title: Two Novel Nanosized Radiolabeled Analogues of Somatostatin for Neuroendocrine Tumor Imaging.
abstract: The somatostatin receptors (SR), which are overexpressed in a majority of neuroendocrine tumors, are targets for radiopeptide-based imaging using for example the 99mTc-Tyr3-Octreotide peptide. Dendrimers are hyperbranched polymeric structures. The nanoscopic size and near-monodisperse nature properties give polyamidoamine (PAMAM) dendrimers an edge over linear polymers in the context of drug delivery. Gold nanoparticles (AuNPs) conjugated to peptides produces stable multimeric systems with target-specific molecular recognition. The aim of this research was to prepare two nanosized multimeric systems for neuroendocrine tumor imaging, 99mTc-PAMAM-Tyr3-Octreotide and 99mTc-AuNP-Tyr-Octreotide, and to compare their in vitro uptake in SR-positive AR42J cancer cells as well as their biodistribution profile in athymic mice bearing AR42J tumors. [Tyr3, Lys(Boc)5]-Octreotide was conjugated to the carboxylate groups of the PAMAM dendrimer (G3.5) with further Boc deprotection using TFA. 99mTc labeling was carried out by a direct method. 99mTc-Tyr3-Octreotide was conjugated to AuNPs (20 nm) by spontaneous reaction with the thiol group of cysteine. Radiochemical purity (RP) was determined by size-exclusion HPLC and ITLC-SG analyses. In vitro binding studies were carried out in AR42J cancer cells. Biodistribution studies were accomplished in athymic mice with AR42J-induced tumors with blocked and unblocked receptors. Elemental analysis demonstrated that 26 Tyr3-Octreotide molecules were successfully conjugated to one molecule of PAMAM. RP for both nanosized conjugates was > 94% and showed recognition for SR in AR42J cells. The tissue distribution of radioactivity 2 h after 99mTc-PAMAM-Tyr3-Octreotide administration in mice showed specific tumor uptake (4.12 ± 0.57% of injected dose/g) and high accumulation in the pancreas (15.08 ± 3.11% of injected dose/g) which expresses SR. No significant difference in the tumor uptake was found between 99mTc-PAMAM-Tyr3-Octreotide and 99mTc-AuNP-Tyr3-Octreotide. However, the dendrimer-peptide conjugate showed a significant renal excretion. Both radiopharmaceuticals demonstrated properties suitable for use as target-specific agents for molecular imaging of tumors that overexpressed SR.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Orocio-Rodríguez
authors.forename: Guillermina
authors.initials: G
authors.lastname: Ferro-Flores
authors.forename: Clara L
authors.initials: CL
authors.lastname: Santos-Cuevas
authors.forename: Flor de María
authors.initials: Fde M
authors.lastname: Ramírez
authors.forename: Blanca E
authors.initials: BE
authors.lastname: Ocampo-García
authors.forename: Erika
authors.initials: E
authors.lastname: Azorín-Vega
authors.forename: Fatima M
authors.initials: FM
authors.lastname: Sánchez-García
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D050091:Dendrimers / Q000737:chemistry; D006046:Gold / Q000737:chemistry*; D008297:Male; D053768:Metal Nanoparticles / Q000737:chemistry*; D051379:Mice; D008819:Mice, Nude; D018358:Neuroendocrine Tumors / Q000000981:diagnostic imaging*; D015282:Octreotide / Q000737:chemistry*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000737:chemistry*; D051381:Rats; D013004:Somatostatin / Q000031:analogs & derivatives*; D013667:Technetium / Q000737:chemistry; D014018:Tissue Distribution
chemical_list: D050091:Dendrimers; D019275:Radiopharmaceuticals; D013004:Somatostatin; D013667:Technetium; D006046:Gold; D015282:Octreotide