Molecular Cardiology Research Institute, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA.
A.A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Nat Biomed Eng. 2022 Sep;6(9):1045-1056. doi: 10.1038/s41551-022-00904-3. Epub 2022 Jul 11.
Autophagy-the lysosomal degradation of cytoplasmic components via their sequestration into double-membraned autophagosomes-has not been detected non-invasively. Here we show that the flux of autophagosomes can be measured via magnetic resonance imaging or serial near-infrared fluorescence imaging of intravenously injected iron oxide nanoparticles decorated with cathepsin-cleavable arginine-rich peptides functionalized with the near-infrared fluorochrome Cy5.5 (the peptides facilitate the uptake of the nanoparticles by early autophagosomes, and are then cleaved by cathepsins in lysosomes). In the heart tissue of live mice, the nanoparticles enabled quantitative measurements of changes in autophagic flux, upregulated genetically, by ischaemia-reperfusion injury or via starvation, or inhibited via the administration of a chemotherapeutic or the antibiotic bafilomycin. In mice receiving doxorubicin, pre-starvation improved cardiac function and overall survival, suggesting that bursts of increased autophagic flux may have cardioprotective effects during chemotherapy. Autophagy-detecting nanoparticle probes may facilitate the further understanding of the roles of autophagy in disease.
自噬 - 通过将细胞质成分隔离到双层自噬体中来实现的溶酶体降解 - 尚未进行非侵入性检测。在这里，我们展示了可以通过磁共振成像或静脉内注射的氧化铁纳米粒子的连续近红外荧光成像来测量自噬体的通量，这些纳米粒子用天冬氨酸蛋白酶可切割的富含精氨酸的肽进行了修饰，并用近红外荧光染料 Cy5.5 进行了功能化（这些肽有助于早期自噬体摄取纳米粒子，然后被溶酶体中的天冬氨酸蛋白酶切割）。在活鼠的心脏组织中，纳米粒子使通过缺血再灌注损伤或饥饿引起的或通过给予化疗药物或抗生素巴弗洛霉素抑制的自噬通量的变化能够进行定量测量。在接受多柔比星的小鼠中，预先饥饿可改善心脏功能和总体存活率，表明在化疗过程中，自噬通量的爆发性增加可能具有心脏保护作用。自噬检测纳米粒子探针可能有助于进一步了解自噬在疾病中的作用。
