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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

Computational simulation of SAMTA7 (A) and the SAMTA7-paclitaxel complex (B). The initial system containing SAMTA7 peptides was constructed using the Molecular Operating Environment system. Paclitaxel and six SAMTA7 molecules were immersed into an anhydrous simulated box for MD simulations simultaneously which were performed for 10 msec for the anhydrous system. The time step was 1 fsec, and the trajectories were saved every 20 psec for further analysis. A GROMOS96 53a6 force field was used. The reference temperature was set to 310 K. Simulation of a single molecule of SAMTA7 showed that this peptide was remained in a “hairpin-like” conformation upon interaction from RADA fragments. This conformation explored the MMP-2 substrate peptide, PVGLIG fragment, explaining how SAMTA7 is vulnerable to MMP-2 proteolysis. In (B), six SAMTA7 molecules and one paclitaxel molecule were immersed into the simulation box for structural analysis of the supramolecule, data indicating that SMATA7 was capable of wrapping the free paclitaxel in cavity in self-assembling manner. Importantly, formation of the supramolecule did not alter the phenomenon whereby PVGLIG fragments remained exposed against MMP-2 protein.Abbreviation: MMP, matrix metalloproteinase.
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f5-dddt-8-1839: Computational simulation of SAMTA7 (A) and the SAMTA7-paclitaxel complex (B). The initial system containing SAMTA7 peptides was constructed using the Molecular Operating Environment system. Paclitaxel and six SAMTA7 molecules were immersed into an anhydrous simulated box for MD simulations simultaneously which were performed for 10 msec for the anhydrous system. The time step was 1 fsec, and the trajectories were saved every 20 psec for further analysis. A GROMOS96 53a6 force field was used. The reference temperature was set to 310 K. Simulation of a single molecule of SAMTA7 showed that this peptide was remained in a “hairpin-like” conformation upon interaction from RADA fragments. This conformation explored the MMP-2 substrate peptide, PVGLIG fragment, explaining how SAMTA7 is vulnerable to MMP-2 proteolysis. In (B), six SAMTA7 molecules and one paclitaxel molecule were immersed into the simulation box for structural analysis of the supramolecule, data indicating that SMATA7 was capable of wrapping the free paclitaxel in cavity in self-assembling manner. Importantly, formation of the supramolecule did not alter the phenomenon whereby PVGLIG fragments remained exposed against MMP-2 protein.Abbreviation: MMP, matrix metalloproteinase.

Mentions: The SAMTA7 indicated the molecular dynamic simulation in order to clarify its self-assembling properties and its interaction with paclitaxel. Figure 5A shows that the single SAMTA7 was constrained in a “hairpin”-like conformation upon interaction with RADA fragments. This conformation explored that the MMP-2 substrate peptide, PVGLIG fragment, is vulnerable to MMP-2 proteolysis. Six SAMTA7 molecules and one paclitaxel molecule were put into a simulation box for structural analysis of the supramolecule. Figure 5B indicates that SAMTA7 has self-assembling properties and is able to wrap paclitaxel inside. Also, this formation of supramolecule has not altered the phenomenon that PVGLIG remained exposed against MMP-2 protein.


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)

Computational simulation of SAMTA7 (A) and the SAMTA7-paclitaxel complex (B). The initial system containing SAMTA7 peptides was constructed using the Molecular Operating Environment system. Paclitaxel and six SAMTA7 molecules were immersed into an anhydrous simulated box for MD simulations simultaneously which were performed for 10 msec for the anhydrous system. The time step was 1 fsec, and the trajectories were saved every 20 psec for further analysis. A GROMOS96 53a6 force field was used. The reference temperature was set to 310 K. Simulation of a single molecule of SAMTA7 showed that this peptide was remained in a “hairpin-like” conformation upon interaction from RADA fragments. This conformation explored the MMP-2 substrate peptide, PVGLIG fragment, explaining how SAMTA7 is vulnerable to MMP-2 proteolysis. In (B), six SAMTA7 molecules and one paclitaxel molecule were immersed into the simulation box for structural analysis of the supramolecule, data indicating that SMATA7 was capable of wrapping the free paclitaxel in cavity in self-assembling manner. Importantly, formation of the supramolecule did not alter the phenomenon whereby PVGLIG fragments remained exposed against MMP-2 protein.Abbreviation: MMP, matrix metalloproteinase.
© Copyright Policy
Related In: Results  -  Collection

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

f5-dddt-8-1839: Computational simulation of SAMTA7 (A) and the SAMTA7-paclitaxel complex (B). The initial system containing SAMTA7 peptides was constructed using the Molecular Operating Environment system. Paclitaxel and six SAMTA7 molecules were immersed into an anhydrous simulated box for MD simulations simultaneously which were performed for 10 msec for the anhydrous system. The time step was 1 fsec, and the trajectories were saved every 20 psec for further analysis. A GROMOS96 53a6 force field was used. The reference temperature was set to 310 K. Simulation of a single molecule of SAMTA7 showed that this peptide was remained in a “hairpin-like” conformation upon interaction from RADA fragments. This conformation explored the MMP-2 substrate peptide, PVGLIG fragment, explaining how SAMTA7 is vulnerable to MMP-2 proteolysis. In (B), six SAMTA7 molecules and one paclitaxel molecule were immersed into the simulation box for structural analysis of the supramolecule, data indicating that SMATA7 was capable of wrapping the free paclitaxel in cavity in self-assembling manner. Importantly, formation of the supramolecule did not alter the phenomenon whereby PVGLIG fragments remained exposed against MMP-2 protein.Abbreviation: MMP, matrix metalloproteinase.
Mentions: The SAMTA7 indicated the molecular dynamic simulation in order to clarify its self-assembling properties and its interaction with paclitaxel. Figure 5A shows that the single SAMTA7 was constrained in a “hairpin”-like conformation upon interaction with RADA fragments. This conformation explored that the MMP-2 substrate peptide, PVGLIG fragment, is vulnerable to MMP-2 proteolysis. Six SAMTA7 molecules and one paclitaxel molecule were put into a simulation box for structural analysis of the supramolecule. Figure 5B indicates that SAMTA7 has self-assembling properties and is able to wrap paclitaxel inside. Also, this formation of supramolecule has not altered the phenomenon that PVGLIG remained exposed against MMP-2 protein.

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