Effect of Surface Chemistry on the Immune Responses and Cellular Interactions of Porous Silicon Nanoparticles

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Title: Effect of Surface Chemistry on the Immune Responses and Cellular Interactions of Porous Silicon Nanoparticles
Author: Shahbazi, Mohammad-Ali
Contributor: University of Helsinki, Faculty of Pharmacy, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy
Thesis level: Doctoral dissertation (article-based)
Abstract: Porous silicon nanoparticles (PSi NPs) have recently drawn increasing interest for therapeutic applications due to their easily modifiable surface, large pore volumes, high surface area, nontoxic nature, and high biocompatibility. Nevertheless, there is no comprehensive understanding about the role of the surface chemistry of these NPs on the biological interactions and the therapeutic effect of the PSi-based nanosystems. Therefore, extensive attempts are still needed for the development of optimal PSi-based therapeutics. The first step for evaluating the biological activity of the NPs was to investigate the potential toxic effects. Accordingly, the immunotoxicity and hemocompatibility of the PSi NPs with different surface chemistries were assessed at different concentrations on the immune cells and red blood cells, since these are the first biological cells in contact with the NPs after intravenous injection. PSi NPs with positively charged amine functional groups showed higher toxicity compared to negatively charged particles. The toxicity of the negatively charged particles was also highly dependent on the hydrophobic nature of the NPs. Moreover, RBC hemolysis and imaging assay revealed a significant correlation between the PSi NP surface chemistry and hemotoxicity. To further understand the impact of the surface chemistry on the immunological effects of the PSi NPs, the immunostimulatory responses induced by a non-toxic concentration of the PSi NPs were evaluated by measuring the maturation of dendritic cells, T cell proliferation and cytokine secretion. Overall, the results suggested that all the PSi NPs containing higher amounts of nitrogen or oxygen on the outermost surface layer have lower immunostimulatory effects than the PSi NPs with higher amounts of C‒H structures on the NPs surface. Combination cancer therapy by the PSi NPs was then studied by evaluating the synergistic therapeutic effects of the nanosystems. Sorafenib-loaded PSi NPs were biofunctionalized with anti-CD326 monoclonal antibody on their surface. The targeted PSi NPs showed a sustained drug release and increased interactions with the breast cancer cells expressing the CD326 antigen on their surface. These NPs also showed higher antiproliferation effect on the CD326 positive cancer cells compared to the pure drug and sorafenib-loaded PSi NPs, suggesting CD326 as an appropriate receptor for the antibody-mediated drug delivery. In addition, anti-CD326 antibody acted as an immunotherapeutic agent by inducing antibody-dependent cellular cytotoxicity and enhancing the interactions of immune cells with cancer cells for the subsequent phagocytosis and cytokine secretion. Next, the development of a stable PSi NP with low toxicity, high cellular internalization, efficient endosomal escape, and optimal drug release profile was tested by using a layer-by-layer method to covalently conjugate polyethyleneimine and poly(methyl vinyl ether-co-maleic acid) copolymers on the surface of the PSi NPs, forming a zwitterionic nanocomposite. The surface smoothness and hydrophilicity of the polymer functionalized NPs improved considerably the colloidal and plasma stability of the NPs. Moreover, the double layer conjugation sustained the drug release from the PSi NPs and improved the cytotoxicity profile of the drug-loaded PSi NPs. In conclusion, this work showed that the surface modification of the PSi NPs with different chemical groups, antibodies and polymers can affect the toxicological profiles, the cellular interactions and the therapeutic effects of the NPs by modifying the charge, stability, hydrophilicity, the drug release kinetics and targeting properties of the PSi NPs.NA
URI: URN:ISBN:978-951-51-0555-4
Date: 2015-02-13
Subject: pharmaceutical Technology
Rights: This publication is copyrighted. You may download, display and print it for Your own personal use. Commercial use is prohibited.

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