonstrate the potential of carefully designing the surface composition of TNDDSs to optimize their target affinity and specificity.