(700d) Development of a Metal Tungstate-Based Nanoparticle Platform for CT-Guided Chemo/Radio Therapy

X-ray computed tomography (CT) is currently one of the most powerful, non-invasive, clinical in vivo imaging techniques, which has resulted from advances in both X-ray device and contrast enhancement technologies. Our recent work demonstrates that metal tungstates (such as CaWO₄) are promising contrast agents for X-ray, radiation and CT imaging, because of the high X-ray mass attenuation of tungsten. We have developed a method of formulation, in which CaWO₄ (CWO) nanoparticles (NPs) are encapsulated within a bio-compatible poly(ethylene glycol-b-D,L-lactic acid) (PEG-PLA) block copolymer (BCP) capsule. BCP-encapsulated CWO NPs can be used as radio-sensitizers that make cancer cells easier to kill with radiation therapy [1]. The self-assembled nature of BCP-encapsulated CWO NPs is also expected to enable incorporation of additional therapeutic modalities (such as anticancer drugs) inside the hydrophobic domain, thus combining chemo therapeutic and radiological imaging capabilities. As a first step toward realizing this potential, we tested the in vivo safety and radio contrast capability of BCP-encapsulated CWO NPs.

CWO NPs were synthesized by a micro-emulsion method [2]. The PEG-PLA BCP material was synthesized by ring-opening polymerization. CWO NPs were encapsulated with PEG-PLA using a solvent exchange method. This procedure produced fully PEGylated CWO NPs that are devoid of impurities and stable against aggregation under physiological solution conditions for very long periods of time (> several months).

This encapsulated CWO has been confirmed to possess no detectable cytotoxicity against cultured human cancer cells (p53-mutant HN31). A study is in progress to determine the maximum tolerated dose (MTD) of BCP-coated CWO NPs in mice (BALB/C). As of the time of this writing, it has been confirmed that the MTD of this material is, at least, 200 mg per kg body weight following a single i.v. administration; this material is thus, at least, as safe as commercially available dextran-coated iron oxide nanoparticles that are currently used clinically as MRI contrast agents (MTD in mice â?? 168 mg/kg per dose i.v.). Major excretory organs (heart, liver, lungs, spleen and kidney) were harvested for histopathologic detection of gross organ damage. No organ damage was detected.

Compared with the conventional radio-contrast agents (iodine and barium), CWO has a significantly higher X-ray absorbing capability because X-ray mass attenuation increases as approximately Z³ (Z is the atomic number, Z = 53 (I), 56 (Ba), and 74 (W)); in the range of X-ray energy used for most diagnostic studies (i.e., 10 â?? 100 keV) the mass attenuation coefficient of W is three to four-fold higher than that of I or Ba. Our data confirmed this trend. The X-ray attenuation properties of BCP-coated CWO NPs were measured in comparison with a conventional iodine-based contrast agent (Iohexol). Measurements were performed using a clinical CT scanner instrument (140 kV, 700 mA). Results confirm that at identical molar concentrations of I vs. W atoms, PEGylated CWO NPs produce a higher contrast and lower transmission than Iohexol.

Results to date support that PEG-PLA-coated CWO NPs have the potential to be used as theranostic agents for CT-guided chemo/radio therapy.

References

[1] Y.-Y. Won, J. Lee, S. D. Jo, M. K. Joo, B. S. Lee, S. Y. Kim, S. H. Kim, â??Radio-Luminescent Particles for Enhancement of Radiation Cancer Therapyâ?, pending PCT/U.S. Patent, Application No. 16/12616, filed on January 8, 2016.

[2] J. Lee, N.J. Rancilio, J.M. Poulson, Y.-Y. Won, â??Block-Copolymer-Encapsulated CaWO₄ Nanoparticles: Synthesis, Formulation, and Characterizationâ?, ACS Applied Materials & Interfaces, 8(13), 8608â??8619, 2016 (DOI: 10.1021/acsami.6b00727).