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Updated: May 16, 2026
Construction of Cyclic Cell-Penetrating Peptides for Enhanced Penetration of Biological Barriers
Published on: September 19, 2022
De novo design of a tumor-penetrating peptide
Luca Alberici1, Lise Roth, Kazuki N Sugahara
1Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.
Abstract:
Poor penetration of antitumor drugs into the extravascular tumor tissue is often a major factor limiting the efficacy of cancer treatments. Our group has recently described a strategy to enhance tumor penetration of chemotherapeutic drugs through use of iRGD peptide (CRGDK/RGPDC). This peptide comprises two sequence motifs: RGD, which binds to αvβ3/5 integrins on tumor endothelia and tumor cells, and a cryptic CendR motif (R/KXXR/K-OH). Once integrin binding has brought iRGD to the tumor, the peptide is proteolytically cleaved to expose the cryptic CendR motif. The truncated peptide loses affinity for its primary receptor and binds to neuropilin-1, activating a tissue penetration pathway that delivers the peptide along with attached or co-administered payload into the tumor mass. Here, we describe the design of a new tumor-penetrating peptide based on the current knowledge of homing sequences and internalizing receptors. The tumor-homing motif in the new peptide is the NGR sequence, which binds to endothelial CD13. The NGR sequence was placed in the context of a CendR motif (RNGR), and this sequence was embedded in the iRGD framework. The resulting peptide (CRNGRGPDC, iNGR) homed to tumor vessels and penetrated into tumor tissue more effectively than the standard NGR peptide. iNGR induced greater tumor penetration of coupled nanoparticles and co-administered compounds than NGR. Doxorubicin given together with iNGR was significantly more efficacious than the drug alone. These results show that a tumor-specific, tissue-penetrating peptide can be constructed from known sequence elements. This principle may be useful in designing tissue-penetrating peptides for other diseases.
Insights
A novel peptide, iNGR, enhances drug delivery into tumors by targeting CD13 and activating tissue penetration pathways. This improved tumor penetration increases the efficacy of chemotherapy, offering a new strategy for cancer treatment.
Area of Science:
- Biomedical Engineering
- Cancer Research
- Drug Delivery
Background:
- Poor drug penetration into solid tumors limits cancer treatment efficacy.
- Integrin-binding RGD peptides and CendR motifs facilitate tumor targeting and tissue penetration.
- Previous strategies utilized iRGD peptide for enhanced drug delivery.
Purpose of the Study:
- To design and evaluate a new tumor-penetrating peptide (iNGR) based on known homing sequences and internalizing receptors.
- To assess iNGR's efficacy in enhancing tumor homing, tissue penetration, and therapeutic outcomes compared to standard peptides.
- To explore the potential of combining known sequence elements for novel drug delivery systems.
Main Methods:
- Designed a novel peptide, iNGR (CRNGRGPDC), incorporating an NGR tumor-homing motif and a CendR motif within an iRGD framework.
- Evaluated iNGR's tumor vessel homing and tissue penetration capabilities.
- Assessed the enhanced delivery of coupled nanoparticles and co-administered compounds by iNGR.
- Determined the therapeutic efficacy of doxorubicin when administered with iNGR.
Main Results:
- The iNGR peptide demonstrated superior tumor vessel homing and tissue penetration compared to the standard NGR peptide.
- iNGR significantly enhanced the penetration of coupled nanoparticles and co-administered compounds into tumor tissue.
- Doxorubicin combined with iNGR showed significantly greater efficacy than doxorubicin alone.
- The designed peptide effectively utilizes known sequence elements for targeted drug delivery.
Conclusions:
- A novel tumor-specific, tissue-penetrating peptide (iNGR) can be constructed by combining known sequence elements.
- iNGR enhances drug delivery and therapeutic efficacy by improving tumor penetration.
- This peptide design strategy holds promise for developing advanced tissue-penetrating peptides for various diseases.
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