Proteolysis: A Biological Process Adapted in Drug Delivery, Therapy, and Imaging

Law, Benedict; Tung, Ching–Hsuan

doi:10.1021/bc800500a

Cited by 118 publications

(92 citation statements)

References 142 publications

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“…Proteinase K (also protease K or endopeptidase K) is a serine protease with broad substrate specificity [47]. Incubation of the dppzNB ligand with proteinase K for 4 h at 37 • C and analysis of the products generated by mass spectrometry showed that the amide bond in dppzNB undergoes digestion (see the electronic supplementary material, figure S9).…”

Section: Results and Discussion (A) Design Synthesis And General Aspmentioning

confidence: 99%

Biotin-conjugated tumour-targeting photocytotoxic iron(III) complexes

Saha

Majumdar

Hussain

et al. 2013

Phil. Trans. R. Soc. A.

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Iron(III) complexes [FeL(B)] ( 1 – 4 ) of a tetradentate phenolate-based ligand (H 3 L) and biotin-conjugated dipyridophenazine bases (B), viz. 7-aminodipyrido [3,2- a :2′,3′- c ]-phenazine (dppza in 1 ), ( N -dipyrido[3,2- a :2′,3′- c ]-phenazino)amidobiotin (dppzNB in 2 ), dipyrido [3,2- a :2′,3′- c ]-phenazine-11-carboxylic acid (dppzc in 3 ) and 2-((2-biotinamido)ethyl) amido-dipyrido[3,2- a :2′,3′- c ]-phenazine (dppzCB in 4 ) are prepared, characterized and their interaction with streptavidin and DNA and their photocytotoxicity and cellular uptake in various cells studied. The high-spin iron(III) complexes display Fe(III)/Fe(II) redox couple near −0.7 V versus saturated calomel electrode in dimethyl sulfoxide–0.1 M tetrabutylammonium perchlorate. The complexes show non-specific interaction with DNA as determined from the binding studies. Complexes with appended biotin moiety show similar binding to streptavidin as that of free biotin, suggesting biotin conjugation to dppz does not cause any loss in its binding affinity to streptavidin. The photocytotoxicity of the complexes is tested in HepG2, HeLa and HEK293 cell lines. Complex 2 shows higher photocytotoxicity in HepG2 cells than in HeLa or HEK293, forming reactive oxygen species. This effect is attributed to the presence of overexpressed sodium-dependent multi-vitamin transporters in HepG2 cells. Microscopic studies in HepG2 cells show internalization of the biotin complexes 2 and 4 essentially occurring by receptor-mediated endocytosis, which is similar to that of native biotin and biotin fluorescein isothiocyanate conjugate.

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Section: Results and Discussion (A) Design Synthesis And General Aspmentioning

confidence: 99%

Biotin-conjugated tumour-targeting photocytotoxic iron(III) complexes

Saha

Majumdar

Hussain

et al. 2013

Phil. Trans. R. Soc. A.

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“…This area has considerable potential. Further examples are provided by Choi et al [3] and Law and Tung [4] .…”

Section: Opportunities For Drug Targetingmentioning

confidence: 99%

“…Despite their potential as therapeutic targets, however, a clinically useful agent has yet to materialise, despite several MMP inhibitors having been developed and evaluated in clinical trials [2] . More recently, attention has turned to the potential utility of MMPs as activators of targeted prodrug therapies [3][4][5] .…”

Section: Introductionmentioning

confidence: 99%

Membrane-type matrix metalloproteinases: expression, roles in metastatic prostate cancer progression and opportunities for drug targeting

Falconer¹,

Loadman²

2017

JCMT

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The membrane-type matrix metalloproteinases (MT-MMPs), an important subgroup of the wider MMP family, demonstrate widespread expression in multiple tumor types, and play key roles in cancer growth, migration, invasion and metastasis. Despite a large body of published research, relatively little information exists regarding evidence for MT-MMP expression and function in metastatic prostate cancer. This review provides an appraisal of the literature describing gene and protein expression in prostate cancer cells and clinical tissue, summarises the evidence for roles in prostate cancer progression, and examines the data relating to MT-MMP function in the development of bone metastases. Finally, the therapeutic potential of targeting MT-MMPs is considered. While MT-MMP inhibition presents a significant challenge, utilisation of MT-MMP expression and proteolytic capacity in prostate tumors is an attractive drug development opportunity. Key words:Matrix metalloproteinase, membrane-type, metastasis, prostate cancer, microenvironment ABSTRACTArticle history:

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“…Proteolysis is a simple hydrolytic process that separates two adjacent amino acid residues at the amide bond and is triggered by proteases. 15 Enzyme cleavable conjugates, containing enzyme-sensitive substrate, mainly take advantage of the selectivity and specificity of enzymes that are differentially active in the immediate environment of tumor cells.…”

Section: Introductionmentioning

confidence: 99%

Enhancing cellular uptake of activable cell-penetrating peptide–doxorubicin conjugate by enzymatic cleavage

Shi¹,

Gao²,

Xiang³

et al. 2012

IJN

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Abstract:The use of activable cell-penetrating peptides (ACPPs) as molecular imaging probes is a promising new approach for the visualization of enzymes. The cell-penetrating function of a polycationic cell-penetrating peptide (CPP) is efficiently blocked by intramolecular electrostatic interactions with a polyanionic peptide. Proteolysis of a proteinase-sensitive substrate present between the CPP and polyanionic peptide affords dissociation of both domains and enables the activated CPP to enter cells. This ACPP strategy could also be used to modify antitumor agents for tumor-targeting therapy. Here, we aimed to develop a conjugate of ACPP with antitumor drug doxorubicin (DOX) sensitive to matrix metalloproteinase-2 and -9 (MMP-2/9) for tumor-targeting therapy purposes. The ACPP-DOX conjugate was successfully synthesized. Enzymatic cleavage of ACPP-DOX conjugate by matrix metalloproteinase (MMP)-2/9 indicated that the activation of ACPP-DOX occurred in an enzyme concentration-dependent manner. Flow cytometry and laser confocal microscope studies revealed that the cellular uptake of ACPP-DOX was enhanced after enzymatic-triggered activation and was higher in HT-1080 cells (overexpressed MMPs) than in MCF-7 cells (under-expressed MMPs). The antiproliferative assay showed that ACPP had little toxicity and that ACPP-DOX effectively inhibited HT-1080 cell proliferation. These experiments revealed that the ACPP-DOX conjugate could be triggered by MMP-2/9, which enabled the activated CPP-DOX to enter cells. ACPP-DOX conjugate may be a potential prodrug delivery system used to carry antitumor drugs for MMP-related tumor therapy.

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Proteolysis: A Biological Process Adapted in Drug Delivery, Therapy, and Imaging

Cited by 118 publications

References 142 publications

Biotin-conjugated tumour-targeting photocytotoxic iron(III) complexes

Biotin-conjugated tumour-targeting photocytotoxic iron(III) complexes

Membrane-type matrix metalloproteinases: expression, roles in metastatic prostate cancer progression and opportunities for drug targeting

Enhancing cellular uptake of activable cell-penetrating peptide–doxorubicin conjugate by enzymatic cleavage

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Proteolysis: A Biological Process Adapted in Drug Delivery, Therapy, and Imaging

Cited by 118 publications

References 142 publications

Biotin-conjugated tumour-targeting photocytotoxic iron(III) complexes

Biotin-conjugated tumour-targeting photocytotoxic iron(III) complexes

Membrane-type matrix metalloproteinases: expression, roles in metastatic prostate cancer progression and opportunities for drug targeting

Enhancing cellular uptake of activable cell-penetrating peptide&ndash;doxorubicin conjugate by enzymatic cleavage

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Enhancing cellular uptake of activable cell-penetrating peptide–doxorubicin conjugate by enzymatic cleavage