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

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.

Keywords:

• matrix metalloproteinase
• self-assembly
• drug targeting system
• paclitaxel

Supplementary material

Figure S1 The over-expressed MMP-2 on HT1080 cells induced the release of free paclitaxel from the SAMTA7-paclitaxel complex, which resulted in an extremely high concentration of palitaxel surrounding the cells. On MTT assay, paclitaxel crystals (indicated by arrows in figures) were found to be adhering to cells only in the HT1080 cell line. It was presumed that the complex released paclitaxel specifically in the presence of MMP-2, and that paclitaxel became oversaturated and then crystallized. This finding provided another explanation that the SAMTA7-paclitaxel complex can release paclitaxel in MMP-2 specific proteolysis.

Abbreviations: MMP, matrix metalloproteinase; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide.

Acknowledgments

This study was supported by funds from the National Science and Technology Major Project of the Ministry of Science and Technology of China (2014ZX09507005-003) and from the Natural Science Foundation of Tianjin, People’s Republic of China (12JCYBJC31500 and 13RCGFSY19700), and also funded by The National Natural Science foundation (81400932).

Disclosure

The authors report no conflicts of interest in this work.