Radionuclides transform chemotherapeutics into phototherapeutics for precise treatment of disseminated cancer

Nalinikanth Kotagiri,Xinming Xu,Le Moyne Habimana-Griffin ,Lynne Marsala,Mingzhou Zhou,Lu Liu ,Xiaoxia Yang,Michael P Rettig ,Katherine N Weilbaecher ,Gregory M Lanza ,John F Dipersio,Julie L Prior ,Chantiya Chanswangphuwana,Christopher Egbulefu,Partha Karmakar,Grace Cui,Monica Shokeen,Matthew Cooper ,Michael H Tomasson ,Gail Sudlow,Samuel Achilefu

doi:10.1038/s41467-017-02758-9

Nalinikanth Kotagiri, Xinming Xu + Show 19 more

Open Access

https://doi.org/10.1038/s41467-017-02758-9

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Abstract

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.

Highlights

Most cancer patients succumb to disseminated disease because conventional systemic therapies lack spatiotemporal control of their toxic effects in vivo, in a complicated milieu such as bone marrow where progenitor stem cells reside
Using multiple myeloma (MM) and metastatic breast cancer models in mice, we demonstrate that incorporating unmodified and pristine hydrophobic light-sensitive drugs in tumour-targeted lipid nanomicelles or human serum albumin (HSA) nanoparticles, selectively deliver the agents in disseminated cancer cells
Subsequent in vivo administration of a radiopharmaceutical for Cerenkov radiation-induced therapy (CRIT) inhibits the proliferation of disseminated multiple myeloma and aggressive metastatic breast cancer cells in mice

Summary

Introduction

Most cancer patients succumb to disseminated disease because conventional systemic therapies lack spatiotemporal control of their toxic effects in vivo, in a complicated milieu such as bone marrow where progenitor stem cells reside. 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. Using multiple myeloma (MM) and metastatic breast cancer models in mice, we demonstrate that incorporating unmodified and pristine hydrophobic light-sensitive drugs in tumour-targeted lipid nanomicelles or human serum albumin (HSA) nanoparticles, selectively deliver the agents in disseminated cancer cells. Our treatment strategy transforms chemotherapeutics to spatiotemporally photoactivatable drugs using clinically relevant radiopharmaceuticals and expands the use of phototherapy for treating previously inaccessible metastatic disease

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Results