Alkylphosphocholine Analogs for Broad-Spectrum Cancer Imaging and Therapy

Abstract

Many solid tumors contain an overabundance of phospholipid ethers relative to normal cells. Capitalizing on this difference, we created cancer-targeted alkylphosphocholine (APC) analogs through structure-activity analyses. Depending on the iodine isotope used, radioiodinated APC analog CLR1404 was used as either a positron emission tomography (PET) imaging (124I) or molecular radiotherapeutic (131I) agent. CLR1404 analogs displayed prolonged tumor-selective retention in 55 in vivo rodent and human cancer and cancer stem cell models. 131I-CLR1404 also displayed efficacy (tumor growth suppression and survival extension) in a wide range of human tumor xenograft models. Human PET/CT (computed tomography) and SPECT (single-photon emission computed tomography)/CT imaging in advanced-cancer patients with 124I-CLR1404 or 131I-CLR1404, respectively, demonstrated selective uptake and prolonged retention in both primary and metastatic malignant tumors. Combined application of these chemically identical APC-based radioisosteres will enable personalized dual modality cancer therapy of using molecular 124I-CLR1404 tumor imaging for planning 131I-CLR1404 therapy.

Fluorescent Cancer-Selective Alkylphosphocholine Analogs for Intraoperative Glioma Detection

“…29 Extensive in vitro and in vivo testing show the inherent advantage of this new, broad spectrum cancer-targeting platform: all APC analogs have identical tumor-specific uptake and persistence regardless of the added radioactive or fluorescence label. 29 Tumor-specific APC uptake partly through the lipid raft-rich compartment of cancer cell membranes, coupled with elimination from normal tissues over time, yields high tumor specific discrimination and targeting for imaging and therapy. 29 Depending on the conjugated radiolabel, CLR1404 may be used for tumor selective PET imaging ( 124 I-CLR1404) or therapeutic radiation ( 131 I-CLR1404).…”

“…29 Tumor-specific APC uptake partly through the lipid raft-rich compartment of cancer cell membranes, coupled with elimination from normal tissues over time, yields high tumor specific discrimination and targeting for imaging and therapy. 29 Depending on the conjugated radiolabel, CLR1404 may be used for tumor selective PET imaging ( 124 I-CLR1404) or therapeutic radiation ( 131 I-CLR1404). Two fluorescent CLR1404 derivatives were also developed by substituting iodine with fluorescent moieties: CLR1501 (green) and CRL1502 (near infrared) (Figure 1A).…”

“…CLR1501 and CLR1502 also exhibit tumor selectivity in vitro and in vivo for human glioblastoma stem-like (GSC) cell lines and xenografts. 29 We envision and are developing the APC cancer-targeting platform for multiple steps in clinical cancer management: diagnostic cancer imaging, surgical tumor detection, and adjuvant cancer therapy. This study compares CLR1501 and CLR1502 with 5-ALA as tumor fluorescence agents, and serves as a proof-of-principle for potential use of fluorescent APC analogs in cancer surgery.…”

Fluorescent chemical probes for accurate tumor diagnosis and targeting therapy

“…APCs target cellular and intracellular membranes, inhibit phosphatidylcholine biosynthesis, interfere with lipid transduction pathways, block the endoplasmic reticular transport of cholesterol, and ultimately disrupt cholesterol homeostasis and membrane lipid raft function. 122,123 Kuo et al developed two APC-based cancer-selective fluorescent probes CLR1501 (32) and CLR1502 (33) for discriminating tumors from normal brain tissue in fluorescence-guided glioma surgery. 123,124 These two probes provided high tumorto-normal brain contrast in fluorescence discrimination with glioblastoma multiforme and glioblastoma stem cell-derived xenografts in mouse models.…”

“…122,123 Kuo et al developed two APC-based cancer-selective fluorescent probes CLR1501 (32) and CLR1502 (33) for discriminating tumors from normal brain tissue in fluorescence-guided glioma surgery. 123,124 These two probes provided high tumorto-normal brain contrast in fluorescence discrimination with glioblastoma multiforme and glioblastoma stem cell-derived xenografts in mouse models. Moreover, 33 showed a superior tumor-to-brain fluorescence ratio compared with 5-aminolevulinic acid, which is the current standard for fluorescence-guided neurosurgery.…”