Novel Targeted System To Deliver Chemotherapeutic Drugs to EphA2-Expressing Cancer Cells

Abstract

The efficacy of anti-cancer drugs is often limited by their systemic toxicities and adverse side effects. We report that the EphA2 receptor is over-expressed preferentially in several human cancer cell lines compared to normal tissues and that an EphA2 targeting peptide (YSAYPDSVPMMS) can be effective in delivering anti-cancer agents to such tumors. Hence, we report on the synthesis and characterizations of a novel EphA2-targeting agent conjugated with the chemotherapeutic drug paclitaxel. We found that the peptide-drug conjugate is dramatically more effective than paclitaxel alone at inhibiting tumor growth in a prostate cancer xenograft model, delivering significantly higher levels of drug to the tumor site. We believe these studies open the way to the development of a new class of therapeutic compounds that exploit the EphA2 receptor for drug delivery to cancer cells.

Δ5-Cholenoyl-amino acids as selective and orally available antagonists of the Eph–ephrin system

“…pancreatic, breast and lung cancers), and to reduce the insurgence of peripheral metastasis. Furthermore, the EphA2 receptor has been exploited to deliver cytotoxic anticancer drugs into EphA2-expressing cancer cells, using peptides selectively targeting the EphA2 receptor [8]. From these premises, EphA2 emerges as a promising target for the development of antiangiogenic and antitumorigenic therapies [9].…”

EphA2 Targeting Pegylated Nanocarrier Drug Delivery System for Treatment of Lung Cancer

“…Alternatively, Jackson et al (44) developed an EphA2 monoclonal antibody conjugate to target tumors expressing high levels of EphA2. Similarly, Wamg et al (45) showed effective targeting of YSA-paclitaxel conjugate to prostate cancer. However, protein-based therapeutic strategies still have the drawbacks ( e.g .…”

The Quest for an Effective Treatment for an Intractable Cancer

“…Targeting peptides (YSAYPDSVPMMS) were produced that, similar to the natural ligand for this receptor, selectively bind to EphA2 and cause receptor activation and internalization (Wang et al, 2012). These peptides when linked to commonly used chemotherapeutic drugs provide a specific delivery strategy for these drugs to tumor cells.…”

“…These peptides when linked to commonly used chemotherapeutic drugs provide a specific delivery strategy for these drugs to tumor cells. Once the receptor is activated, the peptide and its attached drug are internalized into a lysosome, where the peptide is degraded and the drug is free to exert its toxic effects on the cell (Wang et al, 2012). Previous studies have shown that paclitaxel conjugated with these peptides shows increased efficacy in prostate and renal cancers (Wang et al, 2013).…”