title: Positron emission tomography based analysis of long-circulating cross-linked triblock polymeric micelles in a U87MG mouse xenograft model and comparison of DOTA and CB-TE2A as chelators of copper-64.
abstract: Copolymers of ABC-type (PEG-PHEMA-PCMA) architecture were prepared by atom transfer radical polymerization and formulated as micelles with functionalizable primary alcohols in the shell-region (PHEMA-block) to which the metal-ion chelators DOTA or CB-TE2A were conjugated. Using this micelle system we compared the in vivo stabilities of DOTA and CB-TE2A as chelators of (64)Cu in micelle nanoparticles. The coumarin polymer (PCMA-block) micelle core was cross-linked by UV irradiation at 2 W/cm(2) for 30 min. The cross-linked micelles were labeled with (64)Cu at room temperature for 2 h (DOTA) or 80 °C for 3 h (CB-TE2A), giving labeling efficiencies of 60-76% (DOTA) and 40-47% (CB-TE2A). (64)Cu-micelles were injected into tumor-bearing mice (8 mg/kg) and PET/CT scans were carried out at 1, 22, and 46 h postinjection. The micelles showed good blood stability (T1/2: 20-26 h) and tumor uptake that was comparable with other nanoparticle systems. The DOTA micelles showed a biodistribution similar to the CB-TE2A micelles and the tumor uptake was comparable for both micelle types at 1 h (1.9% ID/g) and 22 h (3.9% ID/g) but diverged at 46 h with 3.6% ID/g (DOTA) and 4.9% ID/g (CB-TE2A). On the basis of our data, we conclude that cross-linked PEG-PHEMA-PCMA micelles have long circulating properties resulting in tumor accumulation and that DOTA and CB-TE2A (64)Cu-chelates show similar in vivo stability for the studied micelle system.
authors.affiliation: The Hevesy Laboratory, DTU Nutech, Technical University of Denmark , Roskilde, Denmark.
authors.forename: Andreas I
authors.initials: AI
authors.lastname: Jensen
authors.forename: Tina
authors.initials: T
authors.lastname: Binderup
authors.forename: Pramod
authors.initials: P
authors.lastname: Kumar EK
authors.forename: Andreas
authors.initials: A
authors.lastname: Kjær
authors.forename: Palle H
authors.initials: PH
authors.lastname: Rasmussen
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Andresen
mesh_terms: D000818:Animals; D002614:Chelating Agents / Q000032:analysis / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D056831:Coordination Complexes / Q000032:analysis / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D003301:Copper Radioisotopes / Q000032:analysis / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000032:analysis / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D005260:Female; D005909:Glioblastoma / Q000378:metabolism; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry; D051379:Mice; D008819:Mice, Nude; D008823:Micelles; D053758:Nanoparticles / Q000032:analysis / Q000737:chemistry / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000378:metabolism; D009942:Organometallic Compounds / Q000737:chemistry; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography; D014466:Ultraviolet Rays
chemical_list: C483895:(4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo(6.6.2)hexadecane)copper(II); D002614:Chelating Agents; D056831:Coordination Complexes; D003301:Copper Radioisotopes; D004337:Drug Carriers; D006573:Heterocyclic Compounds, 1-Ring; D008823:Micelles; D009942:Organometallic Compounds; D011108:Polymers; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid