Open AccessOsteotropic Radiolabeled Nanophotosensitizer for Imaging and Treating Multiple Myeloma
Author(s) -
Rui Tang,
Alexander Zheleznyak,
Matthew Mixdorf,
Anchal Ghai,
Julie L. Prior,
Kathleen Black,
Monica Shokeen,
Nathan Reed,
Pratim Biswas,
Samuel Achilefu
Publication year - 2020
Publication title -
acs nano
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.554
H-Index - 382
eISSN - 1936-086X
pISSN - 1936-0851
DOI - 10.1021/acsnano.9b09618
Subject(s) - biodistribution , in vivo , bone marrow , nanomedicine , cancer research , bioluminescence imaging , cancer cell , cancer , chemistry , multiple myeloma , preclinical imaging , positron emission tomography , materials science , medicine , pathology , nuclear medicine , in vitro , nanotechnology , immunology , nanoparticle , biochemistry , biology , gene , transfection , microbiology and biotechnology , luciferase
Rapid liver and spleen opsonization of systemically administered nanoparticles (NPs) for in vivo applications remains the Achilles' heel of nanomedicine, allowing only a small fraction of the materials to reach the intended target tissue. Although focusing on diseases that reside in the natural disposal organs for nanoparticles is a viable option, it limits the plurality of lesions that could benefit from nanomedical interventions. Here we designed a theranostic nanoplatform consisting of reactive oxygen (ROS)-generating titanium dioxide (TiO 2 ) NPs, coated with a tumor-targeting agent, transferrin (Tf), and radiolabeled with a radionuclide ( 89 Zr) for targeting bone marrow, imaging the distribution of the NPs, and stimulating ROS generation for cell killing. Radiolabeling of TiO 2 NPs with 89 Zr afforded thermodynamically and kinetically stable chelate-free 89 Zr-TiO 2 -Tf NPs without altering the NP morphology. Treatment of multiple myeloma (MM) cells, a disease of plasma cells originating in the bone marrow, with 89 Zr-TiO 2 -Tf generated cytotoxic ROS to induce cancer cell killing via the apoptosis pathway. Positron emission tomography/X-ray computed tomography (PET/CT) imaging and tissue biodistribution studies revealed that in vivo administration of 89 Zr-TiO 2 -Tf in mice leveraged the osteotropic effect of 89 Zr to selectively localize about 70% of the injected radioactivity in mouse bone tissue. A combination of small-animal PET/CT imaging of NP distribution and bioluminescence imaging of cancer progression showed that a single-dose 89 Zr-TiO 2 -Tf treatment in a disseminated MM mouse model completely inhibited cancer growth at euthanasia of untreated mice and at least doubled the survival of treated mice. Treatment of the mice with cold Zr-TiO 2 -Tf, 89 Zr-oxalate, or 89 Zr-Tf had no therapeutic benefit compared to untreated controls. This study reveals an effective radionuclide sensitizing nanophototherapy paradigm for the treatment of MM and possibly other bone-associated malignancies.