Cover Picture: Design, Synthesis and Bioevaluation of an EphA2 Receptor-Based Targeted Delivery System (ChemMedChem 7/2014)
Because of its overexpression in a range of solid tumors, the EphA2 receptor is a validated target for cancer therapeutics. We recently described a new targeted delivery system based on specific EphA2-targeting peptides conjugated with the chemotherapeutic agent paclitaxel. Here, we investigate the chemical determinants responsible for the stability and degradation of these agents in plasma. Introducing modifications in both the peptide and the linker between the peptide and paclitaxel resulted in drug conjugates that are both long-lived in rat plasma and that markedly decrease tumor size in a prostate cancer xenograft model compared with paclitaxel alone treatment. These studies identify critical rate-limiting degradation sites on the peptide-drug conjugates, enabling the design of agents with increased stability and efficacy. These results provide support for our central hypothesis that peptide-drug conjugates targeting EphA2 represent an innovative and potentially effective strategy to selectively deliver cytotoxic drugs to cancer cells.
- [Show abstract] [Hide abstract]
ABSTRACT: With therapies that date back to the 1950s, and few newly approved treatments in the last 20 years, pancreatic cancer remains a significant challenge for the development of novel therapeutics. Current regimens have successfully extended patient survival, although they still lead to prognoses measured in months rather than years. The genetic diversity inherent in pancreatic tumors forms the roadblocks that must be overcome in future therapeutics. Recent insight into the genetic patterns found in tumor cells may provide clues leading to better understanding of the challenges hindering the development of treatments. Here, we review currently used drugs and established combination therapies that comprise the standard of care for a highly recalcitrant disease. Novel approaches can improve upon current therapies in a variety of ways. Enhancing specificity, such that growth inhibition and cytotoxic effects act preferentially on tumor cells, is one approach to advance treatments. This can be accomplished through the targeting of extracellular markers specific to cancer cells. Additionally, enlisting natural defenses and overcoming tumor-driven immune suppression could prove to be a useful tactic. Recent studies utilizing these approaches have yielded promising results and could contribute to an ongoing effort battling a particularly difficult cancer. © 2015 Elsevier Inc. All rights reserved.
- [Show abstract] [Hide abstract]
ABSTRACT: The development of novel, targeted delivery agents for anti-cancer therapies requires the design and optimization of potent and selective tumor-targeting agents that are stable and amenable to conjugation with chemotherapeutic drugs. While short peptides represent potentially an excellent platform for these purposes, they often get degraded and are eliminated too rapidly in vivo. In this study, we used a combination of nuclear magnetic resonance-guided structure-activity relationships along with biochemical and cellular studies to derive a novel tumor-homing agent, named 123B9, targeting the EphA2 tyrosine kinase receptor ligand-binding domain. Conjugating 123B9 to the chemotherapeutic drug paclitaxel (PTX) via a stable linker results in an agent that is significantly more effective than the unconjugated drug in both a pancreatic cancer xenograft model and a melanoma lung colonization and metastases model. Hence, 123B9 could represent a promising strategy for the development of novel targeted therapies for cancer. Copyright © 2015 Elsevier Ltd. All rights reserved.
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.