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Updated: Sep 13, 2025
Construction of Cyclic Cell-Penetrating Peptides for Enhanced Penetration of Biological Barriers
Published on: September 19, 2022
Applying Unbiased, Functional Criteria Allows Selection of Novel Cyclic Peptides for Effective Targeted Drug Delivery
Anna Cohen1, Maysoon Kashkoosh1, Vipin Sharma1
1Department of Chemical Engineering, Ariel University, Ariel 40700, Israel.
Abstract:
Background: Metastatic prostate cancer (mPrC), with a median survival of under 2 years, represents an important unmet medical need which may benefit from the development of more effective targeted drug delivery systems. Several cell surface receptors have been identified as candidates for targeted drug delivery to mPrC cells; however, these receptors were selected for their overabundance on PrC cells rather than for their suitability for targeted delivery and uptake of cytotoxic drug payloads. Methods: We describe a novel, unbiased strategy to isolate peptides that fulfill functional criteria required for effective intracellular drug delivery and the specific cytotoxicity of PrC cells without prior knowledge of the targeted receptor. Phage clones displaying 7-mer cyclic peptides were negatively selected in vivo and then positively biopanned through a series of parent and drug-resistant mPrC cells. Peptides from the internalized clones were then subjected to a panel of biochemical and functional tests that led to the selection of several peptide candidates. Results: The selected peptides do not bind PSMA. Peptide-drug conjugates (PDCs) incorporating one of the peptides selectively killed wild-type and drug-resistant PrC cell lines and patient PrC cells but not normal prostate tissue cells in vitro. The PDC also halted the growth of PC3 tumors in a xenograft model. Conclusions: Our study demonstrates that adding unbiased, functional criteria into drug carrier selection protocols can lead to the discovery of novel peptides with appropriate properties required for effective targeted drug delivery into target cancer cells.
Insights
Researchers developed a new method to find peptides for targeted drug delivery in metastatic prostate cancer (mPrC). These novel peptide-drug conjugates effectively kill mPrC cells while sparing normal tissue.
Area of Science:
- Oncology
- Drug Delivery Systems
- Molecular Biology
Background:
- Metastatic prostate cancer (mPrC) has a poor prognosis and requires improved targeted therapies.
- Current drug delivery strategies often target receptors based on abundance, not functional suitability for payload delivery.
- There is a need for novel drug carriers optimized for intracellular delivery and cancer cell specificity.
Purpose of the Study:
- To develop an unbiased strategy for isolating functional peptides for targeted drug delivery in mPrC.
- To identify novel peptide-drug conjugates (PDCs) with selective cytotoxicity against prostate cancer cells.
- To evaluate the efficacy of these PDCs in vitro and in vivo.
Main Methods:
- Employed negative in vivo selection followed by positive biopanning on drug-resistant mPrC cells to isolate phage clones displaying 7-mer cyclic peptides.
- Utilized a series of biochemical and functional assays to select promising peptide candidates.
- Constructed peptide-drug conjugates (PDCs) and tested their efficacy against various prostate cancer cell lines and in a xenograft model.
Main Results:
- Identified novel peptides that selectively kill wild-type and drug-resistant mPrC cell lines and patient-derived cells in vitro.
- Demonstrated that the PDCs do not harm normal prostate tissue cells in vitro.
- Showed that a PDC incorporating a selected peptide halted PC3 tumor growth in a xenograft model.
- Confirmed that the selected peptides do not bind to PSMA.
Conclusions:
- An unbiased, functional selection approach yields peptides suitable for targeted drug delivery.
- Novel PDCs exhibit selective cytotoxicity against mPrC, offering a promising therapeutic strategy.
- This method advances the development of targeted therapies for metastatic prostate cancer.
