Functional Amphiphiles for Gene Delivery
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Functional
Amphiphiles for Gene Delivery
Philippe Barthélémy and Michel Camplo Abstract The design of safe and efficient gene transfer vectors remains one of the key challenges in gene therapy. Despite their remarkable transfection efficiency, viral vectors suffer from known safety issues. Consequently, significant research activity has been undertaken to develop nonviral approaches to gene transfer during the last decade. Numerous academic and industrial research groups are investigating synthetic cationic vectors, such as cationic amphiphiles, with the objective of increasing the gene transfection activity. Within this area, the development of functional synthetic vectors that respond to local environmental effects have met with success. These synthetic vectors are based on mechanistic principles and represent a significant departure from earlier systems. Many of these systems for gene delivery in vitro and in vivo are discussed in this article. Keywords: cationic lipids, charge reversal amphiphiles, nucleolipids, supramolecular assemblies.
Introduction Despite the promise of gene therapy, the technology remains limited due to the lack of acceptable and efficient vector systems. Among the different options currently available, viral transfection is the method that most often comes to mind when people think of gene therapy. This type of vector is efficient, but its use in the clinic has not been all positive. A recent example is the tragic case of Jesse Gelsinger, a young patient who died from inflammation and other complications associated with gene therapy using an adenoviral vector.1 As a consequence of the problems associated with the use of viral vectors, there has been renewed interest in developing nonviral transfection vectors. In general, synthetic nonviral vectors are much safer and could become a powerful alternative to viral vectors for transporting genetic material to cells. However, most of the current nonviral systems are not efficient enough to be clinically viable. Consequently, to improve both transport and delivery of nucleic acids, a large number of research groups have explored different strategies mainly based on the modulation of the physicochemical prop-
MRS BULLETIN • VOLUME 30 • SEPTEMBER 2005
erties of the carriers. Within this framework, numerous structural parameters have been altered to identify the optimal conditions for transfection. The morphology, stability, size, and surface properties of complexes of nonviral DNA–cationic lipids (lipoplexes) or DNA–cationic polymers (polyplexes) have been investigated intensively. Besides the modulation of structural parameters, an alternative approach based on the design of functional synthetic vectors has been investigated to facilitate gene transfection. Recently, this approach has provided several efficient transfecting systems, including amphiphilic structures that possess either molecular recognition functionalities or chemical features responding to local environmental effects. In the first section of this article, we will focus on t
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