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

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 p...

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Bibliographic Details
Published in:International journal of nanomedicine 2012-01, Vol.7, p.1613-1621
Main Authors: Shi, Nian-Qiu, Gao, Wei, Xiang, Bai, Qi, Xian-Rong
Format: Article
Language:English
Subjects:
Acid Phosphatase
activable cell-penetrating peptide
Antineoplastic Agents - administration & dosage
Antineoplastic Agents - metabolism
Antineoplastic Agents - therapeutic use
antiproliferative
Biological Transport, Active
Breast Neoplasms - drug therapy
Breast Neoplasms - metabolism
Breast Neoplasms - pathology
Cell Line, Tumor
Cell Proliferation - drug effects
cellular uptake
Doxorubicin - administration & dosage
Doxorubicin - metabolism
Doxorubicin - therapeutic use
Drug Delivery Systems
enzymatic cleavage
Female
Fibrosarcoma - drug therapy
Fibrosarcoma - metabolism
Fibrosarcoma - pathology
Humans
matrix metalloproteinase
Matrix Metalloproteinase 2 - metabolism
Matrix Metalloproteinase 9 - metabolism
Nanomedicine
Original Research
Peptides
Protein Tyrosine Phosphatases - administration & dosage
Protein Tyrosine Phosphatases - metabolism
proteinase-sensitive substrate
tumor extracellular environment
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Summary: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.
ISSN:1178-2013
1176-9114
1178-2013
DOI:10.2147/IJN.S30104