Gene Delivery by Immobilization to Cell-Adhesive Substrates
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Gene Delivery by
Immobilization to Cell-Adhesive Substrates
Zain Bengali and Lonnie D. Shea Abstract Biomaterials can potentially enhance the delivery of viral and nonviral vectors for both basic science and clinical applications. Vectors typically consist of nucleic acids (DNA, RNA) packaged with proteins, lipids, or cationic polymers, which facilitate cellular internalization and trafficking. These vectors can associate with biomaterials that support cell adhesion, a process we term substrate-mediated delivery. Substrate immobilization localizes the DNA and the delivery vector to the cellular microenvironment. The interaction between the vector and substrate must be appropriately balanced to mediate immobilization, yet allow for cellular internalization. Balancing the binding between the biomaterial and the vector is dependent upon the surface chemistries of the material and the vector, which can be designed to provide both specific (e.g., biotin–avidin, the strongest known noncovalent interaction between a protein and its ligand) and nonspecific (e.g., van der Waals) interactions. In this review, we describe the biomaterial and vector properties that mediate binding and gene transfer, identify potential applications, and present opportunities for further development. Keywords: biomaterials, gene therapy, plasmid delivery, reverse transfection, solidphase delivery, tissue engineering, transfected cell arrays.
Introduction Gene delivery has tremendous potential for use therapeutically, such as in gene therapy and tissue engineering, and in research applications, such as functional genomics. A critical factor limiting the development of these applications is the inefficiency of gene transfer. Successful gene transfer requires delivery of the nucleic acid (e.g., DNA, RNA) to the target tissue or cell population without being degraded, followed by internalization by the cell, escape from the endosome into the cytoplasm, transport into the nucleus for transcription, and ultimately protein production (Figure 1). Gene delivery vectors have been developed to enhance the efficiency of gene transfer to the target cells. Vectors consist of nucleic acids packaged by proteins, lipids, or polymers, which produce small particles that protect against degradation, and are less negatively
MRS BULLETIN • VOLUME 30 • SEPTEMBER 2005
charged relative to the nucleic acid. The small size of the particles promotes internalization, and the properties of the protein, lipid, or polymer can facilitate intracellular trafficking. Viral and nonviral vectors target many of the intracellular barriers in gene transfer, whereas biomaterialbased delivery addresses extracellular barriers to enhance gene transfer.1 Biomaterials can enhance gene transfer by maintaining consistent levels of the vector in the microenvironment of the cell and reducing the amount of DNA required, which can decrease cell toxicity.2 Traditionally, delivery of vectors by injection or inhalation, known as systemic or bolus delivery, leads to the presence of vector in the
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