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

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 similar to 2.4 +/- 0.1 x 10(4) M (1) s (1)) over shorter sequences (k(cat)/K-m similar to 4.4 +/- 0.2 x 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. (C) 2008 Elsevier Inc. All rights reserved.