Harvard Medical School and Wellman Center for Photomedicine, Massachusetts General Hospital, 65 Landsdowne St., UP-5, Cambridge, MA, 02139, USA.
Harvard Medical School and Wellman Center for Photomedicine, Massachusetts General Hospital, 65 Landsdowne St., UP-5, Cambridge, MA, 02139, USA.
Biomaterials. 2023 May;296:122079. doi: 10.1016/j.biomaterials.2023.122079. Epub 2023 Mar 2.
Self-luminescent photodynamic therapy (PDT) has gained attention owing to its potential to enable effective phototherapy without the bottleneck of shallow light penetration into tissues. However, the biosafety concerns and low cytotoxic effect of self-luminescent reagents in vivo have been problems. Here, we demonstrate efficacious bioluminescence (BL)-PDT by using bioluminescence resonance energy transfer (BRET) conjugates of a clinically approved photosensitizer, Chlorin e6, and a luciferase, Renilla reniformis; both derived from biocompatible, natural molecules. With over 80% biophoton utilization efficiency and membrane-fusion liposome-assisted intracellular delivery, these conjugates produce effective, targeted cancer cell killing. Specifically, in an orthotopic mouse model of 4T1 triple-negative breast cancer, BL-PDT showed strong therapeutic effects on large primary tumors and a neoadjuvant outcome in invasive tumors. Furthermore, BL-PDT resulted in complete tumor remission and prevention of metastasis for early-stage tumors. Our results demonstrate the promise of molecularly-activated, clinically viable, depth-unlimited phototherapy.
自发光光动力疗法（PDT）因其能够在不受到组织浅层光穿透限制的情况下实现有效光疗而受到关注。然而，自发光试剂在体内的生物安全性问题和低细胞毒性一直是问题所在。在这里，我们使用生物相容性、天然分子衍生的临床批准的光敏剂氯乙酮和荧光素酶 Renilla reniformis 的生物发光共振能量转移（BRET）缀合物，展示了有效的生物发光（BL）-PDT。这些缀合物具有超过 80%的生物光子利用效率和膜融合脂质体辅助的细胞内传递，可有效靶向杀伤癌细胞。具体来说，在 4T1 三阴性乳腺癌的原位小鼠模型中，BL-PDT 对大型原发性肿瘤和侵袭性肿瘤的新辅助治疗效果均表现出强烈的治疗效果。此外，BL-PDT 导致早期肿瘤完全缓解和转移预防。我们的结果表明，分子激活、临床可行、深度不限的光疗具有广阔的应用前景。
