Atherosclerosis is the leading cause of death in the United States. Surgical treatment for this disease often fails due to restenosis. Restenosis is the narrowing of the artery in response to interventions. This response is characterized by the proliferation of Vascular Smooth Muscle Cells (VSMC), which results in neointimal hyperplasia. Inhibiting neointimal hyperplasia can improve surgery outcomes. Cinnamic Aldehyde (CA) is a nrf2 activator that inhibits neointimal hyperplasia. We hypothesized that: 1) Flash NanoPrecipitation (FNP) can achieve high-efficiency encapsulation of bioactive CA conjugates in nanoparticles (NPs); and 2) CA-NPs will activate nrf2 and inhibit VSMC proliferation. CA conjugates of different hydrophobicity were synthesized using hydrazides of different carbon chain length: butyric (C4), and palmitic (C16). A CA-decanoic acid (C10) conjugate was commercially obtained. Synthesis of the conjugates was confirmed by proton nuclear magnetic resonance. CA-NPs were synthesized by FNP using 75% CA conjugate and 25% stabilizing block co-polymer PEG-PLA or Pluronic P84. CA-NPs were characterized by dynamic light scattering and NP tracking analysis (NTA). VSMC were exposed to NPs to assess proliferation by MTT, and nrf2 activation by Western Blot (WB). We synthesized NPs of CA conjugates C10 and C16. The NPs size range from: 102.1 ± 6.9 nm (C10-P84), 118.5 ± 7.2 nm (C10-PLA-PEG), 154.7 ± 0.9 (C16-P84), and 118.4 ± 0.4 (C16-PLAPEG). CA-NPs activated nrf2 as assessed by WB. CA inhibited VSMC proliferation with an EC50 of 230 uM CA. CA-NPs inhibition of the VSMC was statistically significant (p&lt;0.05). We successfully used FNP for high-efficiency encapsulation of CA into NPs. CA-NPs activated nrf2 and inhibited proliferation of VSMC, suggesting that bioactive CA is released.

Cinnamic aldehyde conjugate-based nanoparticles for the treatment of arterial restenosis

255th National Meeting (2018)

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