Evaluation of metalloporphyrins as contrast agents for tumors in magnetic resonance imaging

Porphyrins are cyclic tetrapyrazoles which are known to be selectively retained by neoplastic tissue in animals and humans. It has been demonstrated that chelation of a paramagnetic metal which can significantly increase the relaxation rate (1/T$\sb1)$ of water with a porphyrin may serve as potential contrast agents for tumors in Magnetic Resonance Imaging (MRI). Mn(III), Fe(II), and Gd(III) complexes of tetraphenyl (4-sulfonato) porphine (TPPS$\sb4)$ and other porphyrins were evaluated as potential MRI contrast agents. Based on consideration of relaxivity, solubility, stability, toxicity, uptake and distribution, MnTPPS$\sb4$ was determined to be the best model compound to provide insight into the question of selectivity in neoplastic tissue as well as determining its clinical utility as a MRI contrast agent. The question of neoplastic selectivity was pursued with normal and neoplastic human breast cell lines in vitro to quantitatively determine the differences in metalloporphyrin uptake. It was observed that the neoplastic breast cell line, MCF-7 WT, had a six-fold greater difference in uptake when compared to the normal human breast cell line, Hs 578 Bst. This result not only confirmed that there was enhanced uptake in a neoplastic cell line as compared to a normal (control) cell line, but that tissue culture results that involved uptake of metalloporphyrins could be used to adequately predict the uptake and plateau phases in vivo with the same implanted neoplastic cells. This is the first time that normal and neoplastic breast cell lines from similar in vivo loci have been used to compare the neoplastic selectivity of a metalloporphyrin in vitro. In vitro human cell models and in vivo murine animal models were utilized to determine the distribution and toxicity of the metalloporphyrin, MnTPPS$\sb4.$ Distribution studies indicated that the agent located primarily intracellularly in vitro and in viable tumor in vivo. Toxicity studies were conducted primarily to determine the IC$\sb{50}$ of the metalloporphyrin in vitro and the ID$\sb{50}$ of the metalloporphyrin in vivo, in order to determine the working range of the compound under both in vivo and in vitro conditions. The agent was injected into murine animal models bearing human colon and human breast carcinoma. It was shown that effective soft tissue contrast of neoplastic tissue by IP injected metalloporphyrin utilizing MRI, is observed at 24 hours and 48 hours respectively with contrast enhancement evident in the tumor for as long as eight days. In conclusion, paramagnetic metalloporphyrins may provide a useful clinical modality for the determination of neoplastic tissue by MRI if the dose to contrast ratio can be increased for safe clinical efficacy.