Abstract
Objective
We propose an innovative strategy of nanoparticle-mediated-peptide receptor radionuclide therapy (PRRT) employing PLGA-nanoparticles together with anti-β-hCG antibodies that can protect kidneys from radiation damage while simultaneously enhancing its tumor targeting and cytotoxic ability for somatostatin receptor (SSR) positive tumors.
Methods
PEG-coated-177Lu-DOTATATE-PLGA-nanoparticles (PEG-LuD-NP) were formulated and characterized. In vitro toxicity of these particles was tested on human glioblastoma cell line U87MG over a radiation dose range of 19–78 Gy, using MTT assay and flow cytometry. To further enhance cytotoxicity and test the feasibility of active tumor targeting, apoptosis-inducing anti-β-hCG monoclonal antibodies were employed in vitro, after confirming expression of β-hCG on U87MG. In vivo tumor targeting ability of these particles, in comparison to uncoated particles and un-encapsulated 177Lu-DOTATATE, was assessed by intravenous administration in tumor-induced wistar rats. Rats were first imaged in a gamma camera followed by euthanasia for organ extraction and counting in gamma counter.
Results
The particles were spherical in shape with mean diameter of 300 nm. Highest cytotoxicity that could be achieved with PEG-LuD-NP, on radio-resistant U87MG cells, was 35.8 % due to complex cellular response triggered by ionizing radiation. Interestingly, synergistic action of antibodies and PEG-LuD-NP doubled the cytotoxicity (80 %). PEG-LuD-NP showed the highest tumor uptake (4.3 ± 0.46 % ID/g) as compared to 177Lu-DOTATATE (3.5 ± 0.31 %) and uncoated-177Lu-DOTATATE-nanoparticles (3.4 ± 0.35 %) in tumor-inoculated wistar rats (p < 0.001). Renal uptake/retention was decreased 3–4 folds with these particles, resulting in the highest tumor-to-kidney ratio (8.58; p < 0.01) while tumor-to-liver and tumor-to-bone ratios were comparable to un-encapsulated-drug.
Conclusion
Nanocarrier-mediated-PRRT is an effective way of targeting SSR positive tumors for enhanced cytoxicity and reduced renal radiation dose associated with conventional PRRT. To our knowledge of literature, this is the first study to establish in vitro and in vivo efficacy profile of nanoparticles in PRRT providing a stepping-stone for undergoing and future research endeavors in the direction of abating associated radiation concerns of radionuclide therapy and may offer a paradigm shift in PRRT strategy.
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Acknowledgements
Authors are thankful to the faculty and staff of Sophisticated Analytical Instrument Facility (SAIF) at All India Institute of Medical Sciences (AIIMS, New Delhi, India) set up by Department of Science and Technology (New Delhi, India) for the support and guidance provided for electron microscope studies. The authors are also thankful to Dr. G.P. Talwar, Talwar Research Foundation (Saket, Delhi, India) for the kind gift of anti-β-hCG antibodies. We express our gratitude to Dr. D.K. Mitra, Department of Immunology, AIIMS and to Dr. A.K. Dinda, Department of Pathology, AIIMS, New Delhi, India, for their cooperation in flow cytometry and histopathology studies respectively. The work was funded by Department of Science and Technology (Government of India), New Delhi, India under “Nanomission” scheme.
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Arora, G., Dubey, P., Shukla, J. et al. Evaluation of cytotoxic and tumor targeting capability of 177Lu-DOTATATE-nanoparticles: a trailblazing strategy in peptide receptor radionuclide therapy. Ann Nucl Med 30, 334–345 (2016). https://doi.org/10.1007/s12149-016-1067-x
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DOI: https://doi.org/10.1007/s12149-016-1067-x