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Cell-Specific Targeting of Nanoparticles by Multivalent Attachment of Small Molecules

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Nanomaterials with precise biological functions have considerable potential for biomedical applications due to the ability of surface modifications and coating to modulate pharmacokinetic properties. Unlike high-cost conjugated nanoparticles, the small-molecule modification approach is a promising alternative to change the biological properties of nanoparticles by permitting site-specific targeting through its molecule-mediated multivalent binding to cell-surface receptors. The most critical of achieving the approach is to describe the creation of a small-molecule nanoparticle library to develop the magnetofluorescent reporters to rapidly screen the biological activity of the resulting nanomaterials. Specifically, a library of model nanoparticles was screened against different cell lines and states to identify nanomaterials that can distinguish between distinct cell types or different physiological states of a given cell type.

The application of such small-molecule approaches in the preparation of nanomaterials makes it possible for new nanomaterials to be used in a wider range of higher throughput methods in the diagnosis and treatment of disease. The combination between nanotechnology and small-molecule chemistry may lead to the development of new nanomaterials for a wide range of biomedical applications.

Two important materials were used in the study, namely certain chemicals, such as sulfo-NHS, SPDP (N-succinimidyl 3-(2- pyridyldithio) propionate), SIA (succinimidyl iodo acetate), and the nanoparticle synthesis. In more detail, the nanoparticle used in this study was a monocrystalline magnetic nanoparticle with a 3-nm core of (Fe2O3)n(Fe3O4)m, covered with a dextran layer of 10 kDA, cross-linked with epichlorohydrin, and aminated by ammonia reaction to provide primary amine groups. Besides, methods of small molecule conjugation, macrophage differentiation method, screening and in vivo detection of selected fluorescence-labeled compounds in mouse models were used as the basis of the experiment.

1. Using an improved robotic system, 146 different small molecules were conjugated to nanoparticles in an array format to synthesize and purify nanoparticles with water-soluble, magnetic, fluorescent, and long-term storage properties. These synthetic nanoparticles are capable of chemical modification and represent the first step toward creating a nanoparticle library.

2. In order to test the nanoparticle library for its effects on mammalian cells, the results of a log of mean cellular uptake of different nanoparticles in five different cell types were screened from over 30 experiments. Studies have shown that these screened unique nanoparticles are capable of changing the cellular affinity and developing more efficiently targeted nanomaterials.

3. The synthesis of two nanoparticles (CLIO-bentri and CLIO-gly) identified through primary screening was expanded to examine the activation status of macrophages that can be detected with selected materials. The result indicates that these compounds are promising candidates for developing more efficient agents for treating autoimmune diseases or detecting vulnerable atherosclerotic plaques. Furthermore, based on these screening results, it has been shown that by modification that on the surface of nanoparticles, non-specific uptake of nanoparticles by macrophages can be reduced, further enhancing other amplification strategies.

4. To determine the compounds that are used to identify preferentially targeted cancer cells but had concomitantly low uptake in macrophages and endothelial cells via experiments. These results suggest that small molecules have modifications that endow nanoparticles with unique functions and promote in vivo targeting.

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