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

Biomacromolecules. 2014 May 12;15(5):1625-33. doi: 10.1021/bm401871w. Epub 2014 Apr 7.

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.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Chelating Agents / analysis
  • Chelating Agents / chemistry*
  • Chelating Agents / metabolism
  • Chelating Agents / pharmacokinetics
  • Coordination Complexes / analysis
  • Coordination Complexes / chemistry
  • Coordination Complexes / metabolism
  • Coordination Complexes / pharmacokinetics
  • Copper Radioisotopes / analysis
  • Copper Radioisotopes / chemistry*
  • Copper Radioisotopes / metabolism
  • Copper Radioisotopes / pharmacokinetics
  • Disease Models, Animal
  • Drug Carriers / analysis
  • Drug Carriers / chemistry*
  • Drug Carriers / metabolism
  • Drug Carriers / pharmacokinetics
  • Female
  • Glioblastoma / metabolism
  • Heterocyclic Compounds, 1-Ring / chemistry
  • Mice
  • Mice, Nude
  • Micelles*
  • Nanoparticles / analysis
  • Nanoparticles / chemistry
  • Nanoparticles / metabolism
  • Neoplasms, Experimental / metabolism
  • Organometallic Compounds / chemistry
  • Polymers / chemical synthesis
  • Polymers / chemistry*
  • Polymers / metabolism
  • Polymers / pharmacokinetics*
  • Positron-Emission Tomography*
  • Ultraviolet Rays

Substances

  • (4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo(6.6.2)hexadecane)copper(II)
  • Chelating Agents
  • Coordination Complexes
  • Copper Radioisotopes
  • Drug Carriers
  • Heterocyclic Compounds, 1-Ring
  • Micelles
  • Organometallic Compounds
  • Polymers
  • 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid