In vivo evaluation of matrix metalloproteinase responsive silk-elastinlike protein polymers for cancer gene therapy.
Silk-elastinlike protein polymers (SELPs) have been effectively used as controlled release matrices for the delivery of viruses for cancer gene therapy in preclinical models. However, the degradability of these polymers needs to be tuned for improved localized intratumoral gene delivery. Using recombinant techniques, systematic modifications in distinct regions of the polymer backbone, namely, within the elastin blocks, silk blocks, and adjacent to silk and elastin blocks, have been made to impart sensitivity to specific matrix metalloproteinases (MMPs) known to be overexpressed in the tumor environment. In this report we investigated the structure-function relationship of MMP-responsive SELPs for viral mediated gene therapy of head and neck cancer. These polymers showed significant degradation in vitro in the presence of MMPs. Their degradation rate was a function of the location of the MMP-responsive sequence in the polymer backbone when in hydrogel form. Treatment efficacy of the adenoviral vectors released from the MMP responsive SELP analogs in a xenograft mouse model of head and neck squamous cell carcinoma (HNSCC) was shown to be polymer structure dependent. These results demonstrate the tunable nature of MMP-responsive SELPs for localized matrix-mediated gene delivery.
['Price|Robert|R|', 'Poursaid|Azadeh|A|', 'Cappello|Joseph|J|', 'Ghandehari|Hamidreza|H|']
D000256:Adenoviridae D000818:Animals D002294:Carcinoma, Squamous Cell D045744:Cell Line, Tumor D003692:Delayed-Action Preparations D004549:Elastin D005260:Female D018014:Gene Transfer Techniques D015316:Genetic Therapy D005822:Genetic Vectors D006258:Head and Neck Neoplasms D006801:Humans D020782:Matrix Metalloproteinases D008819:Mice, Nude D047011:Silk D000077195:Squamous Cell Carcinoma of Head and Neck
Matrix metalloproteinase Cancer Drug delivery Recombinant polymers Silk–elastinlike polymers