Biomimetic Dendrimer-Exosome Hybrid Nanoparticles for Efficient Cancer Targeting

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Non-Technical Part: The present program is unique in that it will mimic a naturally occurring targeting mechanism of exosomes (are cell-derived vesicles) and take advantage of efficient targeting and tumor penetration behaviors of dendrimers. This approach will have implications, and potentially high reward in the emerging area of Biomimetic Nanotechnology. Successful achievement of the proposed study will: i) significantly advance the understanding on cancer targeting using multiple targeting mechanisms; ii) establish a database describing biotic/abiotic combinations that control the biological responses; and ultimately iii) present a novel, transformative platform technology for targeted cancer therapy in a truly personalized manner.The study of the proposed biomimetic hybrid nanoparticles will lead to a new paradigm for designing a personalized medicine with maximum targeting efficacy, without immunogenicity issues, which will ultimately offer an effective therapeutic delivery platform for patients suffering from cancers and other debilitating disease. The PI will create and expand the education and outreach activities. First, this proposed study will provide excellent opportunities in interdisciplinary training and career development of graduate students. Second, this project intimately incorporates research training for undergraduate students from University of Wisconsin-Madison as well as other local community colleges that have limited resources. Third, this research program will be integrated with an outreach plan that aims to provide hands-on science experiences to K-12 students and teachers to spark their interests in STEM. For broader dissemination, we will produce a couple of YouTube videos highlighting basic polymer chemistry and our nanocarrrier research.Technical Abstract:Although recent advances in nanotechnology have culminated in a myriad of promising delivery platforms for tumor targeting, successful clinical implementation of such technologies has been hindered largely due to a lack of understanding on nano-bio interactions, resulting in unmet targeting efficacy, immunogenicity, and toxicity of nanocarriers. Here a novel delivery system is proposed that integrates engineered poly(amidoamine) (PAMAM) dendrimers and biologically extracted exosomes derived from human mesenchymal stem cells (hMSCs). It is hypothesized that overall tumor targeting of the novel biomimetic hybrid nanoparticles, or BioHNPs, will be significantly enhanced, with minimized potential immunogenicity or toxicity concerns. Specifically, BioHNPs will take advantage of three unique mechanisms: i) hMSC homing to inflamed tissue, involving rolling, firm adhesion, and extravasation, which is frequently observed in activated, angiogenic cancerous regions; ii) dendrimer-mediated multivalent targeting; and iii) efficient penetration of dendrimers across tumor tissue. In addition, using such exosomes derived from individual patients as outer layers of the nanocarriers, this approach will ultimately achieve truly personalized medicine, which will be potentially transformative in designing and engineering not only BioHNPs proposed here but also other novel nanocarriers. The new design of the nanocarriers will be validated via a series of physicochemical and biological assays through achieving three objectives: i) Functionalization and hybridization of hMSC-derived exosomes and PAMAM dendrimers; ii) In vitro selectivity tests of BioHNPs against endothelial and cancer cells; and iii) Tumor spheroid model study for tissue penetration and diffusion of BioHNPsThis award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.