3D MR angiography of intratumoral vasculature using a novel macromolecular MR contrast agent

Noninvasive methods to visualize blood flow in the intratumoral vasculature have not previously been studied. In the present study, the use of a novel intravascular MR contrast agent with a generation‐6 polyamidoamine dendrimer core (G6‐(1B4M‐Gd)192; MW: 175kD) was investigated, and the vasculature in experimental tumors was visualized using 3D MR angiography (MRA). Xenografted tumors in nude mice of two different histologies—KT005 (human osteogenic sarcoma) and LS180 (human colon carcinoma)—were used to obtain 3D MRA using G6‐(1B4M‐Gd)192 and Gd‐DTPA. The contrast MR sectional images were correlated with the corresponding histological sections. The intratumoral vasculature in the KT005 tumor was clearly visualized by 3D MRA, which became more evident with the growth of the tumor xenograft. In contrast, the intratumoral vasculature in the LS180 tumor was sparser and much less developed than that in KT005 tumors. Blood vessels with a diameter as small as 100 μm based on histology were visualized using 0.033 mmol Gd/kg of G6‐(1B4M‐Gd)192. In conclusion, intratumoral vasculature with a 100‐μm diameter was visualized better using 3D MRA with G6‐(1B4M‐Gd)192 than with Gd‐DTPA. Magn Reson Med 46:579–585, 2001. © 2001 Wiley‐Liss, Inc.

[1]  M. Brechbiel,et al.  Pharmacokinetics and enhancement patterns of macromolecular MR contrast agents with various sizes of polyamidoamine dendrimer cores , 2001, Magnetic resonance in medicine.

[2]  M. Brechbiel,et al.  3D‐micro‐MR angiography of mice using macromolecular MR contrast agents with polyamidoamine dendrimer core with reference to their pharmacokinetic properties , 2001, Magnetic resonance in medicine.

[3]  H. Maeda,et al.  Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. , 2000, Journal of controlled release : official journal of the Controlled Release Society.

[4]  A J Hayes,et al.  Antivascular therapy: a new approach to cancer treatment , 1999, BMJ.

[5]  M. Brechbiel,et al.  Evaluation of the in vivo biodistribution of indium-111 and yttrium-88 labeled dendrimer-1B4M-DTPA and its conjugation with anti-Tac monoclonal antibody. , 1999, Bioconjugate chemistry.

[6]  A. Harris Are angiostatin and endostatin cures for cancer? , 1998, The Lancet.

[7]  B. Zetter,et al.  Angiogenesis and tumor metastasis. , 1998, Annual review of medicine.

[8]  N. van Bruggen,et al.  Assessing tumor angiogenesis using macromolecular MR imaging contrast media , 1997, Journal of magnetic resonance imaging : JMRI.

[9]  D M Shames,et al.  Mammary carcinoma model: correlation of macromolecular contrast-enhanced MR imaging characterizations of tumor microvasculature and histologic capillary density. , 1996, Radiology.

[10]  N. Hylton,et al.  Evaluation of the effects of intravascular MR contrast media (gadolinium dendrimer) on 3D time of flight magnetic resonance angiography of the body , 1996, Journal of magnetic resonance imaging : JMRI.

[11]  R K Jain,et al.  Vascular permeability in a human tumor xenograft: molecular size dependence and cutoff size. , 1995, Cancer research.

[12]  P. Singh,et al.  Starburst dendrimers: enhanced performance and flexibility for immunoassays. , 1994, Clinical chemistry.

[13]  J. Fréchet,et al.  Functional polymers and dendrimers: reactivity, molecular architecture, and interfacial energy. , 1994, Science.

[14]  Martin W. Brechbiel,et al.  Metal-chelate-dendrimer-antibody constructs for use in radioimmunotherapy and imaging , 1994 .

[15]  P C Lauterbur,et al.  Dendrimer‐based metal chelates: A new class of magnetic resonance imaging contrast agents , 1994, Magnetic resonance in medicine.

[16]  R. Barth,et al.  Boronated starburst dendrimer-monoclonal antibody immunoconjugates: evaluation as a potential delivery system for neutron capture therapy. , 1994, Bioconjugate chemistry.

[17]  V. Budach,et al.  Vascular patterns of tumors: scanning and transmission electron microscopic studies on human xenografts. , 1992, Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft ... [et al].

[18]  T. Yokota,et al.  Rapid tumor penetration of a single-chain Fv and comparison with other immunoglobulin forms. , 1992, Cancer research.

[19]  William A. Goddard,et al.  Starburst Dendrimers: Molecular‐Level Control of Size, Shape, Surface Chemistry, Topology, and Flexibility from Atoms to Macroscopic Matter , 1990 .

[20]  H. Maeda,et al.  Tumoritropic and lymphotropic principles of macromolecular drugs. , 1989, Critical reviews in therapeutic drug carrier systems.

[21]  H. Maeda,et al.  A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. , 1986, Cancer research.

[22]  J. Toguchida,et al.  Recognition of serum alkaline phosphatase by murine monoclonal antibodies against human osteosarcoma cells. , 1986, Cancer research.

[23]  D. Goldenberg,et al.  Human colon adenocarcinoma cells. II. Tumorigenic and organoid expression in vivo and in vitro. , 1977, Journal of the National Cancer Institute.