Selective delivery of therapeutic and diagnostic agents to malignant tumors versus normal tissues continues to be an important goal in cancer research and clinical practice. We have been developing cancer specific, iodinated phospholipid ether (PLE) analogs for tumor imaging and molecular radiotherapy. These PLEs localize in cancer cells selectively via plasma membrane lipid rafts, more abundant in cancer cells compared to normal cells, using them as portals of entry. Isosteric iodine substitution in CLR1404 affords either a diagnostic/imaging agent (e.g. using 124I for cancer-selective PET imaging) or a molecular radiotherapeutic agent (e.g. using 131I for cancer-selective cytotoxicity), both of which are in clinical development. We suggest the term “diapeutic” to describe such drugs which can be used in one form to identify and characterize patients who will benefit from a specific therapy and, in another form, to effect that therapy. A fluorescent analog of CLR1404, CLR1501, as well as a radioactive homolog displayed increased, lipid raft-dependent selective uptake and prolonged retention in a wide variety of cancer cell lines in comparison to normal human cells. Intracellular accumulation was observed in organellar membranes (ER, Golgi, mitochondria, autophagosomes). Lipid raft involvement in uptake was supported by co-localization of CLR1501 and lipid raft molecular markers. Lipid raft-dependence of uptake into cancer cells was confirmed by the finding that it was significantly decreased after disruption of lipid rafts with Filipin III. In vivo, nuclear imaging with radioiodinated CLR1404 revealed tumor-selective uptake and retention in 52 of 54 rodent cancer models tested, including human tumor xenograft, transgenic and spontaneous tumor models. In these models, 124I-CLR1404 clearly imaged both primary tumors and metastases. In vivo tumor conspicuity was apparent by 24 hours after i.v. administration and appeared undiminished at 120 hours. In contrast, the extra-tumoral 124I-CLR1404 PET signal decreased dramatically over the same time period as the agent was excreted. By 48 hours, no other tissues or organs showed significant labeling above the background of the blood compartment. Tumor uptake was not seen in models of benign hyperplasia. SPECT/CT imaging after administration of 131I-CLR1404 to cancer patients in the context of a Phase 1a dosimetric clinical trial also demonstrated selective uptake into malignant tumors, including metastases. Used in tandem, these chemically identical isosteres offer a personalized, diapeutic approach to cancer therapy, with 124I-CLR1404 imaging serving as an ideal qualitative and quantitative biomarker for subsequent treatment with 131I-CLR1404.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5740. doi:1538-7445.AM2012-5740