Limits...
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.

Show MeSH

Related in: MedlinePlus

Evaluation of inhibition of tumor cell metastasis in HT-1080 (A) and HEp2 (B). The SAMTA7-paclitaxel complex had a remarkable antiproliferation effect on HT1080 cells.Notes: HT1080 and HEp2 cells were seeded in 24-well plates and cultured overnight to form a confluent monolayer. After being scratched with a sterile p200 pipette tip, the cell culture containing either paclitaxel or SAMTA7-paclitaxel (final concentration of paclitaxel 5 μg/mL, molar ratio 1:6) was added to scratched plates and incubated at 37°C in a 5% CO2 atmosphere for 24 hours. The distances between the two edges of the scratched cells were observed using microscopy. The metastasis inhibition rate was calculated by: inhibition rate = (distance of experimental group after inhibition – distance of control group after inhibition – distance prior to inhibition)/distance prior to healing ×100. Compared with the migration inhibiting effect of free paclitaxel in HT1080 cells, the supramolecule showed a 5.3-fold increase in antimigratory activity. However, the SAMTA7-paclitaxel complex showed poor antimigratory activity in HEp2 cells, which do not express MMP-2. It was assumed that the inhibitory effect of the supramolecule on the cellular migrating phenotype is due to the specific release of paclitaxel in the presence of MMP-2 enzyme.Abbreviations: PBS, phosphate-buffered saline; MMP, matrix metalloproteinase.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4206202&req=5

f3-dddt-8-1839: Evaluation of inhibition of tumor cell metastasis in HT-1080 (A) and HEp2 (B). The SAMTA7-paclitaxel complex had a remarkable antiproliferation effect on HT1080 cells.Notes: HT1080 and HEp2 cells were seeded in 24-well plates and cultured overnight to form a confluent monolayer. After being scratched with a sterile p200 pipette tip, the cell culture containing either paclitaxel or SAMTA7-paclitaxel (final concentration of paclitaxel 5 μg/mL, molar ratio 1:6) was added to scratched plates and incubated at 37°C in a 5% CO2 atmosphere for 24 hours. The distances between the two edges of the scratched cells were observed using microscopy. The metastasis inhibition rate was calculated by: inhibition rate = (distance of experimental group after inhibition – distance of control group after inhibition – distance prior to inhibition)/distance prior to healing ×100. Compared with the migration inhibiting effect of free paclitaxel in HT1080 cells, the supramolecule showed a 5.3-fold increase in antimigratory activity. However, the SAMTA7-paclitaxel complex showed poor antimigratory activity in HEp2 cells, which do not express MMP-2. It was assumed that the inhibitory effect of the supramolecule on the cellular migrating phenotype is due to the specific release of paclitaxel in the presence of MMP-2 enzyme.Abbreviations: PBS, phosphate-buffered saline; MMP, matrix metalloproteinase.

Mentions: Since MMP-2 plays a critical role in tumor progression, tumor angiogenesis, and metastasis, the ability of the SAM-TA7-paclitaxel supramolecule to inhibit tumor cell metastasis was evaluated using the cellular scratch assay. The results of this assay showed that the SAMTA7-paclitaxel supramolecule significantly inhibited migration of HT1080 cells but not HEp2 cells (Figure 3). Compared with the migration inhibiting effect of free paclitaxel in HT1080 cells, the supramolecule showed a 5.3-fold increase in antimigratory activity, along with the specific targeting properties as it was presumed that MMP-2 specific self assembling peptide could provide a specific drug release upon the presence of MMP-2 protein. It was assumed that the inhibitory effect of the supramolecule on the cellular migrating phenotype is due to the specific release of paclitaxel in the presence of the MMP-2 enzyme.


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)

Evaluation of inhibition of tumor cell metastasis in HT-1080 (A) and HEp2 (B). The SAMTA7-paclitaxel complex had a remarkable antiproliferation effect on HT1080 cells.Notes: HT1080 and HEp2 cells were seeded in 24-well plates and cultured overnight to form a confluent monolayer. After being scratched with a sterile p200 pipette tip, the cell culture containing either paclitaxel or SAMTA7-paclitaxel (final concentration of paclitaxel 5 μg/mL, molar ratio 1:6) was added to scratched plates and incubated at 37°C in a 5% CO2 atmosphere for 24 hours. The distances between the two edges of the scratched cells were observed using microscopy. The metastasis inhibition rate was calculated by: inhibition rate = (distance of experimental group after inhibition – distance of control group after inhibition – distance prior to inhibition)/distance prior to healing ×100. Compared with the migration inhibiting effect of free paclitaxel in HT1080 cells, the supramolecule showed a 5.3-fold increase in antimigratory activity. However, the SAMTA7-paclitaxel complex showed poor antimigratory activity in HEp2 cells, which do not express MMP-2. It was assumed that the inhibitory effect of the supramolecule on the cellular migrating phenotype is due to the specific release of paclitaxel in the presence of MMP-2 enzyme.Abbreviations: PBS, phosphate-buffered saline; MMP, matrix metalloproteinase.
© Copyright Policy
Related In: Results  -  Collection

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

f3-dddt-8-1839: Evaluation of inhibition of tumor cell metastasis in HT-1080 (A) and HEp2 (B). The SAMTA7-paclitaxel complex had a remarkable antiproliferation effect on HT1080 cells.Notes: HT1080 and HEp2 cells were seeded in 24-well plates and cultured overnight to form a confluent monolayer. After being scratched with a sterile p200 pipette tip, the cell culture containing either paclitaxel or SAMTA7-paclitaxel (final concentration of paclitaxel 5 μg/mL, molar ratio 1:6) was added to scratched plates and incubated at 37°C in a 5% CO2 atmosphere for 24 hours. The distances between the two edges of the scratched cells were observed using microscopy. The metastasis inhibition rate was calculated by: inhibition rate = (distance of experimental group after inhibition – distance of control group after inhibition – distance prior to inhibition)/distance prior to healing ×100. Compared with the migration inhibiting effect of free paclitaxel in HT1080 cells, the supramolecule showed a 5.3-fold increase in antimigratory activity. However, the SAMTA7-paclitaxel complex showed poor antimigratory activity in HEp2 cells, which do not express MMP-2. It was assumed that the inhibitory effect of the supramolecule on the cellular migrating phenotype is due to the specific release of paclitaxel in the presence of MMP-2 enzyme.Abbreviations: PBS, phosphate-buffered saline; MMP, matrix metalloproteinase.
Mentions: Since MMP-2 plays a critical role in tumor progression, tumor angiogenesis, and metastasis, the ability of the SAM-TA7-paclitaxel supramolecule to inhibit tumor cell metastasis was evaluated using the cellular scratch assay. The results of this assay showed that the SAMTA7-paclitaxel supramolecule significantly inhibited migration of HT1080 cells but not HEp2 cells (Figure 3). Compared with the migration inhibiting effect of free paclitaxel in HT1080 cells, the supramolecule showed a 5.3-fold increase in antimigratory activity, along with the specific targeting properties as it was presumed that MMP-2 specific self assembling peptide could provide a specific drug release upon the presence of MMP-2 protein. It was assumed that the inhibitory effect of the supramolecule on the cellular migrating phenotype is due to the specific release of paclitaxel in the presence of the MMP-2 enzyme.

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