title: In vivo evaluation of matrix metalloproteinase responsive silk-elastinlike protein polymers for cancer gene therapy.
abstract: 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.
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, USA; Utah Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Price
authors.affiliation: Utah Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT, USA; Department of Bioengineering, University of Utah, Salt Lake City, UT, USA.
authors.forename: Azadeh
authors.initials: A
authors.lastname: Poursaid
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Cappello
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, USA; Utah Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT, USA; Department of Bioengineering, University of Utah, Salt Lake City, UT, USA. Electronic address: hamid.ghandehari@pharm.utah.edu.
authors.forename: Hamidreza
authors.initials: H
authors.lastname: Ghandehari
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D003692:Delayed-Action Preparations / Q000737:chemistry / Q000378:metabolism*; D004549:Elastin / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D006801:Humans; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008819:Mice, Nude; D047011:Silk / Q000737:chemistry / Q000378:metabolism*; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: D003692:Delayed-Action Preparations; D047011:Silk; D004549:Elastin; D020782:Matrix Metalloproteinases
keywords: Cancer; Drug delivery; Matrix metalloproteinase; Recombinant polymers; Silk–elastinlike polymers