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Potent tumor targeting drug release system comprising MMP-2 specific peptide fragment with self-assembling characteristics.

Hua D, Kong W, Zheng X, Zhou Z, Yu B, Li Y, Wang Y, Yang X, Liu C, Tang L, Li Y, Gong M - Drug Des Devel Ther (2014)

Bottom Line: These complexes are beneficial for improving the pharmacological properties and pharmacokinetics of cytotoxic agents, such as doxorubicin and paclitaxel.In the present study, this self-assembling feature was successfully integrated into a hexapeptide with matrix metalloproteinase (MMP)-2 specific targeting activity, producing a supramolecule possessing controlled drug release characteristics.In addition, residence time of the complex in blood was prolonged since paclitaxel was wrapped into the supramolecule.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmacy, Tianjin Medical University, Tianjin, People's Republic of China.

ABSTRACT
Self-assembling peptides are capable of forming a complex containing a cavity where cytotoxic agents can be wrapped in a self-assembling manner. These complexes are beneficial for improving the pharmacological properties and pharmacokinetics of cytotoxic agents, such as doxorubicin and paclitaxel. In the present study, this self-assembling feature was successfully integrated into a hexapeptide with matrix metalloproteinase (MMP)-2 specific targeting activity, producing a supramolecule possessing controlled drug release characteristics. The MMP-2 specific substrate fragment, PVGLIG, makes this supramolecule disassociate in the presence of MMP-2, and this system is considered to be a powerful tool for the treatment of tumors with high expression of MMP-2 or tumor metastasis. Our findings show that this modified self-assembling peptide with the PVGLIG fragment was able to significantly enhance specificity against HT1080 cells, a tumor cell line with high expression of MMP-2. In addition, residence time of the complex in blood was prolonged since paclitaxel was wrapped into the supramolecule. Our results suggest that the modified MMP-2 specific substrate, SAMTA7, could act as a controlled and sustained drug carrier for treatment of tumors with high expression of MMP-2 and for tumor metastasis.

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Related in: MedlinePlus

Paclitaxel released from a self-assembling supramolecule in the presence of the MMP-2 enzyme. Various complexes of peptides and paclitaxel (paclitaxel 100 μg) were incubated with MMP-2 (5 μg) in phosphate-buffered saline (pH 7.0) containing 100 μM ZnSO4 at 37°C for 48 hours. High-performance liquid chromatography-mass spectrometry was then used to monitor the free paclitaxel released. The results indicate that the presence of the MMP-2 enzyme induced the release of paclitaxel from the SAMTA7-paclitaxel complex, compared with other complexes formed by other peptides. The supramolecule formed by SAMTA7 initiated drug release at 2 hours after incubation with MMP-2 and the paclitaxel release from the supramolecules was complete at 24 hours for SAMTA7. It was considered that SAMTA7 formed an MMP-2-sensitive supramolecule containing paclitaxel.Abbreviation: MMP, matrix metalloproteinase.
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f2-dddt-8-1839: Paclitaxel released from a self-assembling supramolecule in the presence of the MMP-2 enzyme. Various complexes of peptides and paclitaxel (paclitaxel 100 μg) were incubated with MMP-2 (5 μg) in phosphate-buffered saline (pH 7.0) containing 100 μM ZnSO4 at 37°C for 48 hours. High-performance liquid chromatography-mass spectrometry was then used to monitor the free paclitaxel released. The results indicate that the presence of the MMP-2 enzyme induced the release of paclitaxel from the SAMTA7-paclitaxel complex, compared with other complexes formed by other peptides. The supramolecule formed by SAMTA7 initiated drug release at 2 hours after incubation with MMP-2 and the paclitaxel release from the supramolecules was complete at 24 hours for SAMTA7. It was considered that SAMTA7 formed an MMP-2-sensitive supramolecule containing paclitaxel.Abbreviation: MMP, matrix metalloproteinase.

Mentions: Upon formation of the SAMTA7 and paclitaxel supramolecule, it was necessary to investigate whether this supramolecule is able to release paclitaxel in the presence of the MMP-2 enzyme. A proteolysis assay and an MS study were performed to detect release of paclitaxel from the supramolecule over 24 hours. As seen in Figure 2, the supramolecule formed by SAMTA7 started releasing the drug after incubation with MMP-2 for 2 hours. Paclitaxel seemed to be fully released from the supramolecules by 24 hours; result indicated that SAMTA7 provided complete wrapping for paclitaxel, compared with other peptides.


Potent tumor targeting drug release system comprising MMP-2 specific peptide fragment with self-assembling characteristics.

Hua D, Kong W, Zheng X, Zhou Z, Yu B, Li Y, Wang Y, Yang X, Liu C, Tang L, Li Y, Gong M - Drug Des Devel Ther (2014)

Paclitaxel released from a self-assembling supramolecule in the presence of the MMP-2 enzyme. Various complexes of peptides and paclitaxel (paclitaxel 100 μg) were incubated with MMP-2 (5 μg) in phosphate-buffered saline (pH 7.0) containing 100 μM ZnSO4 at 37°C for 48 hours. High-performance liquid chromatography-mass spectrometry was then used to monitor the free paclitaxel released. The results indicate that the presence of the MMP-2 enzyme induced the release of paclitaxel from the SAMTA7-paclitaxel complex, compared with other complexes formed by other peptides. The supramolecule formed by SAMTA7 initiated drug release at 2 hours after incubation with MMP-2 and the paclitaxel release from the supramolecules was complete at 24 hours for SAMTA7. It was considered that SAMTA7 formed an MMP-2-sensitive supramolecule containing paclitaxel.Abbreviation: MMP, matrix metalloproteinase.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4206202&req=5

f2-dddt-8-1839: Paclitaxel released from a self-assembling supramolecule in the presence of the MMP-2 enzyme. Various complexes of peptides and paclitaxel (paclitaxel 100 μg) were incubated with MMP-2 (5 μg) in phosphate-buffered saline (pH 7.0) containing 100 μM ZnSO4 at 37°C for 48 hours. High-performance liquid chromatography-mass spectrometry was then used to monitor the free paclitaxel released. The results indicate that the presence of the MMP-2 enzyme induced the release of paclitaxel from the SAMTA7-paclitaxel complex, compared with other complexes formed by other peptides. The supramolecule formed by SAMTA7 initiated drug release at 2 hours after incubation with MMP-2 and the paclitaxel release from the supramolecules was complete at 24 hours for SAMTA7. It was considered that SAMTA7 formed an MMP-2-sensitive supramolecule containing paclitaxel.Abbreviation: MMP, matrix metalloproteinase.
Mentions: Upon formation of the SAMTA7 and paclitaxel supramolecule, it was necessary to investigate whether this supramolecule is able to release paclitaxel in the presence of the MMP-2 enzyme. A proteolysis assay and an MS study were performed to detect release of paclitaxel from the supramolecule over 24 hours. As seen in Figure 2, the supramolecule formed by SAMTA7 started releasing the drug after incubation with MMP-2 for 2 hours. Paclitaxel seemed to be fully released from the supramolecules by 24 hours; result indicated that SAMTA7 provided complete wrapping for paclitaxel, compared with other peptides.

Bottom Line: These complexes are beneficial for improving the pharmacological properties and pharmacokinetics of cytotoxic agents, such as doxorubicin and paclitaxel.In the present study, this self-assembling feature was successfully integrated into a hexapeptide with matrix metalloproteinase (MMP)-2 specific targeting activity, producing a supramolecule possessing controlled drug release characteristics.In addition, residence time of the complex in blood was prolonged since paclitaxel was wrapped into the supramolecule.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmacy, Tianjin Medical University, Tianjin, People's Republic of China.

ABSTRACT
Self-assembling peptides are capable of forming a complex containing a cavity where cytotoxic agents can be wrapped in a self-assembling manner. These complexes are beneficial for improving the pharmacological properties and pharmacokinetics of cytotoxic agents, such as doxorubicin and paclitaxel. In the present study, this self-assembling feature was successfully integrated into a hexapeptide with matrix metalloproteinase (MMP)-2 specific targeting activity, producing a supramolecule possessing controlled drug release characteristics. The MMP-2 specific substrate fragment, PVGLIG, makes this supramolecule disassociate in the presence of MMP-2, and this system is considered to be a powerful tool for the treatment of tumors with high expression of MMP-2 or tumor metastasis. Our findings show that this modified self-assembling peptide with the PVGLIG fragment was able to significantly enhance specificity against HT1080 cells, a tumor cell line with high expression of MMP-2. In addition, residence time of the complex in blood was prolonged since paclitaxel was wrapped into the supramolecule. Our results suggest that the modified MMP-2 specific substrate, SAMTA7, could act as a controlled and sustained drug carrier for treatment of tumors with high expression of MMP-2 and for tumor metastasis.

Show MeSH
Related in: MedlinePlus