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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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HPLC comparison of paclitaxel, SAMTA7, and the SAMTA7-paclitaxel combination mixed in different ratios.Notes: Shown are HPLC spectra for (A) paclitaxel, (B) SAMTA7, and the SAMTA7-paclitaxel combination at a ratio of (C) 1:1, (D) 1:5, and (E) 1:6. Samples were injected into an HPLC C18 column and detected at an ultraviolet wavelength of 214 nm. The retention time of paclitaxel and SAMTA7 was 29.6 minutes (A) and 5.4 minutes (B), respectively. A peak at 13.5 minutes was identified as an increased molar ratio of SAMTA7 and paclitaxel (D). At a molar ratio of 1:6, the peak of paclitaxel disappeared, while the appearance of a peak at 13.5 minutes indicated that SAMTA7 might interact with paclitaxel and form a stable complex (E).Abbreviation: HPLC, high-performance liquid chromatography.
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f1-dddt-8-1839: HPLC comparison of paclitaxel, SAMTA7, and the SAMTA7-paclitaxel combination mixed in different ratios.Notes: Shown are HPLC spectra for (A) paclitaxel, (B) SAMTA7, and the SAMTA7-paclitaxel combination at a ratio of (C) 1:1, (D) 1:5, and (E) 1:6. Samples were injected into an HPLC C18 column and detected at an ultraviolet wavelength of 214 nm. The retention time of paclitaxel and SAMTA7 was 29.6 minutes (A) and 5.4 minutes (B), respectively. A peak at 13.5 minutes was identified as an increased molar ratio of SAMTA7 and paclitaxel (D). At a molar ratio of 1:6, the peak of paclitaxel disappeared, while the appearance of a peak at 13.5 minutes indicated that SAMTA7 might interact with paclitaxel and form a stable complex (E).Abbreviation: HPLC, high-performance liquid chromatography.

Mentions: The designed peptides were incubated with free paclitaxel, followed by an HPLC study in order to identify which peptide is capable of forming a supramolecule with paclitaxel. The chromatographic results suggest that the self-assembling properties of SAMTA7 were significant. Figure 1A and 1B show the HPLC spectra for SAMTA7 and free paclitaxel, respectively. SAMTA7 appeared not to interact with free paclitaxel at a molar ratio at 1:1, similarly in Figure 1C. The HPLC spectra for the complex of free paclitaxel and SAMTA7 at a molar ratio at 1:5 is shown in Figure 1D, where a peak retention time of 13.5 minutes is identified, as well as the peak indicating free paclitaxel is diminished (at 30 minutes) suggesting that a complex of SAMTA7 and paclitaxel was formed. In order to confirm the components of the peak, the fraction collected was treated with 100 mM ammonium acetate. The sample was then loaded onto the HPLC-MS system for analysis and the spectrum showed two distinct peaks; the MS result confirmed these to be for paclitaxel and SAMTA7. In addition, it was revealed that the components of collected peak at 13.5 minutes were consisted of SAMTA7 and paclitaxel upon the molar ratio at 6:1. The complex was prepared accordingly and then analyzed by HPLC. The spectra showed a distinct peak at 13.5 minutes and the peaks of SAMTA7 and paclitaxel disappeared (see Figure 1E).


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)

HPLC comparison of paclitaxel, SAMTA7, and the SAMTA7-paclitaxel combination mixed in different ratios.Notes: Shown are HPLC spectra for (A) paclitaxel, (B) SAMTA7, and the SAMTA7-paclitaxel combination at a ratio of (C) 1:1, (D) 1:5, and (E) 1:6. Samples were injected into an HPLC C18 column and detected at an ultraviolet wavelength of 214 nm. The retention time of paclitaxel and SAMTA7 was 29.6 minutes (A) and 5.4 minutes (B), respectively. A peak at 13.5 minutes was identified as an increased molar ratio of SAMTA7 and paclitaxel (D). At a molar ratio of 1:6, the peak of paclitaxel disappeared, while the appearance of a peak at 13.5 minutes indicated that SAMTA7 might interact with paclitaxel and form a stable complex (E).Abbreviation: HPLC, high-performance liquid chromatography.
© Copyright Policy
Related In: Results  -  Collection

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

f1-dddt-8-1839: HPLC comparison of paclitaxel, SAMTA7, and the SAMTA7-paclitaxel combination mixed in different ratios.Notes: Shown are HPLC spectra for (A) paclitaxel, (B) SAMTA7, and the SAMTA7-paclitaxel combination at a ratio of (C) 1:1, (D) 1:5, and (E) 1:6. Samples were injected into an HPLC C18 column and detected at an ultraviolet wavelength of 214 nm. The retention time of paclitaxel and SAMTA7 was 29.6 minutes (A) and 5.4 minutes (B), respectively. A peak at 13.5 minutes was identified as an increased molar ratio of SAMTA7 and paclitaxel (D). At a molar ratio of 1:6, the peak of paclitaxel disappeared, while the appearance of a peak at 13.5 minutes indicated that SAMTA7 might interact with paclitaxel and form a stable complex (E).Abbreviation: HPLC, high-performance liquid chromatography.
Mentions: The designed peptides were incubated with free paclitaxel, followed by an HPLC study in order to identify which peptide is capable of forming a supramolecule with paclitaxel. The chromatographic results suggest that the self-assembling properties of SAMTA7 were significant. Figure 1A and 1B show the HPLC spectra for SAMTA7 and free paclitaxel, respectively. SAMTA7 appeared not to interact with free paclitaxel at a molar ratio at 1:1, similarly in Figure 1C. The HPLC spectra for the complex of free paclitaxel and SAMTA7 at a molar ratio at 1:5 is shown in Figure 1D, where a peak retention time of 13.5 minutes is identified, as well as the peak indicating free paclitaxel is diminished (at 30 minutes) suggesting that a complex of SAMTA7 and paclitaxel was formed. In order to confirm the components of the peak, the fraction collected was treated with 100 mM ammonium acetate. The sample was then loaded onto the HPLC-MS system for analysis and the spectrum showed two distinct peaks; the MS result confirmed these to be for paclitaxel and SAMTA7. In addition, it was revealed that the components of collected peak at 13.5 minutes were consisted of SAMTA7 and paclitaxel upon the molar ratio at 6:1. The complex was prepared accordingly and then analyzed by HPLC. The spectra showed a distinct peak at 13.5 minutes and the peaks of SAMTA7 and paclitaxel disappeared (see Figure 1E).

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