| dc.description.abstract | Procedures to treat occlusive vascular diseases, such as stenting, angioplasty, and bypass grafting, often fail due to intimal hyperplasia (IH), where contractile vascular smooth muscle cells (VSMCs) dedifferentiate to synthetic VSMCs, which are highly proliferative, inflammatory, and fibrotic and contribute to thickening of the intima layer that necessitates further intervention. Current treatments for IH consist of administration of proliferation-targeting drugs, such as paclitaxel and sirolimus. While these drugs are somewhat effective, they non-specifically inhibit cell proliferation, preventing regeneration of the protective endothelial layer that is essential for long-term vessel stability. Therefore, there is a need for a therapy that inhibits IH after vascular interventions by targeting VSMC phenotype switching and allowing for vessel re-endothelialization.
Here, we establish MAPKAP kinase 2 (MK2) as a critical node in VSMC phenotype switching and a potential target for IH prevention. Using an MK2 inhibitory peptide (MK2i) electrostatically complexed with poly(propyl acrylic acid) (PPAA) into MK2i nanopolyplexes (MK2i-NPs), we show that long-lasting MK2 inhibition leads to broad genetic changes in VSMCs that maintain their healthy contractile phenotype. Through a brief intraoperative MK2i-NP treatment, we were able to significantly block IH development and VSMC phenotype switching in an in vivo rabbit bypass graft model.
Success with MK2i-NP treatment led us to adapt MK2i+PPAA therapy for in vivo delivery to prevent IH at sites of angioplasty. We validated and optimized two methods of intravascular MK2i+PPAA delivery – convective perfusion and a layer-by-layer (LbL) drug coated balloon (DCB). Both of these delivery methods achieved long-term retention and bioactivity of MK2i in ex vivo rat aortas incubated in a flow loop bioreactor system, leading to significantly inhibited cell proliferation, fibrosis, and phenotype switching in the vascular wall. Finally, an in vivo rat carotid artery balloon injury model was used to assess the translatability of the MK2i DCB. The MK2i DCB significantly blocked angioplasty-induced IH development 14 days after surgery by inhibiting hallmarks of VSMC phenotype switching. Together, we have shown the effectiveness of targeting MK2 as a therapy for IH inhibition after vascular interventions, and we have optimized two translatable intravascular delivery methods for MK2i administration to sites of angioplasty. | |
