Reagents for the Design of Targeted Multifunctional Nanomaterials

描述（由申请人提供）：需要最大化肿瘤摄取，最小化其他器官的摄取，这是许多药物输送和成像应用的共同和艰巨的障碍。为了实现这一目标，需要新的化学物质将多个功能基团连接到底物（底物=纳米颗粒，蛋白质，肽）上，因此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轻松检测单个探针在生物系统中的命运。此外，这些化学物质需要同时改变探针的物理性质（如亲水性、电荷），以最大限度地靶向肿瘤。最后，至关重要的是，这些新化学物质为探针提供临床翻译所需的严格定义的化学性质。在多功能材料设计中，这三个问题的解决方案在于一类新的试剂，称为多功能单附着点（MSAP）。MSAP由一个短肽支架组成，多个官能团和一个单一的反应基团，如NHS酯或马来酰亚胺，附着在支架上。然后，MSAP的RG在一次反应中将MSAP（及其多个官能团）附着在底物上，从而产生多功能探针。（注：MSAP试剂+底物=多功能探针）。MSAP试剂中使用的官能团(i)允许在生物系统中确定最终探针的配置（官能团可以是发色团、荧光染料、螯合基团或免疫反应性半抗原），（ii）允许控制和优化最终探针的物理性质（官能团=亲水性聚合物或小型带电结构）。多功能基于MSAP的探针实现了基于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基本特征。我们将通过合成MSAP试剂面板来扩展MSAP化学，并证明它们在三种不同类型底物上的广泛适用性：(i) NP底物，获得增强的胶质瘤靶向),（ii）抗CEA scFv抗体底物（增强的肿瘤CEA靶向），（iii） bombesin （BN）肽底物（增强的肿瘤GRP受体靶向）。

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.