Evaluation of cytotoxic and tumor targeting capability of 177 Lu-DOTATATE-nanoparticles: a trailblazing strategy in pept
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ORIGINAL ARTICLE
Evaluation of cytotoxic and tumor targeting capability of 177Lu-DOTATATE-nanoparticles: a trailblazing strategy in peptide receptor radionuclide therapy Geetanjali Arora1 • Priyanka Dubey2 • Jaya Shukla3 • Sourabh Ghosh2 Gurupad Bandopadhyaya1
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Received: 21 December 2015 / Accepted: 29 January 2016 Ó The Japanese Society of Nuclear Medicine 2016
Abstract Objective We propose an innovative strategy of nanoparticle-mediated-peptide receptor radionuclide therapy (PRRT) employing PLGA-nanoparticles together with anti-b-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-b-hCG monoclonal antibodies were employed in vitro, after confirming expression of b-hCG on U87MG. In vivo tumor targeting ability of these
Electronic supplementary material The online version of this article (doi:10.1007/s12149-016-1067-x) contains supplementary material, which is available to authorized users. & Gurupad Bandopadhyaya [email protected] 1
Department of Nuclear Medicine, All India Institute of Medical Sciences, New Delhi, India
2
Department of Textile Technology, Indian Institute of Technology, New Delhi, India
3
Department of Nuclear Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, Punjab, India
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 177LuDOTATATE (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 viv
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