Tumor-Penetrating Peptides

Cancer Research Center, Sanford-Burnham Medical Research Institute , La Jolla, CA , USA
Frontiers in Oncology 08/2013; 3:216. DOI: 10.3389/fonc.2013.00216
Source: PubMed


Tumor-homing peptides can be used to deliver drugs into tumors. Phage library screening in live mice has recently identified homing peptides that specifically recognize the endothelium of tumor vessels, extravasate, and penetrate deep into the extravascular tumor tissue. The prototypic peptide of this class, iRGD (CRGDKGPDC), contains the integrin-binding RGD motif. RGD mediates tumor-homing through binding to αv integrins, which are selectively expressed on various cells in tumors, including tumor endothelial cells. The tumor-penetrating properties of iRGD are mediated by a second sequence motif, R/KXXR/K. This C-end Rule (or CendR) motif is active only when the second basic residue is exposed at the C-terminus of the peptide. Proteolytic processing of iRGD in tumors activates the cryptic CendR motif, which then binds to neuropilin-1 activating an endocytic bulk transport pathway through tumor tissue. Phage screening has also yielded tumor-penetrating peptides that function like iRGD in activating the CendR pathway, but bind to a different primary receptor. Moreover, novel tumor-homing peptides can be constructed from tumor-homing motifs, CendR elements and protease cleavage sites. Pathologies other than tumors can be targeted with tissue-penetrating peptides, and the primary receptor can also be a vascular "zip code" of a normal tissue. The CendR technology provides a solution to a major problem in tumor therapy, poor penetration of drugs into tumors. The tumor-penetrating peptides are capable of taking a payload deep into tumor tissue in mice, and they also penetrate into human tumors ex vivo. Targeting with these peptides specifically increases the accumulation in tumors of a variety of drugs and contrast agents, such as doxorubicin, antibodies, and nanoparticle-based compounds. Remarkably the drug to be targeted does not have to be coupled to the peptide; the bulk transport system activated by the peptide sweeps along any compound that is present in the blood.

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Available from: Tambet Teesalu, Oct 14, 2014
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    • "In general, a well-thought-out prodrug strategy could achieve tissue-specific actions and reduce the undesired toxic effects, as the prodrug was designed according to the difference between the target environment and the abnormal physicochemical properties, like pH, temperature, over-expressed enzymes, receptors , and transporters etc. Considering that the common mechanism of the resistance to chemotherapy is the inability of drug transport across the cell membranes, transport moiety is especially critical in the case of anticancer therapy for protein drug [16], and various prodrug strategies were developed to achieve the selectivity issue [16] [17] [18] [19] [20] [21]. Except for Prodrug strategy, various approaches based on carriers, like antibodies [22], tumor homing peptides [23] [24] [25], various nanoparticles [26] [27] [28] [29] [30] [31], red blood cells [31] [32] [33], or even small molecule ligands [34] [35] have been utilized in the purpose of directing the macromolecular drugs only to the cancer cells [36] [37]. Our strategy, therefore, combines both of the attributes of prodrug and target drug delivery methods into a single delivery system, expecting to deliver the macromolecular drugs to specific tissue targets with minimal toxicity. "
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    ABSTRACT: Traditionally, any drug intended for combating the tumor would distribute profoundly to other organs and tissues as lack of targeting specificity, thus resulting in limited therapeutic effects toward the tumor but severe drug-induced toxic side effects. To prevail over this obstacle of drug-induced systemic toxicity, a novel approach termed "ATTEMPTS" (antibody targeted triggered electrically modified prodrug type strategy) was invented, which directly introduces both of the targeting and prodrug features onto the protein drugs. The ATTEMPTS system is composed of the antibody targeting components consisting of antibodies linked with heparin, and the cell penetrating peptide (CPP) modified drug component. The two components mentioned above self-assembled into a tight complex via the charge to charge interaction between the anionic heparin and cationic CPP. Once accumulated at the targeting site, the CPP modified drug is released from the blockage by a second triggering agent, while remaining inactive in the circulation during tumor targeting thus aborting its effect on normal tissues. We utilized a heparin-induced inhibition on the cell-penetrating activity of CPP to create the prodrug feature, and subsequently the protamine-induced reversal of heparin inhibition to resume cell transduction of the protein drug via the CPP function. Our approach is the first known system to overcome this selectivity issue, enabling CPP-mediated cellular drug delivery to be practically applicable clinically. In this review, we thoroughly discussed the historical and novel progress of the "ATTEMPTS" system. Copyright © 2014. Published by Elsevier B.V.
    Journal of Controlled Release 12/2014; 205. DOI:10.1016/j.jconrel.2014.12.002 · 7.71 Impact Factor
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    • "Indeed, Cys-X-iRGD induced more accumulation than iRGD of two long-circulating drugs (trastuzumab and nab-paclitaxel) in extravascular tumor regions, which should translate into a better therapeutic outcome. Other tumor penetrating peptides (LyP-1 [16], iNGR [17], etc.) may benefit from disulfide-mediated albumin hitchhiking similar to what we described here. Albumin has attracted much attention as a drug carrier not only because of its lack of toxicity and immunogenicity, but also its preferential accumulation in tumors and inflamed tissues [5]. "
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    ABSTRACT: The accessibility of extravascular tumor tissue to drugs is critical for therapeutic efficacy. We previously described a tumor-targeting peptide (iRGD) that elicits active transport of drugs and macromolecules (covalently coupled or co-administered) across the vascular wall into tumor tissue. Short peptides (iRGD is a 9-amino acid cyclic peptide) generally have a plasma half-life measured in minutes. Since short half-life limits the window of activity obtained with a bolus injection of iRGD, we explored to extend the half-life of the peptide. We show here that addition of a cysteine residue prolongs the plasma half-life of iRGD and increases the accumulation of the peptide in tumors. This modification prolongs the activity of iRGD in inducing macromolecular extravasation and leads to greater drug accumulation in tumors than is obtained with the unmodified peptide. This effect is mediated by covalent binding of iRGD to plasma albumin through a disulfide bond. Our study provides a simple strategy to improve peptide pharmacokinetics and activity. Applied to RGD, it provides a means to increase the entry of therapeutic agents into tumors.
    Journal of Controlled Release 12/2013; 175(1). DOI:10.1016/j.jconrel.2013.12.006 · 7.71 Impact Factor
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    ABSTRACT: Neuropilin 1 (NRP1) is a transmembrane glycoprotein that acts as a co-receptor for a number of extracellular ligands including class III/IV semaphorins, certain isoforms of vascular endothelial growth factor and transforming growth factor beta. An exact understanding of the role of NRP1 in the immune system has been obscured by the differences in NRP1 expression observed between mice and humans. In mice, NRP1 is selectively expressed on thymic-derived Tregs and greatly enhances immunosuppressive function. In humans, NRP1 is expressed on plasmacytoid dendritic cells (pDCs) where it aids in priming immune responses and on a subset of T regulatory cells (Tregs) isolated from secondary lymph nodes. Preliminary studies that show NRP1 expression on T cells confers enhanced immunosuppressive activity. However, the mechanism by which this activity is mediated remains unclear. NRP1 expression has also been identified on activated T cells and Tregs isolated from inflammatory microenvironments, suggesting NRP1 might represent a novel T cell activation marker. Of clinical interest, NRP1 may enhance Treg tumour infiltration and a decrease in NRP1+ Tregs correlates with successful chemotherapy, suggesting a specific role for NRP1 in cancer pathology. As a therapeutic target, NRP1 allows simultaneous targeting of NRP1-expressing tumour vasculature, NRP1+ Tregs and pDCs. With the development of anti-NRP1 monoclonal antibodies and cell-penetrating peptides, NRP1 represents a promising new target for cancer therapies. This paper reviews current knowledge on the role and function of NRP1 in Tregs and pDCs, both in physiological and cancer settings, as well as its potential as a therapeutic target in cancer.
    Cancer Immunology and Immunotherapy 11/2013; 63(2). DOI:10.1007/s00262-013-1500-0 · 3.94 Impact Factor
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