Targeting Cell-Impermeable Prodrug Activation to Tumor Microenvironment Eradicates Multiple Drug-Resistant Neoplasms

Wu, Wei; Luo, Yunping; Sun, Changqi; Liu, Yuan; Kuo, P. L.; Varga, János; Xiang, Rong; Reisfeld, Ralph A.; Janda, Kim D.; Edgington, Thomas S.; Liu, Cheng

doi:10.1158/0008-5472.can-05-2591

Cited by 108 publications

(102 citation statements)

References 33 publications

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“…One of the most interesting ways in which legumain has been applied to the development of novel anticancer agents is in the design of antitumor prodrug platforms that specifically require asparagine at the P1 site of their substrate 28 . In fact, a prototype prodrug synthesized by the addition of doxorubicin to a legumain-specific substrate peptide through a peptide bond markedly reduced the toxicity of doxorubicin and increased its tumoricidal activity 29 .…”

Section: Discussionmentioning

confidence: 99%

Legumain protease-activated TAT-liposome cargo for targeting tumours and their microenvironment

et al. 2014

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Specific targeting and cellular internalization are key properties for carriers of antitumor therapeutic agents. Here, we develop a drug carrier through the attachment of substrate of endoprotease legumain, alanine-alanine-asparagine (AAN), to cell-penetrating peptides (TAT, trans-activating factor). The addition of the AAN moiety to the fourth lysine in the TAT creates a branched peptide moiety, which leads to a decrease in the transmembrane transport capacity of TAT by 72.65%. Legumain efficiently catalyses the release of TAT-liposome from the AAN-TAT-liposome and thereby recovers the penetrating capacity of TAT. Doxorubicin carried by the AAN-TAT-liposome led to an increase in the tumoricidal effect of doxorubicin and a reduction in its systemic adverse effects in comparison with doxorubicin carried by a control delivery system. Thus, the specific targeting and high efficiency of this delivery platform offers a novel approach to limit the toxicity of anticancer agents as well as increasing their efficacy in cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Legumain protease-activated TAT-liposome cargo for targeting tumours and their microenvironment

et al. 2014

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“…A novel legumainactivated, cell-impermeable doxorubicin prodrug LEG-3 designed to be activated exclusively in the TME showed a profound increase of the end product doxorubicin in nuclei of cells in tumors but little in other tissues. This TME-activated prodrug completely arrested growth of a variety of tumor types, including multidrug-resistant tumor in vivo, and significantly extended survival without evidence of myelosuppression or cardiac toxicity in mice models (66). This approach of targeting the TME is likely to be feasible in PDA.…”

Section: Therapeutic Strategiesmentioning

confidence: 96%

Tumor-stroma interactions in pancreatic ductal adenocarcinoma

Mahadevan

Hoff

2007

Molecular Cancer Therapeutics

540

426

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“…Wu et al demonstrated the benefit of such an initiative by creating a cell-impermeable doxorubicin-based pro-drug [125]. Doxorubicin becomes released by the action of the protease legumain that was shown to be secreted by tumorassociated macrophages and endothelial cells and accumulates in the ECM.…”

Section: Experimental Cell Impermeable Pro-drugsmentioning

confidence: 99%

A Digest on the Role of the Tumor Microenvironment in Gastrointestinal Cancers

Augsten

Hägglöf

Peña

et al. 2010

Cancer Microenvironment

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Experimental studies and analyses of clinical material have convincingly demonstrated that tumor formation and progression occurs through a concerted action of malignant cells and the surrounding microenvironment of the tumor stroma. The tumor microenvironment is comprised of various cell types like fibroblasts, immune cells, vascular cells and bone-marrow-derived cells embedded in the extracellular matrix. This review, focusing on recent findings in the context of gastrointestinal tumors, introduces the different stromal cell types and delineates their contributions to cancer initiation, growth and metastasis. By selected examples we also present how the tumor microenvironment is emerging as a promising target for therapeutic intervention.

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Targeting Cell-Impermeable Prodrug Activation to Tumor Microenvironment Eradicates Multiple Drug-Resistant Neoplasms

Abstract: The tumor microenvironment is notably enriched with a broad spectrum of proteases. The proteolytic specificities of peptide substrates provide modular chemical tools for the rational design of cell

Cited by 108 publications

References 33 publications

Legumain protease-activated TAT-liposome cargo for targeting tumours and their microenvironment

Legumain protease-activated TAT-liposome cargo for targeting tumours and their microenvironment

Tumor-stroma interactions in pancreatic ductal adenocarcinoma

A Digest on the Role of the Tumor Microenvironment in Gastrointestinal Cancers

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