Size-tuneable nanometric MRI contrast agents for the imaging of molecular weight dependent transport processes

Mazen M. El-Hammadi, Steven MacLellan, Christine Dufès, William M. Holmes, Barrie Condon, Ijeoma F. Uchegbu, Andreas G. Schatzlein

Research output: Contribution to journalArticle

Abstract

The purpose of the current study was to evaluate size-tuneable polymeric glycol-chitosan (GC)-DTPAGadolinium (Gd) conjugates as MRI contrast agents that can be used as a platform for imaging of molecular weight (MW) dependent transport processes. GC-DTPA-Gd conjugates of precisely controlled MWs were synthesised and evaluated in mice against Gd-DTPA using time series of high-resolution MRI images of trunk, head, and xenograft flank tumours. GC-DTPA modification ratio was one DTPA per 3.9-5.13 of GC monomers. GC-DTAP-Gd provided overall superior contrast compared to Gd-DTPA with the duration of the enhancement depending on MW (≥1hr for 40kD). The kidneys showed early enhancement also, particularly in the renal pelvis, suggesting renal elimination. Imaging of the head with GC-DTPA-Gd allowed detailed anatomical identification of specific blood vessels in particular with the high MW CA agent. Sequential, high-resolution, isotropic imaging of established A431 xenograft flank tumours with DTPA-Gd and GC-DTPA-Gd demonstrated that the initial distribution of the contrast agents was well correlated with blood vessels and supply. In contrast, subsequent tissue transport was primarily by diffusion and limited by CA molecular weight. The data also highlight the role of heterogeneity in CA distribution which was more prominent for the high MW agent. Precise control of glycol chitosan (GC) polymer chemistry facilitates synthesis of a family of Gd-based MRI contrast agents of tuneable MW but otherwise identical physicochemical properties. Such agents allow isotropic high-resolution threedimensional imaging of MW dependent transport processes relevant to the clinical and pre-clinical prediction of drug transport processes.
LanguageEnglish
Pages129-137
Number of pages9
JournalPharmaceutical Nanotechnology
Volume2
Issue number3
DOIs
StatePublished - 2014

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Pentetic Acid
Contrast Media
Molecular Weight
Heterografts
Blood Vessels
Head
Kidney Pelvis
glycol-chitosan
Neoplasms
Polymers
Kidney
glycated chitosan

Keywords

  • gadolinium
  • glycol chitosan
  • molecular weight
  • MRI contrast agents

Cite this

El-Hammadi, M. M., MacLellan, S., Dufès, C., Holmes, W. M., Condon, B., Uchegbu, I. F., & Schatzlein, A. G. (2014). Size-tuneable nanometric MRI contrast agents for the imaging of molecular weight dependent transport processes. Pharmaceutical Nanotechnology, 2(3), 129-137. DOI: 10.2174/2211738503999141222224739
El-Hammadi, Mazen M. ; MacLellan, Steven ; Dufès, Christine ; Holmes, William M. ; Condon, Barrie ; Uchegbu, Ijeoma F. ; Schatzlein, Andreas G./ Size-tuneable nanometric MRI contrast agents for the imaging of molecular weight dependent transport processes. In: Pharmaceutical Nanotechnology. 2014 ; Vol. 2, No. 3. pp. 129-137
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El-Hammadi, MM, MacLellan, S, Dufès, C, Holmes, WM, Condon, B, Uchegbu, IF & Schatzlein, AG 2014, 'Size-tuneable nanometric MRI contrast agents for the imaging of molecular weight dependent transport processes' Pharmaceutical Nanotechnology, vol. 2, no. 3, pp. 129-137. DOI: 10.2174/2211738503999141222224739

Size-tuneable nanometric MRI contrast agents for the imaging of molecular weight dependent transport processes. / El-Hammadi, Mazen M.; MacLellan, Steven; Dufès, Christine; Holmes, William M.; Condon, Barrie; Uchegbu, Ijeoma F.; Schatzlein, Andreas G.

In: Pharmaceutical Nanotechnology, Vol. 2, No. 3, 2014, p. 129-137.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Size-tuneable nanometric MRI contrast agents for the imaging of molecular weight dependent transport processes

AU - El-Hammadi,Mazen M.

AU - MacLellan,Steven

AU - Dufès,Christine

AU - Holmes,William M.

AU - Condon,Barrie

AU - Uchegbu,Ijeoma F.

AU - Schatzlein,Andreas G.

PY - 2014

Y1 - 2014

N2 - The purpose of the current study was to evaluate size-tuneable polymeric glycol-chitosan (GC)-DTPAGadolinium (Gd) conjugates as MRI contrast agents that can be used as a platform for imaging of molecular weight (MW) dependent transport processes. GC-DTPA-Gd conjugates of precisely controlled MWs were synthesised and evaluated in mice against Gd-DTPA using time series of high-resolution MRI images of trunk, head, and xenograft flank tumours. GC-DTPA modification ratio was one DTPA per 3.9-5.13 of GC monomers. GC-DTAP-Gd provided overall superior contrast compared to Gd-DTPA with the duration of the enhancement depending on MW (≥1hr for 40kD). The kidneys showed early enhancement also, particularly in the renal pelvis, suggesting renal elimination. Imaging of the head with GC-DTPA-Gd allowed detailed anatomical identification of specific blood vessels in particular with the high MW CA agent. Sequential, high-resolution, isotropic imaging of established A431 xenograft flank tumours with DTPA-Gd and GC-DTPA-Gd demonstrated that the initial distribution of the contrast agents was well correlated with blood vessels and supply. In contrast, subsequent tissue transport was primarily by diffusion and limited by CA molecular weight. The data also highlight the role of heterogeneity in CA distribution which was more prominent for the high MW agent. Precise control of glycol chitosan (GC) polymer chemistry facilitates synthesis of a family of Gd-based MRI contrast agents of tuneable MW but otherwise identical physicochemical properties. Such agents allow isotropic high-resolution threedimensional imaging of MW dependent transport processes relevant to the clinical and pre-clinical prediction of drug transport processes.

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KW - gadolinium

KW - glycol chitosan

KW - molecular weight

KW - MRI contrast agents

U2 - 10.2174/2211738503999141222224739

DO - 10.2174/2211738503999141222224739

M3 - Article

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JO - Pharmaceutical Nanotechnology

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ER -