In vivo studies of Gd‐DTPA‐monoclonal antibody and gd‐porphyrins: Potential magnetic resonance imaging contrast agents for melanoma

Abstract

New tumor-specific contrast agents for clinical imaging and therapy for cancer are required. To this end Gd-H (Gd-hematoporphyrin), Gd-TCP (Gd-tetra-carboranylmethoxyphenyl-porphyrin), Gd-DTPA-WM53, and Gd-DTPA-9.2.27 were synthesized and administered by systemic injection to nude mice with human melanoma (MM-138) xenografts. The biodistribution T 1 relaxation times and magnetic resonance (MR) image signal enhancement of the contrast agents are presented for the first time and compared for each group of five mice. A change (20%) in T 1 relaxation times of water in human melanoma tumor xenografts was revealed 24 hours after injection of the labeled immunoconjugate Gd-DTPA-9.2.27. The percent of injected antibody or gadolinium that localized to the tumor was measured by inductively coupled plasma atomic emission spectroscopy (ICP-AES) to be approximately 35%. A higher concentration of gadolinium was achieved compared with nonspecific compounds, indicating selective delivery of Gd-DTPA-9.2.27 to the melanoma xenografts. Porphyrin-based contrast agents (Gd-H and Gd-TCP) also showed significant uptake in melanomas. The uptake of Gd-TCP by the tumor was sufficient to deliver boron atoms into the tumor, making possible dual use for both MR imaging ( Index terms: MRI; monoclonal antibody; Gd-DTPA; Gd-porphyrins; melanoma MAGNETIC RESONANCE IMAGING (MRI) using varied pulse sequences provides a sharp contrast between tissues with different intrinsic T 1 or T 2 relaxation times. By exploiting the differences in relaxation times, images have been produced that provide previously unobtainable physiologic and mobility information (1). The use of contrast agents to shorten relaxation times and give enhanced signal intensity (SI) may extend the potential of MRI to the diagnosis of currently subclinical tumors. Two approaches are investigated to increase the specificity of MR image contrast agents by using metalloporphyrins and a monoclonal antibody coupled with Gd-DTPA.Porphyrins are a unique class of metal chelating agents that have shown selective affinity for a variety of tumors (2). The high water solubility and stability under physiological conditions (3), low propensity for causing photoxicity (4), and intracellular localization in mitochondria for more efficient tumor cell killing (5) are reasons why these complexes have been used as tumor-specific contrast agents. Tumor-specific contrast agents with potential for clinical imaging and therapy for cancer are Gd-hematoporphyrin (gadolinium-[18,13-bis (hydroxyethyl)-3,7,12,17-tetramethyl-21H, 23H porphine-2, 18-dipropionic acid]) and Gd-TCP (gadolinium-tetra-carboranylomethoxyphenyl-porphyrin).In a second approach, monoclonal antibodies against leukemia and melanoma are used. These are chelated with Gd to form the Gd immunoconjugates Gd-DTPA-WM53 and Gd-DTPA-9.2.27. These agents are tested in the nude mice model with a human melanoma (MM-138) xenograft to investigate their pharmacokinetics. The biodistribution T 1 relaxation times and signal enhancement of the contrast agen...

The detection limit of a Gd3+-based T1 agent is substantially reduced when targeted to a protein microdomain

“…There is a great deal of interest in enhancing the utility of these tools in medicine and research through the development of molecularly-targeted MRI contrast agents. One example might be a chimeric molecule comprised of a contrast agent tethered to a molecule capable of binding to a specific protein or other biomolecular target with high affinity and specificity [4][5][6][7][8][9][10][11][12][13][14][15][16][17]. For example, we previously reported that a peptide selected from a phage display library to bind the yeast Gal80 protein can be linked to GdDOTA to create a reagent capable of imaging Gal80 protein in vitro [18,19].…”

Novel Nanosized Gd3+-ALGD-G2-C595: In vivo Dual Selective MUC-1 Positive Tumor Molecular MR Imaging and Therapeutic Agent

“…T 1 -weighted MR imaging procedures were performed at different time intervals after injection. For the confirmation of the data obtained by MR imaging, a digestive acid method was done followed by sacrificing some mice and removing critical organs using ICP-AES (inductive coupled plasma atomic emission spectroscopy) method described previously [17].…”

“…One of the targets is breast specific membrane antigen, MUC-1, a high molecular weight transmembrane glycoprotein antigen [15][16][17][18][19]. Additionally, tumor marker antigen MUC-1 is a proposed molecular target for a novel imaging or therapy for breast cancer [20].…”

Trends in Interdisciplinary Studies Revealing Porphyrinic Compounds Multivalency Towards Biomedical Application

“…It was recently shown that a porphyrin-based MRI molecular imaging agent, Mn-(DPA-C 2 ) 2 -TPPS 3 , effectively penetrates cells and persistently stains living brain tissue in intracranially injected rats. Due to cromogenicity, its distribution can also be observed by histology (Chen, 1984;Shahbazi-Gahrouei, 2001). Porphyrin-based complexes were also identified as necrosis-avid contrast agents (NACAs) for noninvasive MRI identification of acute myocardial infarction, assessment of tissue or organ viability, and therapeutic evaluation after interventional therapies (Ni, 2008).…”