Tumor-penetrating therapy for β5 integrin-rich pancreas cancer

Mendoza, Tatiana Hurtado de; Mose, Evangeline; Botta, Gregory P.; Braun, Gary B.; Kotamraju, Venkata Ramana; French, Randall; Suzuki, Kodai; Miyamura, Norio; Teesalu, Tambet; Ruoslahti, Erkki; Lowy, Andrew M.; Sugahara, Kazuki N.

doi:10.1038/s41467-021-21858-1

Cited by 42 publications

(37 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Finally, we sought to reveal whether iRGD reduced hypoxia and enhanced the efficacy of IR through NRP‐1. Cyclic peptide iRGD can bind to α V β 3 /β 5 integrins and NRP‐1 38 . Truncated iRGD (t‐iRGD, CRGDK) loses much of its affinity for integrin, but possesses the affinity for NRP‐1 39 .…”

Section: Resultsmentioning

confidence: 99%

“…Cyclic peptide iRGD can bind to α V β 3 /β 5 integrins and NRP‐1. 38 Truncated iRGD (t‐iRGD, CRGDK) loses much of its affinity for integrin, but possesses the affinity for NRP‐1. 39 The percentage of hypoxic cells in MCTS decreased greatly when MCTS were treated with t‐iRGD, suggesting that NRP‐1 may mediate hypoxia reduction (Figure 8A ).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Tumor‐penetrating peptide internalizing RGD enhances radiotherapy efficacy through reducing tumor hypoxia

Meng

Wei

et al. 2022

Cancer Science

View full text Add to dashboard Cite

Resistance to irradiation (IR) remains a major therapeutic challenge in tumor radiotherapy. The development of novel tumor-specific radiosensitizers is crucial for effective radiotherapy against solid tumors. Here, we revealed that remodeling tumor tissue penetration via tumor-penetrating peptide internalizing arginine-glycine-aspartic acid RGD (iRGD) enhanced irradiation efficacy. The growth of 4T1 and CT26 multicellular tumor spheroids (MCTS) and tumors was delayed significantly by the treatment with IR and iRGD. Mechanistically, iRGD reduced hypoxia in MCTS and tumors, resulting in enhanced apoptosis after MCTS and tumors were treated with IR and iRGD. This is the first report that shows enhanced radiation efficacy by remodeling tumorspecific tissue penetration with iRGD, implying the potential clinical application of peptides in future tumor therapy.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Tumor‐penetrating peptide internalizing RGD enhances radiotherapy efficacy through reducing tumor hypoxia

Meng

Wei

et al. 2022

Cancer Science

View full text Add to dashboard Cite

show abstract

“…Mechanistically this is brought about by post-translational stabilization of AMP-activated kinase (Hupfer et al 2021 ). In PDAC models, CAFs have in a mechanism involving TGF-β been demonstrated to upregulate αvβ5 levels in PDAC cells, in turn making them an efficient drug target for the tumor-penetrating iRGD peptide (Hurtado de Mendoza et al 2021 ).…”

Section: Tumor Fibrosismentioning

confidence: 99%

Integrin α11β1 in tumor fibrosis: more than just another cancer-associated fibroblast biomarker?

Zeltz

Navab

Heljasvaara

et al. 2022

J. Cell Commun. Signal.

View full text Add to dashboard Cite

There is currently an increased interest in understanding the role of the tumor microenvironment (TME) in tumor growth and progression. In this context the role of integrins in cancer-associated fibroblasts (CAFs) will need to be carefully re-evaluated. Fibroblast-derived cells are not only in the focus in tumors, but also in tissue fibrosis as well as in inflammatory conditions. The recent transcriptional profiling of what has been called “the pan-fibroblast cell lineage” in mouse and human tissues has identified novel transcriptional biomarker mRNAs encoding the secreted ECM proteins dermatopontin and collagen XV as well as the phosphatidylinositol-anchored membrane protein Pi16. Some of the genes identified in these fibroblasts scRNA-seq datasets will be useful for rigorous comparative characterizations of fibroblast-derived cell subpopulations. At the same time, it will be a challenge in the coming years to validate these transcriptional mRNA datasets at the protein-(expression) and at tissue-(distribution) levels and to find useful protein biomarker reagents that will facilitate fibroblast profiling at the cell level. In the current review we will focus on the role of the collagen-binding integrin α11β1 in CAFs, summarizing our own work as well as published datasets with information on α11 mRNA expression in selected tumors. Our experimental data suggest that α11β1 is more than just another biomarker and that it as a functional collagen receptor in the TME is playing a central role in regulating collagen assembly and matrix remodeling, which in turn impact tumor growth and metastasis.

show abstract

“…Therefore, integrins can be used as pharmacological targets for antiangiogenesis effects. The development of integrin ligands that include RGD motif is of great significance for the targeting of integrin-positive tumor cells [50].…”

Section: Targeting Integrinsmentioning

confidence: 99%

Peptide–drug conjugate-based novel molecular drug delivery system in cancer

Zhu

Tang

2021

Trends in Pharmacological Sciences

View full text Add to dashboard Cite

Drug delivery systems are generally believed to comprise drugs and excipients. A peptide-drug conjugate is a single molecule that can simultaneously play multiple roles in a drug delivery system, such as in vivo drug distribution, targeted release, and bioactivity functions. This molecule can be regarded as an integrated drug delivery system, so it is called a molecular drug delivery system. In the context of cancer therapy, a peptide-drug conjugate comprises a tumor-targeting peptide, a payload, and a linker. Tumor-targeting peptides specifically identify membrane receptors on tumor cells, improve drug-targeted therapeutic effects, and reduce toxic and side effects. Payloads with bioactive functions connect to tumor-targeting peptides through linkers. In this review, we explored ongoing clinical work on peptide-drug conjugates targeting various receptors. We discuss the binding mechanisms of tumor-targeting peptides and related receptors, as well as the limiting factors for peptide-drug conjugate-based molecular drug delivery systems. Towards enhanced targeting on tumorsDespite the rapid development of anticancer drugs in the past few decades, cancer is one of the leading causes of death in the world [1]. Due to the lack of an effective means to distinguish tumor cells from normal cells [2], the accumulation efficiency of anticancer drugs in tumor cells is low and the toxic side effects on normal tissues are high. In the treatment process, drug resistance problems are caused by tumor heterogeneity [3], drug inactivation, transport, and metabolism, changes in drug targets, and tumor microenvironment dysfunction [4]. Although advanced drug delivery methods can partially solve problems of targeting, toxicity, and drug resistance [5], difficult industrialization, complicated process control, and huge costs remain insurmountable obstacles.Peptide-drug conjugates are emerging molecular drug delivery system (see Glossary) that achieve precise drug delivery and tumor-targeted release at the molecular level [6]. Current drug delivery systems, such as nano-drug delivery systems, use various complex excipients to assemble nanoscale particles that encapsulate drugs to be passively or actively delivered to target organs. The anticancer efficacy of nano-drug delivery systems is improved by an enhanced permeability retention effect to increase drug accumulation in tumors and the toxicity of nanodrug delivery systems is reduced by the long systemic circulation to decrease drug accumulation in normal organs [7]. However, a reappraisal of nano-drug delivery system design is suggested to improve their clinical efficacy and safety in cancer patients [8].By contrast, molecular drug delivery systems use a single peptide-drug conjugate molecule to achieve in vivo drug delivery, targeted drug release, and bioactivity, which can maximize the targeting effect and reduce drug resistance. Peptide-drug conjugates, which were first reported in 1972 by Freer et al.[9] (Box 1), are similar to the tethering of ligand-targeted drugs [10],

show abstract

Tumor-penetrating therapy for β5 integrin-rich pancreas cancer

Cited by 42 publications

References 53 publications

Tumor‐penetrating peptide internalizing RGD enhances radiotherapy efficacy through reducing tumor hypoxia

Tumor‐penetrating peptide internalizing RGD enhances radiotherapy efficacy through reducing tumor hypoxia

Integrin α11β1 in tumor fibrosis: more than just another cancer-associated fibroblast biomarker?

Peptide–drug conjugate-based novel molecular drug delivery system in cancer

Contact Info

Product

Resources

About