Radionuclides transform chemotherapeutics into phototherapeutics for precise treatment of disseminated cancer

• Published in: Nature communications Vol. 9; no. 1; pp. 275 - 12
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.01.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 147/143; 49/91; 59/5; 59/78; 631/67/1059/602; 631/67/1344; 639/925/352/152; 64/60; 64/86; 96/106; 96/31; Animals; Biocompatibility; Bone marrow; Breast cancer; Cancer; CD49d antigen; Cell Line; Disease control; Drug Resistance, Neoplasm; Drugs; Female; Human serum albumin; Humanities and Social Sciences; Integrin alpha4beta1; Localization; Mammary Neoplasms, Experimental - therapy; Metastases; Metastasis; Mice, Inbred C57BL; Mice, SCID; Micelles; Molecular Targeted Therapy; multidisciplinary; Multiple myeloma; Multiple Myeloma - therapy; Nanoparticles; Organometallic Compounds - administration & dosage; Photochemotherapy; Phototherapy; Proteomics; Radioisotopes; Radiopharmaceuticals - administration & dosage; Rats; Science; Science (multidisciplinary); Serum albumin; Serum Albumin, Human; Stem cells; Toxicity; Xenograft Model Antitumor Assays
• ISSN: 2041-1723; 2041-1723
• 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. Most of the systemic cancer therapies lack spatiotemporal control. Here, the authors show targeted activation of a light-sensitive drug by radiopharmaceuticals in disseminated cancer cells as potential in vivo treatment of metastatic diseases with reduced off-target toxicity.