Improving Drug Penetrability with iRGD Leverages the Therapeutic Response to Sorafenib and Doxorubicin in Hepatocellular Carcinoma

Schmithals, Christian; Köberle, Verena; Korkusuz, H.; Pleli, Thomas; Kakoschky, Bianca; Augusto, Eduardo Alonso; Ibrahim, Ahmed Atef; Arencibia, José M.; Vafaizadeh, Vida; Groner, Bernd; Korf, Horst‐Werner; Kronenberger, Bernd; Zeuzem, Stefan; Vogl, Thomas J.; Waidmann, Oliver; Piiper, Albrecht

doi:10.1158/0008-5472.can-15-0395

Cited by 58 publications

(41 citation statements)

References 29 publications

(41 reference statements)

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“…An important feature of this group of targeting ligands is their ability to cause bystander effect-increased target accumulation of coadministered payloads. Prototypic member of the family, iRGD, increases accumulation and activity of IP coadministered payloads, including anticancer drugs [41–44]. We hypothesized that interaction of the truncated form of the linTT1 with NRP-1 might trigger the transtissue transport pathway for co-administered compounds [22].…”

Section: Resultsmentioning

confidence: 99%

Targeting of p32 in peritoneal carcinomatosis with intraperitoneal linTT1 peptide-guided pro-apoptotic nanoparticles

Hunt

Simón‐Gracia

Tobi

et al. 2017

Journal of Controlled Release

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Gastrointestinal and gynecological malignancies disseminate in the peritoneal cavity - a condition known as peritoneal carcinomatosis (PC). Intraperitoneal (IP) administration can be used to improve therapeutic index of anticancer drugs used for PC treatment. Activity of IP anticancer drugs can be further potentiated by encapsulation in nanocarriers and/or affinity targeting with tumor-specific affinity ligands, such as tumor homing peptides. Here we evaluated a novel tumor penetrating peptide, linTT1 (AKRGARSTA), as a PC targeting ligand for nanoparticles. We first demonstrated that the primary homing receptor for linTTl, p32 (or gClqR), is expressed on the cell surface of peritoneal carcinoma cell lines of gastric (MKN-45P), ovarian (SKOV-3), and colon (CT-26) origin, and that peritoneal tumors in mice and clinical peritoneal carcinoma explants express p32 protein accessible from the IP space. Iron oxide nanoworms (NWs) functionalized with the linTT1 peptide were taken up and routed to mitochondria in cultured PC cells. NWs functionalized with linTT1 peptide in tandem with a pro-apoptotic [D(KLAKLAK)2] peptide showed p32-dependent cytotoxicity in MKN-45P, SKOV-3, and CT- 26 cells. Upon IP administration in mice bearing MKN-45P, SKOV-3, and CT-26 tumors, linTT1-functionalized NWs showed robust homing and penetration into malignant lesions, whereas only a background accumulation was seen in control tissues. In tumors, the linTT1-NW accumulation was seen predominantly in CD31-positive blood vessels, in LYVE-1-positive lymphatic structures, and in CD11b-positive tumor macrophages. Experimental therapy of mice bearing peritoneal MKN-45P xenografts and CT-26 syngeneic tumors with IP linTT1-D(KLAKLAK)2-NWs resulted in significant reduction of weight of peritoneal tumors and significant decrease in the number of metastatic tumor nodules, whereas treatment with untargeted D(KLAKLAK)2-NWs had no effect. Our data show that targeting of p32 with linTTl tumor-penetrating peptide improves tumor selectivity and antitumor efficacy of IP pro-apoptotic NWs. P32-directed intraperitoneal targeting of other anticancer agents and nanoparticles using peptides and other affinity ligands may represent a general strategy to increase their therapeutic index.

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Section: Resultsmentioning

confidence: 99%

Targeting of p32 in peritoneal carcinomatosis with intraperitoneal linTT1 peptide-guided pro-apoptotic nanoparticles

Hunt

Simón‐Gracia

Tobi

et al. 2017

Journal of Controlled Release

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“…This circumstance explains the remarkable feature of the CendR system is that, in addition to covalently attached payloads, it will transport payloads co-administered with the peptide, but not attached to it (the “by-stander effect”). As discussed below, a number of laboratories have used iRGD is this manner to enhance drug delivery in preclinical studies [25,26,27,28]. …”

Section: The Cendr Pathwaymentioning

confidence: 99%

“…For example, cells that lack the NRP-1-interacting cytoplasmic protein, GIPC1 do not take up CendR cargo, regardless of NRP-1 expression [24]. Imaging the iRGD effect in a patient before the start of therapy may be the best way of predicting response, as was done by Schmithals et al [28]. These authors also showed, by analyzing mouse hepatocellular carcinomas ex vivo , that iRGD increased the inhibitory effect of sorafenib on cellular phosphorylation in the tumors.…”

Section: Tumor-penetrating Cendr Peptides In Drug Delivery: Generamentioning

confidence: 99%

Tumor penetrating peptides for improved drug delivery

Ruoslahti

2017

Advanced Drug Delivery Reviews

345

299

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In vivo screening of phage libraries in tumor-bearing mice has been used to identify peptides that direct phage homing to a tumor. The power of in vivo phage screening is illustrated by the recent discovery of peptides with unique tumor-penetrating properties. These peptides activate an endocytic transport pathway related to but distinct from macropinocytosis. They do so through a complex process that involves binding to a primary, tumor-specific receptor, followed by a proteolytic cleavage, and binding to a second receptor. The second receptor, neuropilin-1 (or neuropilin-2) activates the transport pathway. This trans-tissue pathway, dubbed the C-end Rule (CendR) pathway, mediates the extravasation transport through extravascular tumor tissue of payloads ranging from small molecule drugs to nanoparticles. The CendR technology provides a solution to a major problem in tumor therapy, poor penetration of drugs into tumors. Targeted delivery with tumor-penetrating peptides has been shown to specifically increase the accumulation of drugs, antibodies and nanotherapeutics in experimental tumors in vivo, and in human tumors ex vivo. Remarkably the payload does not have to be coupled to the peptide; the peptide activates a bulk transport system that sweeps along a drug present in the blood. Treatment studies in mice have shown improved anti-tumor efficacy and less damage to normal tissues with drugs ranging from traditional chemotherapeutics to antibodies, and to nanoparticle drugs.

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“…Further, in an in vivo model of mammary adenocarcinoma, Ni et al reported that iRGD-grafted nanocrystallites can target cancer stem cells, which are typically inside the tumor core (Ni et al, 2015). In a hepatocarcinoma xenograft model, utilizing the same mouse strain as Sugahara et al, Schmithals et al reported that co-administration of iRGD enhanced the penetration of DOX into tumor tissue as well as reduced tumor size as compared to DOX alone (Schmithals et al, 2015; Sugahara et al, 2010). Utilizing a different chemotherapeutic, Zhang et al reported that in an A549 xenograft model of non-small cell lung cancer, co-administration of iRGD along with gemcitabine lead to increased penetrance of drug to the tumor and decreased tumor volume over the treatment period of 30 days (Zhang et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Replication Study: Coadministration of a tumor-penetrating peptide enhances the efficacy of cancer drugs

Mantis

Kandela

Aird

2017

eLife

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In 2015, as part of the Reproducibility Project: Cancer Biology, we published a Registered Report (Kandela et al., 2015) that described how we intended to replicate selected experiments from the paper “Coadministration of a tumor-penetrating peptide enhances the efficacy of cancer drugs“ (Sugahara et al., 2010). Here we report the results of those experiments. We found that coadministration with iRGD peptide did not have an impact on permeability of the chemotherapeutic agent doxorubicin (DOX) in a xenograft model of prostate cancer, whereas the original study reported that it increased the penetrance of this cancer drug (Figure 2B; Sugahara et al., 2010). Further, in mice bearing orthotopic 22Rv1 human prostate tumors, we did not find a statistically significant difference in tumor weight for mice treated with DOX and iRGD compared to DOX alone, whereas the original study reported a decrease in tumor weight when DOX was coadministered with iRGD (Figure 2C; Sugahara et al., 2010). In addition, we did not find a statistically significant difference in TUNEL staining in tumor tissue between mice treated with DOX and iRGD compared to DOX alone, while the original study reported an increase in TUNEL positive staining with iRGD coadministration (Figure 2D; Sugahara et al., 2010). Similar to the original study (Supplemental Figure 9A; Sugahara et al., 2010), we did not observe an impact on mouse body weight with DOX and iRGD treatment. Finally, we report meta-analyses for each result.DOI: http://dx.doi.org/10.7554/eLife.17584.001

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Improving Drug Penetrability with iRGD Leverages the Therapeutic Response to Sorafenib and Doxorubicin in Hepatocellular Carcinoma

Cited by 58 publications

References 29 publications

Targeting of p32 in peritoneal carcinomatosis with intraperitoneal linTT1 peptide-guided pro-apoptotic nanoparticles

Targeting of p32 in peritoneal carcinomatosis with intraperitoneal linTT1 peptide-guided pro-apoptotic nanoparticles

Tumor penetrating peptides for improved drug delivery

Replication Study: Coadministration of a tumor-penetrating peptide enhances the efficacy of cancer drugs

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