Sivaram Amal J, Wardiana Andri, Alcantara Sheilajen, Sonderegger Stefan E, Fletcher Nicholas L, Houston Zachary H, Howard Christopher B, Mahler Stephen M, Alexander Cameron, Kent Stephen J, Bell Craig A, Thurecht Kristofer J
Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD 4072, Australia.
Centre for Advanced Imaging, The University of Queensland, St Lucia, QLD 4072, Australia.
ACS Nano. 2020 Oct 27;14(10):13739-13753. doi: 10.1021/acsnano.0c06033. Epub 2020 Sep 16.
Integrating nanomaterials with biological entities has led to the development of diagnostic tools and biotechnology-derived therapeutic products. However, to optimize the design of these hybrid bionanomaterials, it is essential to understand how controlling the biological interactions will influence desired outcomes. Ultimately, this knowledge will allow more rapid translation from the bench to the clinic. In this paper, we developed a micellar system that was assembled using modular antibody-polymer amphiphilic materials. The amphiphilic nature was established using either poly(ethylene glycol) (PEG) or a single-chain variable fragment (scFv) from an antibody as the hydrophile and a thermoresponsive polymer (poly(oligoethylene glycol) methyl ether methacrylate) as the hydrophobe. By varying the ratios of these components, a series of nanoparticles with different antibody content was self-assembled, where the surface presentation of targeting ligand was carefully controlled. and analysis of these systems identified a mismatch between the optimal targeting ligand density to achieve maximum cell association compared to tumor accumulation . For this system, we determined an optimum antibody density for both longer circulation and enhanced targeting to tumors that balanced stealthiness of the particle (to evade immune recognition as determined in both mouse models and in whole human blood) with enhanced accumulation achieved through receptor binding on tumor cells in solid tumors. This approach provides fundamental insights into how different antibody densities affect the interaction of designed nanoparticles with both target cells and immune cells, thereby offering a method to probe the intricate interplay between increased targeting efficiency and the subsequent immune response to nanoparticles.
将纳米材料与生物实体相结合已推动了诊断工具和生物技术衍生治疗产品的发展。然而，要优化这些杂化生物纳米材料的设计，了解控制生物相互作用如何影响预期结果至关重要。最终，这些知识将使从实验室到临床的转化更加迅速。在本文中，我们开发了一种胶束系统，该系统由模块化抗体 - 聚合物两亲性材料组装而成。两亲性通过使用聚乙二醇（PEG）或抗体的单链可变片段（scFv）作为亲水部分，以及热响应聚合物（聚（寡聚乙二醇）甲基丙烯酸甲酯）作为疏水部分来实现。通过改变这些组分的比例，自组装出一系列具有不同抗体含量的纳米颗粒，其中靶向配体的表面呈现得到了精心控制。对这些系统的分析表明，与肿瘤积累相比，实现最大细胞结合的最佳靶向配体密度之间存在不匹配。对于该系统，我们确定了一个最佳抗体密度，以实现更长的循环时间并增强对肿瘤的靶向性，该密度平衡了颗粒的隐身性（在小鼠模型和全血中均确定为逃避免疫识别）与通过实体瘤中肿瘤细胞上的受体结合实现的增强积累。这种方法为不同抗体密度如何影响设计的纳米颗粒与靶细胞和免疫细胞的相互作用提供了基本见解，从而提供了一种方法来探究提高靶向效率与随后对纳米颗粒的免疫反应之间的复杂相互作用。
