Osteotropic Radiolabeled Nanophotosensitizer for Imaging and Treating Multiple Myeloma

Abstract

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 (TiO2) NPs, coated with a tumor-targeting agent, transferrin (Tf), and radiolabeled with a radionuclide (89Zr) for targeting bone marrow, imaging the distribution of the NPs, and stimulating ROS generation for cell killing. Radiolabeling of TiO2 NPs with 89Zr afforded thermodynamically and kinetically stable chelate-free 89Zr-TiO2-Tf NPs without altering the NP morphology. Treatment of multiple myeloma (MM) cells, a disease of plasma cells originating in the bone marrow, with 89Zr-TiO2-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 89Zr-TiO2-Tf in mice leveraged the osteotropic effect of 89Zr 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 89Zr-TiO2-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-TiO2-Tf, 89Zr-oxalate, or 89Zr-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.

Effect of Graphene Family Materials on Multiple Myeloma and Non-Hodgkin’s Lymphoma Cell Lines

“…Distribution of nanostructures to bone marrow is barely studied so far; however, it has been proven that some nanocarriers can be accumulated in bones [ 54 , 55 , 56 ]. Recent studies by Tang et al showed that TiO 2 nanoparticles can be used as an effective, targeted platform for multiple myeloma imaging and treatment [ 57 ]. However, it has also been demonstrated that the biokinetics of nanoparticles significantly differ between widely studied rodent models and primates [ 58 ], considering bone marrow distributions.…”

Radiolabelling of nanomaterials for medical imaging and therapy

“…734,735 Most of reported examples of CRIT applications are based on the combination of TiO 2 nanoparticles as photosensitiser material with 68 Ga, 64 Cu, 18 F or 89 Zr radionuclides to generate the CL. [736][737][738][739] Apart of TiO 2 nanoparticles, other materials such as iron oxide NPs and porphyrins have shown a remarkable PDT response in combination with 89 Zr, 740,741 opening a very encouraging field within personalised nanomedicine due to the unique properties of the radiolabelled nanomaterials.…”

Pathogenesis and treatment of multiple myeloma

“…Titanium dioxide (TiO 2 ) nanoparticles coated with Tf and radiolabeled with 89 Zr were able to target the BM and image the distribution of nanoparticles in mouse models. Besides, in the presence of 89 Zr, the TiO 2 nanoparticles were able to generate ROS and induce cell death through the apoptosis pathway 209 …”