New generation CPPs show distinct selectivity for cancer and noncancer cells

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Cell-penetrating peptides (CPPs) facilitate cellular uptake of cargo.
• Recent CPPs show enhanced cell selectivity.
• Venom-derived peptides offer novel CPP properties.

Purpose of the Study:

• To evaluate the tumor cell selectivity of novel CPPs, including mini-crotamine and mini-maurocalcine fragments.
• To assess the internalization of therapeutic antibodies conjugated to these CPPs.
• To explore the theranostic potential of a fluorescent crotamine fragment.

Main Methods:

• Synthesis of CPPs with N-terminal cysteine for cargo conjugation.
• Conjugation of therapeutic antibody trastuzumab to fluorescent dyes.
• Internalization studies comparing CPPs with antibody complexes.
• Fluorescence microscopy to analyze peptide distribution in cancer cells and non-cancerous cells.

Main Results:

• Novel CPPs demonstrated poor internalization of non-covalently complexed trastuzumab.
• Fluorescent mini-crotamine selectively localized to a subpopulation of breast cancer cells.
• Homogeneous distribution of fluorescent mini-crotamine was observed in fibrosarcoma, colon cancer, and non-cancerous endothelial cells.
• CPPs derived from venoms show differential cell uptake.

Conclusions:

• The fluorescent crotamine fragment is a promising theranostic tool for image-guided cancer therapy.
• This peptide can identify tumor heterogeneity, aiding in targeted therapeutic development.
• Selective targeting of cancer cell subpopulations is achievable with novel CPPs.