The First Generation of β‐Galactosidase‐Responsive Prodrugs Designed for the Selective Treatment of Solid Tumors in Prodrug Monotherapy

Mitochondria are vital organelles to eukaryotic cells. Damage to mitochondria will cause irreversible cell death or apoptosis. In this report, we aim at programmed cancer cell death via specific mitochondrial damage. Herein, a functionalized pro-apoptotic peptide demonstrates a dual-targeting capability using folic acid (FA) (targeting agent I) and triphenylphosphonium (TPP) cation (targeting agent II). FA is a cancer-targeting agent, which can increase the cellular uptake of the pro-apoptotic peptide via receptor-mediated endocytosis. And the TPP cation is the mitochondrial targeting agent, which specifically delivers the pro-apoptotic peptide to its particular subcellular mitochondria after internalized by cancer cells. Then the pro-apoptotic peptide accumulates in mitochondria and causes its serious damage. This dual-targeting strategy has the potential to effectively transport the pro-apoptotic peptide to targeted cancer cell mitochondria, inducing mitochondrial dysfunction and triggering the mitochondria-dependent apoptosis to efficiently eliminate cancer cells.

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“…S4) were respectively incubated with DTP22. The FR-negative normal cell line of COS7 cells was also used as control.…”

Section: Resultsmentioning

confidence: 99%

Dual-Targeting Pro-apoptotic Peptide for Programmed Cancer Cell Death via Specific Mitochondria Damage

Chen

Luo

et al. 2013

Sci Rep

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“…29–32 In the case of ADEPT, β-gal is utilized to activate a pro-drug therapy in a two-step approach much like that proposed in this study. In the first step, a drug-activating enzyme is targeted and expressed in tumors.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed for β-gal, several pro-drug substrates do exist, which, when activated, generate toxicity for cancer cells both in vitro and in vivo. 32–35 …”

Section: Discussionmentioning

confidence: 99%

Optical Imaging of Targeted β-Galactosidase in Brain Tumors to Detect EGFR Levels

et al. 2015

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A current limitation in molecular imaging is that it often requires genetic manipulation of cancer cells for noninvasive imaging. Other methods to detect tumor cells in vivo using exogenously delivered and functionally active reporters, such as β-gal, are required. We report the development of a platform system for linking β-gal to any number of different ligands or antibodies for in vivo targeting to tissue or cells, without the requirement for genetic engineering of the target cells prior to imaging. Our studies demonstrate significant uptake in vitro and in vivo of an EGFR-targeted β-gal complex. We were then able to image orthotopic brain tumor accumulation and localization of the targeted enzyme when a fluorophore was added to the complex, as well as validate the internalization of the intravenously administered β-gal reporter complex ex vivo. After fluorescence imaging localized the β-gal complexes to the brain tumor, we topically applied a bioluminescent β-gal substrate to serial sections of the brain to evaluate the delivery and integrity of the enzyme. Finally, robust bioluminescence of the EGFR-targeted β-gal complex was captured within the tumor during noninvasive in vivo imaging.

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“…A macromolecular prodrug designed to take advantage of specific tumor-associated receptors and activation by lysosomal enzymes inside malignant cells represents a "simpler" approach to ADEPT [122]. A macromolecular prodrug designed to take advantage of specific tumor-associated receptors and activation by lysosomal enzymes inside malignant cells represents a "simpler" approach to ADEPT [122].…”

Section: Release In Tumor Sitesmentioning

confidence: 99%

Designing Prodrugs and Bioprecursors

Choi-Sledeski

Wermuth²

2015

The Practice of Medicinal Chemistry

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The First Generation of β‐Galactosidase‐Responsive Prodrugs Designed for the Selective Treatment of Solid Tumors in Prodrug Monotherapy

Cited by 98 publications

References 43 publications

Dual-Targeting Pro-apoptotic Peptide for Programmed Cancer Cell Death via Specific Mitochondria Damage

Dual-Targeting Pro-apoptotic Peptide for Programmed Cancer Cell Death via Specific Mitochondria Damage

Optical Imaging of Targeted β-Galactosidase in Brain Tumors to Detect EGFR Levels

Designing Prodrugs and Bioprecursors

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