Tumor-Targeted Cell-Penetrating Peptides Reveal That Monomethyl Auristatin E Temporally Modulates the Tumor Immune Microenvironment
Chemotherapies remain standard therapy for cancers but have limited efficacy and cause significant side effects, highlighting the need for targeted approaches. In the progression of cancer, tumors increase matrix metalloproteinase (MMP) activity. Leveraging and therapeutically redirecting tumor MMPs...
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MDPI AG
2024-11-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/29/23/5618 |
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| author | Mahsa Mortaja Marcus M. Cheng Alina Ali Jacqueline Lesperance Dina V. Hingorani Mike M. Allevato Kanika Dhawan Maria F. Camargo Rana R. McKay Stephen R. Adams J. Silvio Gutkind Sunil J. Advani |
| author_facet | Mahsa Mortaja Marcus M. Cheng Alina Ali Jacqueline Lesperance Dina V. Hingorani Mike M. Allevato Kanika Dhawan Maria F. Camargo Rana R. McKay Stephen R. Adams J. Silvio Gutkind Sunil J. Advani |
| author_sort | Mahsa Mortaja |
| collection | DOAJ |
| description | Chemotherapies remain standard therapy for cancers but have limited efficacy and cause significant side effects, highlighting the need for targeted approaches. In the progression of cancer, tumors increase matrix metalloproteinase (MMP) activity. Leveraging and therapeutically redirecting tumor MMPs through activatable cell-penetrating peptide (ACPP) technology offers new approaches for tumor-selective drug delivery and for studying how drug payloads engage the tumor immune microenvironment. ACPPs are biosensing peptides consisting of a drug-conjugated polycationic cell-penetrating peptide masked by an autoinhibitory polyanionic peptide through an interlinking peptide linker. Since tumors overexpress MMPs, ACPP tumor-targeting is achieved using an MMP cleavable linker. Monomethyl auristatin E (MMAE) is a potent anti-tubulin and common drug payload in antibody drug conjugates; however there are limited pre-clinical studies on how this clinically effective drug modulates the interplay of cancer cells and the immune system. Here, we report the versatility of ACPP conjugates in syngeneic murine cancer models and interrogate how MMAE temporally alters the tumor immune microenvironment. We show that cRGD-ACPP-MMAE preferentially delivered MMAE to tumors in murine models. Targeted cRGD-ACPP-MMAE demonstrated anti-tumor kill activity that activated the innate and adaptive arms of the immune system. Understanding how targeted MMAE engages tumors can optimize MMAE tumor kill activity and inform rational combinations with other cancer therapeutics. |
| format | Article |
| id | doaj-art-68c3c16ffb55446dae62cfda42fb4f65 |
| institution | OA Journals |
| issn | 1420-3049 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj-art-68c3c16ffb55446dae62cfda42fb4f652025-08-20T02:38:50ZengMDPI AGMolecules1420-30492024-11-012923561810.3390/molecules29235618Tumor-Targeted Cell-Penetrating Peptides Reveal That Monomethyl Auristatin E Temporally Modulates the Tumor Immune MicroenvironmentMahsa Mortaja0Marcus M. Cheng1Alina Ali2Jacqueline Lesperance3Dina V. Hingorani4Mike M. Allevato5Kanika Dhawan6Maria F. Camargo7Rana R. McKay8Stephen R. Adams9J. Silvio Gutkind10Sunil J. Advani11Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA 92093, USADepartment of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA 92093, USADepartment of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA 92093, USADepartment of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA 92093, USADepartment of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA 92093, USADepartment of Pharmacology, University of California San Diego, La Jolla, CA 92093, USADepartment of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA 92093, USADepartment of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA 92093, USADepartment of Medicine, University of California San Diego, La Jolla, CA 92093, USADepartment of Pharmacology, University of California San Diego, La Jolla, CA 92093, USADepartment of Pharmacology, University of California San Diego, La Jolla, CA 92093, USADepartment of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA 92093, USAChemotherapies remain standard therapy for cancers but have limited efficacy and cause significant side effects, highlighting the need for targeted approaches. In the progression of cancer, tumors increase matrix metalloproteinase (MMP) activity. Leveraging and therapeutically redirecting tumor MMPs through activatable cell-penetrating peptide (ACPP) technology offers new approaches for tumor-selective drug delivery and for studying how drug payloads engage the tumor immune microenvironment. ACPPs are biosensing peptides consisting of a drug-conjugated polycationic cell-penetrating peptide masked by an autoinhibitory polyanionic peptide through an interlinking peptide linker. Since tumors overexpress MMPs, ACPP tumor-targeting is achieved using an MMP cleavable linker. Monomethyl auristatin E (MMAE) is a potent anti-tubulin and common drug payload in antibody drug conjugates; however there are limited pre-clinical studies on how this clinically effective drug modulates the interplay of cancer cells and the immune system. Here, we report the versatility of ACPP conjugates in syngeneic murine cancer models and interrogate how MMAE temporally alters the tumor immune microenvironment. We show that cRGD-ACPP-MMAE preferentially delivered MMAE to tumors in murine models. Targeted cRGD-ACPP-MMAE demonstrated anti-tumor kill activity that activated the innate and adaptive arms of the immune system. Understanding how targeted MMAE engages tumors can optimize MMAE tumor kill activity and inform rational combinations with other cancer therapeutics.https://www.mdpi.com/1420-3049/29/23/5618peptide–drug conjugatescell-penetrating peptidesanti-tubulinsmatrix metalloproteinases |
| spellingShingle | Mahsa Mortaja Marcus M. Cheng Alina Ali Jacqueline Lesperance Dina V. Hingorani Mike M. Allevato Kanika Dhawan Maria F. Camargo Rana R. McKay Stephen R. Adams J. Silvio Gutkind Sunil J. Advani Tumor-Targeted Cell-Penetrating Peptides Reveal That Monomethyl Auristatin E Temporally Modulates the Tumor Immune Microenvironment Molecules peptide–drug conjugates cell-penetrating peptides anti-tubulins matrix metalloproteinases |
| title | Tumor-Targeted Cell-Penetrating Peptides Reveal That Monomethyl Auristatin E Temporally Modulates the Tumor Immune Microenvironment |
| title_full | Tumor-Targeted Cell-Penetrating Peptides Reveal That Monomethyl Auristatin E Temporally Modulates the Tumor Immune Microenvironment |
| title_fullStr | Tumor-Targeted Cell-Penetrating Peptides Reveal That Monomethyl Auristatin E Temporally Modulates the Tumor Immune Microenvironment |
| title_full_unstemmed | Tumor-Targeted Cell-Penetrating Peptides Reveal That Monomethyl Auristatin E Temporally Modulates the Tumor Immune Microenvironment |
| title_short | Tumor-Targeted Cell-Penetrating Peptides Reveal That Monomethyl Auristatin E Temporally Modulates the Tumor Immune Microenvironment |
| title_sort | tumor targeted cell penetrating peptides reveal that monomethyl auristatin e temporally modulates the tumor immune microenvironment |
| topic | peptide–drug conjugates cell-penetrating peptides anti-tubulins matrix metalloproteinases |
| url | https://www.mdpi.com/1420-3049/29/23/5618 |
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