Reagents for the Design of Targeted Multifunctional Nanomaterials

点击翻译按钮获取中文摘要

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.