Reagents for the Design of Targeted Multifunctional Nanomaterials

描述(由申请人提供)：对于许多药物输送和成像应用来说，最大化肿瘤摄取和最小化其他器官摄取的需要是一个常见且令人敬畏的障碍。为了实现这一目标，需要新的化学方法将多个功能基团连接到底物(底物=纳米颗粒、蛋白质、多肽)，这样就可以通过确定探针在细胞、组织和整个动物水平上的配置所需的不同模式来轻松检测单个探针在生物系统中的命运。此外，这些化学成分需要同时改变探针的物理性质(例如，亲水性、电荷)，以最大限度地提高肿瘤靶向性。最后，至关重要的是，这些新的化学成分为探针提供了临床翻译所需的严格定义的化学性质。多功能材料设计中这三个问题的解决方案在于一类新的试剂，称为多功能单连接点(MSAP‘s)。MSAP’s是由多个官能团和单个反应性基团(如NHS酯或马来酰亚胺)连接到的短肽支架。然后，MSAP的RG在单个反应中将MSAP(及其多个官能团)连接到底物上，以产生多功能探针。(注：MSAP试剂+底物=多功能探针)。在MSAP试剂中使用的官能团(I)允许在生物系统中确定所得探针的处置(官能团可以是生色团、荧光染料、螯合基团或免疫反应半抗原)，以及(Ii)允许控制和优化所得探针的物理性质(官能团=亲水性聚合物或小带电结构)。基于MSAP试剂的多功能探针实现了基于MSAP试剂的多个官能团之间的化学计量，这是多功能材料最终临床使用的关键特征。我们将通过合成MSAP试剂板来扩展MSAP化学，并展示它们在三种不同底物中的广泛适用性：(I)NP底物，获得增强的胶质瘤靶向；(Ii)抗CEA单链抗体底物(增强的肿瘤CEA靶向)；(Iii)蛙皮素(BN)肽底物(增强的肿瘤GRP受体靶向)。 与公众健康相关：我们的目标是开发一种新型试剂，用于设计多功能纳米材料，使材料能够通过不同的成像模式进行检测，并使它们能够更有效地靶向肿瘤。

DESCRIPTION (provided by applicant): The need to maximize tumor uptake, and minimize uptake by other organs, is a common and formidable hurdle for many drug delivery and imaging applications. To attain this goal, new chemistries are required that attach multiple functional groups to substrates (substrates = nanoparticles, proteins, peptides), so a single probe's fate in biological systems can be easily detected by the different modalities needed to ascertain probe disposition at the cellular, tissue and whole animal levels. In addition, these chemistries need to simultaneously alter the physical properties of the probe (e.g., hydrophilicity, charge), to maximize tumor targeting. Finally, it is essential that these new chemistries provide probes with the rigorously defined chemical properties needed for the clinical translation. A solution to these three problems in multifunctional materials design lies in a new class of reagents termed Multifunctional Single Attachment Point or MSAP's. MSAP's consist of a short peptide scaffolds to which multiple functional groups and a single reactive group, such an NHS ester or maleimide, are attached. The RG of the MSAP then attaches the MSAP (and its multiple functional groups) to a substrate in a single reaction, to yield a multifunctional probe. (Note: MSAP reagent + substrate = multifunctional probe). The functional groups employed in an MSAP reagent (i) permit the disposition of the resulting probe to be determined in biological systems (functional groups can be chromophores, fluorochromes, chelating groups or immunoreactive haptens) and, (ii) permit the physical properties of the resulting probe to be controlled and optimized (functional groups = hydrophilic polymers or a small charged structures). Multifiunctional MSAP based probes achieve a stoichiometry between multiple functional groups based on the MSAP reagent, a feature essential for the eventual clinical use of multifunctional materials. We shall expand MSAP chemistry by synthesizing MSAP reagent panels and demonstrate their broad applicability with three different types of substrates: (i) a NP substrate, obtaining enhanced glioma targeting), (ii) an anti-CEA scFv antibody substrate (enhanced tumor CEA targeting) and, (iii) a bombesin (BN) peptide substrate (enhanced tumor GRP receptor targeting). PUBLIC HEALTH RELEVANCE: Our goal is the development of a new type of reagent for designing multifunctional nanomaterials that will enable materials to be detected by different imaging modalities and which will enable them to target tumors more effectively.