Toll-like receptors (TLRs) play a large role in the recognition of pathogens and modulation of the immune system. Specifically, TLR-4 and TLR-9 are activated by bacterial products and contribute to the initiation and progression of a variety of conditions, such as liver fibrosis, inflammation, and autoimmune disease. The purpose of this work is to synthesize a single liposomal spherical nucleic acid (LSNA) nanoparticle capable of dual inhibition of TLRs 4 and 9 by encapsulating TAK-242, a small molecule inhibitor of TLR4, and functionalizing the surface of the particle with a TLR-9 antagonizing oligonucleotide. We compared different lipid ratios of DOPC, DOPE, DPPC and cholesterol to form the core of the nanoparticle, and delineated size, and encapsulation efficiency of TAK-242. Liposome sizes ranged from 35-60nm. Once functionalized with the TLR-9 targeting moiety, the final LSNA is 50-85nm in diameter. Our group has already shown that in vitro cultured mouse macrophages treated with DOPC liposomes functionalized with a TLR9 targeting oligonucleotide on the surface demonstrate a further suppressed TLR9 downstream response when compared to treatment with dexamethasone, a commonly used anti-inflammatory steroid. These particles are also highly taken up by both murine and human cell lines. These results indicate that dual-target regulation is possible with sub-100nm LSNA particles, which will benefit circulation and clearance times in vivo. These constructs are also easily modulated to encapsulate fluorophores, other small molecules or oligonucleotides, and can additionally be functionalized with targeting peptides or dye-labeled oligonucleotides, which allows tailoring of the material for a wide range of applications. <br/>

Design and synthesis of a dual-targeting liposomal spherical nucleic acid

249th National Meeting (2015)

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