title: Evaluation of cytotoxic and tumor targeting capability of (177)Lu-DOTATATE-nanoparticles: a trailblazing strategy in peptide receptor radionuclide therapy.
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-(177)Lu-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 (177)Lu-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 (177)Lu-DOTATATE (3.5 ± 0.31 %) and uncoated-(177)Lu-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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Nuclear Medicine, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Geetanjali
authors.initials: G
authors.lastname: Arora
authors.affiliation: Department of Textile Technology, Indian Institute of Technology, New Delhi, India.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Dubey
authors.affiliation: Department of Nuclear Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, Punjab, India.
authors.forename: Jaya
authors.initials: J
authors.lastname: Shukla
authors.affiliation: Department of Textile Technology, Indian Institute of Technology, New Delhi, India.
authors.forename: Sourabh
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Department of Nuclear Medicine, All India Institute of Medical Sciences, New Delhi, India. guru47@gmail.com.
authors.forename: Gurupad
authors.initials: G
authors.lastname: Bandopadhyaya
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D045744:Cell Line, Tumor; D018997:Chorionic Gonadotropin, beta Subunit, Human / Q000276:immunology; D005240:Feasibility Studies; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry; D008297:Male; D058990:Molecular Targeted Therapy; D053758:Nanoparticles / Q000737:chemistry*; D015282:Octreotide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D009942:Organometallic Compounds / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D011092:Polyethylene Glycols / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D051381:Rats; D017481:Receptors, Somatostatin / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D018997:Chorionic Gonadotropin, beta Subunit, Human; D009942:Organometallic Compounds; D017481:Receptors, Somatostatin; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D011092:Polyethylene Glycols; C447941:lutetium Lu 177 dotatate; D015282:Octreotide
keywords: Anti-β-hCG antibodies; Glioblastoma multiforme; Nephrotoxicity; PLGA nanoparticles; Peptide receptor radionuclide therapy; Somatostatin receptor positive tumors