Kotagiri Nalinikanth, Cooper Matthew L, Rettig Michael, Egbulefu Christopher, Prior Julie, Cui Grace, Karmakar Partha, Zhou Mingzhou, Yang Xiaoxia, Sudlow Gail, Marsala Lynne, Chanswangphuwana Chantiya, Lu Lan, Habimana-Griffin LeMoyne, Shokeen Monica, Xu Xinming, Weilbaecher Katherine, Tomasson Michael, Lanza Gregory, DiPersio John F, Achilefu Samuel
Department of Radiology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
James L Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, 45267, USA.
Nat Commun. 2018 Jan 18;9(1):275. doi: 10.1038/s41467-017-02758-9.
Most cancer patients succumb to disseminated disease because conventional systemic therapies lack spatiotemporal control of their toxic effects in vivo, particularly in a complicated milieu such as bone marrow where progenitor stem cells reside. Here, we demonstrate the treatment of disseminated cancer by photoactivatable drugs using radiopharmaceuticals. An orthogonal-targeting strategy and a contact-facilitated nanomicelle technology enabled highly selective delivery and co-localization of titanocene and radiolabelled fluorodeoxyglucose in disseminated multiple myeloma cells. Selective ablation of the cancer cells was achieved without significant off-target toxicity to the resident stem cells. Genomic, proteomic and multimodal imaging analyses revealed that the downregulation of CD49d, one of the dimeric protein targets of the nanomicelles, caused therapy resistance in small clusters of cancer cells. Similar treatment of a highly metastatic breast cancer model using human serum albumin-titanocene formulation significantly inhibited cancer growth. This strategy expands the use of phototherapy for treating previously inaccessible metastatic disease.
大多数癌症患者死于播散性疾病，因为传统的全身治疗在体内缺乏对其毒性作用的时空控制，尤其是在祖干细胞所在的骨髓等复杂环境中。在此，我们展示了使用放射性药物的光激活药物治疗播散性癌症。一种正交靶向策略和接触促进纳米胶束技术能够使二茂钛和放射性标记的氟脱氧葡萄糖在播散性多发性骨髓瘤细胞中实现高度选择性递送和共定位。实现了癌细胞的选择性消融，而对驻留干细胞没有明显的脱靶毒性。基因组、蛋白质组和多模态成像分析表明，纳米胶束的二聚体蛋白靶点之一CD49d的下调导致小簇癌细胞产生治疗抗性。使用人血清白蛋白 - 二茂钛制剂对高度转移性乳腺癌模型进行类似治疗可显著抑制癌症生长。这种策略扩展了光疗在治疗以前难以触及的转移性疾病方面的应用。
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