Shu Chien-Gene Lay Department of Bioengineering and the Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, California 92093, United States.
Department of Chemistry, International Institute for Nanotechnology, Simpson-Querrey Institute, Chemistry of Life Processes Institute, Northwestern University, Evanston, Illinois 60208, United States.
Biomacromolecules. 2023 Nov 13;24(11):4695-4704. doi: 10.1021/acs.biomac.3c00421. Epub 2023 Sep 11.
Herein, we have developed a drug-loaded matrix metalloproteinase (MMP)-responsive micellar nanoparticle (NP) intended for minimally invasive intravenous injection during the acute phase of myocardial infarction (MI) and prolonged retention in the heart for small-molecule drug delivery. Peptide-polymer amphiphiles (PPAs) bearing a small-molecule MMP inhibitor (MMPi), PD166793, were synthesized via ring-opening metathesis polymerization (ROMP) and formulated into spherical micelles by transitioning to aqueous solution. The resulting micellar NPs underwent MMP-induced aggregation, demonstrating enzyme responsiveness. Using a rat MI model, we observed that these NPs were capable of successfully extravasating into the infarcted region of the heart where they were retained due to the active, enzyme-mediated targeting, remaining detectable after 1 week post administration without increasing macrophage recruitment. Furthermore, studies show that these NPs demonstrated successful drug release following MMP treatment and maintained drug bioactivity as evidenced by comparable MMP inhibition to free MMPi. This work establishes a targeted NP platform for delivering small-molecule therapeutics to the heart after MI, opening possibilities for myocardial infarction treatment.
在此，我们开发了一种载药基质金属蛋白酶 (MMP) 响应胶束纳米颗粒 (NP)，旨在在心肌梗死 (MI) 的急性期进行微创静脉注射，并在心脏内长时间保留以进行小分子药物输送。通过开环复分解聚合 (ROMP) 合成了带有小分子 MMP 抑制剂 (MMPi) 的肽-聚合物两亲物 (PPA)，并通过过渡到水溶液形成球形胶束。所得胶束 NP 经历了 MMP 诱导的聚集，表现出酶响应性。使用大鼠 MI 模型，我们观察到这些 NP 能够成功地渗出到心脏的梗死区域，由于主动的、酶介导的靶向作用，它们在给药后 1 周仍可检测到，而不会增加巨噬细胞募集。此外，研究表明，这些 NP 在 MMP 处理后表现出成功的药物释放，并保持药物生物活性，因为与游离 MMPi 相比，具有相当的 MMP 抑制作用。这项工作为 MI 后向心脏输送小分子治疗药物建立了一个靶向 NP 平台，为心肌梗死治疗开辟了可能性。
