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Updated: Aug 14, 2025
Delivery of Proteins, Peptides or Cell-impermeable Small Molecules into Live Cells by Incubation with the Endosomolytic Reagent dfTAT
Published on: September 2, 2015
Tumor-specific intracellular delivery: peptide-guided transport of a catalytic toxin
Curtis A Allred1, Claire Gormley1, Indu Venugopal1
1SRI International, Biosciences Division, 140 Research Drive, Harrisonburg, VA, 22802, USA.
Abstract:
There continues to be a need for cancer-specific ligands that can deliver a wide variety of therapeutic cargos. Ligands demonstrating both tumor-specificity and the ability to mediate efficient cellular uptake of a therapeutic are critical to expand targeted therapies. We previously reported the selection of a peptide from a peptide library using a non-small cell lung cancer (NSCLC) cell line as the target. Here we optimize our lead peptide by a series of chemical modifications including truncations, N-terminal capping, and changes in valency. The resultant 10 amino acid peptide has an affinity of <40 nM on four different NSCLC cell lines as a monomer and is stable in human serum for >48 h. The peptide rapidly internalizes upon cell binding and traffics to the lysosome. The peptide homes to a tumor in an animal model and is retained up to 72 h. Importantly, we demonstrate that the peptide can deliver the cytotoxic protein saporin specifically to cancer cells in vitro and in vivo, resulting in an effective anticancer agent.
Insights
Researchers optimized a peptide for targeted cancer therapy. This optimized peptide specifically targets non-small cell lung cancer (NSCLC) cells, delivering therapeutic agents effectively for enhanced cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Drug Delivery
Background:
- Targeted cancer therapies require specific ligands for efficient drug delivery.
- Developing tumor-specific ligands with high cellular uptake is crucial for advancing targeted treatments.
- Previous work identified a peptide targeting non-small cell lung cancer (NSCLC).
Purpose of the Study:
- To optimize a previously identified peptide for enhanced targeting and therapeutic cargo delivery in NSCLC.
- To evaluate the modified peptide's affinity, stability, cellular uptake, and tumor homing capabilities.
- To assess the peptide's efficacy in delivering a cytotoxic agent to cancer cells.
Main Methods:
- Chemical modifications of the lead peptide, including truncations, N-terminal capping, and valency changes.
- Affinity assessment on multiple NSCLC cell lines using nanomolar concentrations (<40 nM).
- In vitro and in vivo studies evaluating serum stability, cellular internalization, lysosomal trafficking, tumor homing, retention, and therapeutic payload delivery.
Main Results:
- A 10-amino acid peptide was optimized with high affinity (<40 nM) for four NSCLC cell lines.
- The optimized peptide demonstrated stability in human serum (>48 hours) and rapid cellular internalization.
- The peptide effectively homed to tumors in vivo, with retention up to 72 hours, and delivered the cytotoxic protein saporin specifically to cancer cells.
Conclusions:
- The optimized peptide serves as a potent and specific ligand for NSCLC targeting.
- This peptide facilitates efficient cellular uptake and lysosomal trafficking of therapeutic cargos.
- The peptide demonstrates potential as a component of an effective targeted anticancer agent for NSCLC.
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