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) approximately 2.4+/-0.1x10(4)M(-1)s(-1)) over shorter sequences (k(cat)/K(m) approximately 4.4+/-0.2x10(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.
Tauro
Jovita R
JR
The University of Illinois, Department of Biopharmaceutical Sciences, Chicago, IL 60612, USA.
Lee
Bao-Shiang
BS
Lateef
Syed S
SS
Gemeinhart
Richard A
RA
D000970:Antineoplastic Agents / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D005910:Glioma; D006801:Humans; D020100:Hydrogels; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D010984:Platinum / Q000378:metabolism; D013379:Substrate Specificity
D000970:Antineoplastic Agents; D020100:Hydrogels; D010455:Peptides; D010984:Platinum; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9