Small Molecule Ligand -Drug Conjugates for Targeted Cancer Therapy

Emory University
posted on 08/10/2010

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Applications

Near-infrared dye-drug conjugates target tumors for imaging and therapy.

Highlights

• Near-infrared cyanine dyes possess intrinsic tumor targeting ability.
• Dye-drug conjugates can be used simultaneously to deliver therapeutics and monitor progress of the intervention.
• Near-infrared dye conjugates possess improved optical properties, reduced interference, and decreased background over existing probes.

Technical Summary

Current cancer diagnostics and therapeutics continue to be largely inadequate. Existing imaging probes used for identifying tumors and metastases are often ineffective due to poor targeting and retention at tumor lesions, shallow tissue penetration, and interference from resident tissue such as skin, hair, liver, and kidney. Of greater concern however, many of the most effective chemotherapeutic agents non-specifically attack cellular processes often damaging tumor cells and normal cells alike. A recently developed series of near-infrared cyanine dyes may address many of these issues. Near-infrared (NIR) cyanine dyes have been discovered that are efficiently absorbed by a range of tumor cells, but not normal tissue. This difference in uptake is thought to be related to differential expression of OATP transporters in cancer cells and imparts the ability of these dyes to simultaneously serve as a targeting ligand and an imaging agent. FDA approved chemotherapeutic agents can also be coupled to these dyes through a succinic ester linker, resulting in a potent small molecule conjugate which targets a tumor, induces tumor-specific cytotoxicity, and serves as a means for monitoring outcome of the intervention. Investigations with a pilot conjugate featuring docetaxel linked to a novel NIR dye indicate the small molecule has remarkable targeting and retention, accumulating specifically at tumor sites and retaining 75% of its original imaging intensity five days after administration. This compound has also been shown to induce apoptosis in a T24 human bladder tumor xenograph model.

Developmental Stage & Potential Market

• Method of synthesis for a prototype dye-drug conjugant that has shown tumor specificity, retention, cytoxicity in a mouse model.
• Rational drug design is being employed to develop additional conjugates.
• The world-wide cancer therapy market is anticipated to reach $60.6 billion by 2011, with new growth driven by development of novel, targeted drugs.