Matrix metalloprotease selective peptide substrates cleavage within hydrogel matrices for cancer chemotherapy activation

Abstract To utilize biologic mechanisms to elicit controlled release in response to disease, protease-sensitive devices have been created. Hydrogels were created with pendant peptide–drug complexes. For the matrix metalloproteases (MMPs) examined, a length of six amino acids greatly improved the specificity of the peptide ( k cat / K m  ∼ 2.4 ± 0.1 × 10 4  M −1  s −1 ) over shorter sequences ( k cat / K m  ∼ 4.4 ± 0.2 × 10 2  M −1  s −1 ). The peptides did not exhibit anti-proliferative effects upon cancer cells, and peptide–platinum complexes showed similar anti-proliferative effects upon the cancer cells compared to the free platinum drugs. Once the peptide–drug complex was incorporated into the hydrogels, the release was dependent upon the presence of MMP in the solution with approximately 35% of platinum released from hydrogels in the presence of MMP and only 10% without MMP in the week examined. The released drug exhibited the expected anti-proliferative activity over several days of incubation. The MMP selective drug delivery holds much potential for treatment of cancer and other diseases.