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. 2020 Apr 28;14(4):4255-4264.
doi: 10.1021/acsnano.9b09618. Epub 2020 Apr 6.

Osteotropic Radiolabeled Nanophotosensitizer for Imaging and Treating Multiple Myeloma

Rui Tang  1 , Alexander Zheleznyak  1 , Matthew Mixdorf  1 , Anchal Ghai  1 , Julie Prior  1 , Kvar C L Black  1 , Monica Shokeen  1   2 , Nathan Reed  3 , Pratim Biswas  3 , Samuel Achilefu  1   2   4
Affiliations

Osteotropic Radiolabeled Nanophotosensitizer for Imaging and Treating Multiple Myeloma

Rui Tang et al. ACS Nano. .

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.

Keywords: Cerenkov radiation; Zr-89; cancer; multiple myeloma; nanoparticles.

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Conflict of interest statement

COMPETING INTERESTS

The authors have declared that no competing interest exists.

Figures

Figure 1:
Figure 1:
Synthesis of 89Zr-TiO2-Tf (A): Radio-TLC profile of 89Zr labeled TiO2 challenged with 10 mM DTPA solution and (B): radiolabeling efficiency of 89Zr-TiO2-Tf with different amounts of TiO2 NPs.
Figure 2:
Figure 2:
Characterization of 89Zr-TiO2-Tf: Ligand challenge stability data acquired with size-exclusion chromatography at 0, 24, 48 and 72 h incubation at 37 °C in saline (A), 10 mM DTPA in water (B), 10 mM DFO in water (C), and mouse serum (D).
Figure 3:
Figure 3:
Characterization of 89Zr-TiO2-Tf: (A) DLS analysis of the cold Zr labeled TiO2-Tf NPs size distribution. (B) Representative TEM images of cold Zr labeled TiO2-Tf NPs; (C) Representative TEM image of TiO2-Tf NPs.
Figure 4:
Figure 4:
In vitro properties of 89Zr-TiO2-Tf: (A) cell-free ROS production 24 h, 48 h, and 72 h after treatment with the indicated compounds; (B) MM1.S cell viability in response to different amounts of 89Zr activity after treatment for 72 h; (C) ROS production by MM1.S cells 72 h after treatment with 89Zr-TiO2-Tf, 89Zr, and TiO2 compared to the untreated cells; (D) MM1.S cell viability 72 h after treatment with indicated compounds; (E) active caspase-3 levels in MM1.S cells 72 h after being treated with the indicated compounds. 89Zr is used as 89Zr-oxalate.
Figure 5:
Figure 5:
In vivo properties of 89Zr-TiO2-Tf in Fox Chase SCID beige triple-immunodeficient mice (6 weeks old): (A) small animal PET/CT sagittal projections of images acquired 48 h after drug administration; (B) SUV for selected organs of interest obtained from images acquired 48 h after drug administration; (C) biodistribution of 89Zr-TiO2-Tf, 89Zr-Tf, and 89Zr-oxalate obtained with γ-emissions; (D) biodistribution comparison of Ti in Zr-TiO2-Tf (blue) and 89Zr-TiO2-Tf (red) acquired with ICP-OES 168 h after administration of compounds (60 μg of each), p = 0.08 for bone uptake; (E) TiO2 distribution between the BM and bone matrix acquired with ICP-OES.
Figure 6:
Figure 6:
Therapeutic efficacy of 89Zr-TiO2-Tf: Therapeutic study of 89Zr-TiO2-Tf (1.11 MBq/60 μg) in SCID mice bearing MM1.S: (A) in vivo drug delivery tracking by PET 48 h after administration, (B) rate of tumor growth (whole body photon flux) in response to 89Zr-TiO2-Tf, (C) rate of tumor progression (whole body photon flux) in response to treatment with Zr-TiO2-Tf, (D) rate of tumor progression in response to treatment with 89Zr-oxalate and 89Zr-Tf, (E) representative BLI images showing tumor localization 50 days after implantation.
Scheme 1:
Scheme 1:
Illustration of 89Zr radiolabeling of TiO2 NP and 89Zr-TiO2-Tf formation
See this image and copyright information in PMC

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