Bioconjug Chem. 2020 May 20;31(5):1344-1353. doi: 10.1021/acs.bioconjchem.0c00079. Epub 2020 Apr 10.
Mitochondria are therapeutic targets in many diseases including cancer, metabolic disorders, and neurodegenerative diseases. Therefore, strategies to deliver therapeutics of interest to mitochondria are important for therapeutic development. As delocalized lipophilic cations (DLCs) preferentially accumulate in mitochondria, DLC-conjugation has been utilized to facilitate therapeutic delivery systems with mitochondrial targeting capability. Here we report that upon DLC-conjugation, anionic polymers exhibit significantly improved mitochondrial targeting when compared to cationic polymers and charge-neutral polymers. Considering that the cell membrane generally bears a net negative charge, the observed phenomenon is unexpected. Notably, the DLC-conjugated anionic polymers circumvent endosomal entrapment. The rapid mitochondrial accumulation of DLC-conjugated anionic polymers is likely a membrane-potential-driven process, along with the involvement of the mitochondrial pyruvate carrier. Moreover, the structural variations on the side chain of DLC-conjugated anionic polymers do not compromise the overall mitochondrial targeting capability, widely extending the applicability of anionic macromolecules in therapeutic delivery systems.
线粒体是许多疾病（包括癌症、代谢紊乱和神经退行性疾病）的治疗靶点。因此，将治疗药物递送到线粒体的策略对于治疗开发非常重要。由于非定位亲脂性阳离子（DLCs）优先积聚在线粒体中，因此已利用 DLC 缀合来促进具有线粒体靶向能力的治疗性递送系统。在这里，我们报告说，与阳离子聚合物和电荷中性聚合物相比，阴离子聚合物在 DLC 缀合后表现出明显改善的线粒体靶向性。考虑到细胞膜通常带有净负电荷，观察到的现象出乎意料。值得注意的是，DLC 缀合的阴离子聚合物避免了内体捕获。DLC 缀合的阴离子聚合物的快速线粒体积累可能是一个膜电位驱动的过程，同时涉及线粒体丙酮酸载体。此外，DLC 缀合的阴离子聚合物侧链上的结构变化不会影响整体线粒体靶向能力，广泛扩展了阴离子大分子在治疗性递送系统中的适用性。
