Co-administration of a Tumor-Penetrating Peptide Enhances the Efficacy of Cancer Drugs

By K. Sugahara, T. Teesalu, P. Karmali, V. R. Kotamraju, L. Agemy, D. Greenwald, Erkki Ruoslahti. Science, 2010

1,045 citations recorded by the source corpus.

Penetrating Attack on Tumors While considerable research effort in oncology is focused on the design of new cancer drugs, an important but relatively understudied research area is the development of methods that optimize the delivery and tumor penetration of existing cancer drugs. Previous work has characterized a peptide (iRGD) that selectively targets and penetrates tumor tissue by virtue of its specific interaction with tumor blood vessels. Now, studying mouse models, Sugahara et al. (p. 1031, see the cover) show that coinjection of the iRGD peptide increases the tumor penetration and antitumor activity of several cancer drugs, including the cytotoxic agent doxorubicin and the therapeutic antibody trastuzumab (Herceptin), without increasing their harmful effects on healthy tissue. Importantly, these effects did not require chemical conjugation of the cancer drugs to the peptide. Anticancer drugs are more effective in mice when they are injected with a peptide that helps the drugs penetrate the tumor. Poor penetration of anticancer drugs into tumors can be an important factor limiting their efficacy. We studied mouse tumor models to show that a previously characterized tumor-penetrating peptide, iRGD, increased vascular and tissue permeability in a tumor-specific and neuropilin-1–dependent manner, allowing coadministered drugs to penetrate into extravascular tumor tissue. Importantly, this effect did not require the drugs to be chemically conjugated to the peptide. Systemic injection with iRGD improved the therapeutic index of drugs of various compositions, including a small molecule (doxorubicin), nanoparticles (nab-paclitaxel and doxorubicin liposomes), and a monoclonal antibody (trastuzumab). Thus, coadministration of iRGD may be a valuable way to enhance the efficacy of anticancer drugs while reducing their side effects, a primary goal of cancer therapy research.

Subfields: Immunology, Immunology and Allergy, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/c9b7a460d0b56ae12cd3487d96c597515c606bab

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Citations in the corpus

Insight into nanoparticle cellular uptake and intracellular targeting (2014, neutral): “Co-administration of a CPP (iRGD) via systemic injection has resulted in improved therapeutic index of a variety of codelivered drug entities (DOX, nab-paclitaxel, DOX liposomes, and trastuzumab) [164].”
Vimentin as a potential molecular target in cancer therapy Or Vimentin, an overview and its potential as a molecular target for cancer therapy (2011, positive): “Currently, we are in the process of testing the effects of co-administering CHP with anti-cancer agents, as recent studies have reported a significant increase in the efficacy of anti-cancer drugs that were co-administered with tumor penetrating peptide fragments (127).”
Causes, consequences, and remedies for growth-induced solid stress in murine and human tumors (2012, background): “Antisolid stress approaches could also be combined with tumor-targeting ligands (65) and matrix-modifying agents (52) to improve drug delivery and efficacy.”
A doxorubicin delivery platform using engineered natural membrane vesicle exosomes for targeted tumor therapy. (2014, background): “iRGD not only strictly binds to av integrins that are highly expressed on tumor cells and tumor-associated vascular endothelium, but also facilitates vascular and tissue penetration of antitumor drugs [23].”
Cancer nanotechnology: the impact of passive and active targeting in the era of modern cancer biology. (2014, background): “is found to be internalized by its targeted tumor cells indicating its cell-penetrating abilities [233, 269].”
Nanomedicine in cancer therapy (2023, background): “134 The iRGD (CRGDK/RGPD/EC) peptide can initially home to tumors by binding to integrin α v β 3 , and is then proteolytically cleaved to produce the CRGDK/R fragment, which gains af ﬁ nity for neuropilin-1 (NRP-1) and triggers tissue penetration.”
Antibody Structure and Function: The Basis for Engineering Therapeutics (2019, background): “There have been efforts to increase tumor access using tumor-penetrating ligands [582].”