Antifouling Peptide Mimetic Polymers

描述（由申请人提供）：消除或最大限度地减少非特异性生物分子-材料相互作用是改善现有和未来生物材料生物学性能的一个组成部分，因为表面生物污染可能导致器械性能受损、成本增加和患者健康问题。例如，在新兴的纳米医学领域，生物界面相互作用在纳米材料的生物分布、靶向和整体性能方面发挥着重要作用。这项研究的长期目标是：1）了解工程表面和生物分子之间相互作用的基本生物界面现象，特别强调接枝聚合物对非特异性蛋白质吸附的抗性; 2）使用这些信息来指导新型二肽模拟聚合物的设计，用于控制医疗器械和纳米颗粒治疗剂的生物污染。为了实现这一目标，我们将整合实验和理论方法来研究N-取代甘氨酸聚合物（类肽）的生物学特性，并将这些类肽作为纳米颗粒抗癌治疗剂的组成部分。在第一个和第二个目标，我们将结合联合收割机分子理论与一个通用的合成策略和详细的蛋白质吸附的实验测量，开发新的生物活性肽。重点将放在糖萼模拟类肽（糖肽），以及N-甲基甘氨酸类肽（肌氨酸）。这些类肽作为表面接枝聚合物的性能将通过实验评估对非特异性蛋白质和细胞污染的抗性，以及与蛋白质的整合。 这些结果与由分子理论获得的结果将使我们能够理解化学组成和链结构对抗污垢性的影响。在目标3中，这些类肽将被移植到金纳米棒（AuNR）上，用MUC 1抗体修饰，并在体外和体内模型系统中研究抗癌功效。这一目标的一个创新方面涉及使用理论预测来指导类肽的结构和组成设计，以实现增强抗MUC 1修饰的AuNR的细胞摄取的结合表面密度和分布。体外研究将使用AuNR的近红外等离子体特性探测糖肽类生物相容性、细胞靶向效率和光热细胞消融。最后，将使用异种移植肿瘤模型来证明抗MUC 1修饰的AuNR作为癌症治疗的新策略的功效。

DESCRIPTION (provided by applicant): The elimination or minimization of nonspecific biomolecule-material interactions is an integral part of refining the biological performance of existing and future biomaterials, as biofouling of surfaces can lead to compromised device performance, increased cost, and health concerns for the patient. In the emerging field of nanomedicine, for example, biointerfacial interactions play an important role in biodistribution, targeting and overall performance of nanomaterials. The long-term goals of this research are 1) to understand the fundamental biointerfacial phenomena surrounding interactions between engineered surfaces and biomolecules, with a specific emphasis on resistance of grafted polymers to nonspecific protein adsorption; and 2) to use this information to guide the design of novel antifouling peptide mimetic polymers for use in controlling biofouling of medical devices and nanoparticle therapeutics. To accomplish this, we will integrate experimental and theoretical approaches to study the antifouling properties of N-substituted glycine polymers (peptoids), and employ these peptoids as an integral component of a nanoparticle anticancer therapeutic. In the first and second aims, we will combine molecular theory with a versatile synthetic strategy and detailed experimental measurements of protein adsorption to develop novel antifouling peptoids. The focus will be on glycocalyx-mimetic peptoids (glycopeptoids), as well as N-methylglycine peptoid (sarcosine). The performance of these peptoids as surface-grafted polymers will be experimentally evaluated for resistance to nonspecific protein and cell fouling, and integration of these results with those obtained by molecular theory will allow us to understand the effects of chemical composition and chain architecture on fouling resistance. In Aim 3, these peptoids will be grafted onto gold nanorods (AuNRs), modified with MUC1 antibody and investigated for anticancer efficacy in in-vitro and in-vivo model systems. An innovative aspect of this aim involves the use of theoretical predictions to guide the architectural and compositional design of peptoids to achieve bound surface densities and distributions that enhance the cellular uptake of anti-MUC1 modified AuNRs. In-vitro studies will probe glycopeptoid biocompatibility, cell-targeting efficiency, and photothermal cell ablation using the near-infrared plasmonic properties of the AuNRs. Finally, a xenograft tumor model will be used to demonstrate the efficacy of the anti-MUC1 modified AuNRs as a novel strategy for cancer therapy.