Rational design of soft nanoparticles for non-invasive drug delivery

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Gene therapy, the targeted insertion of DNA coding for a therapeutic gene into the nuclei of diseased cells or tissues followed by its expression, is one of the most promising new therapies for a host of diseases and conditions. The first gene therapy product, Gendicine (adenoviral vector-based) was approved in China in 2003 for head and neck cancer. On July 24, 2012 the European Medicines Agency approved the adeno-associated viral (AAV) gene therapy, Glybera by uniQure, for lipoprotein lipase deficiency, an orphan disease. uniQure is also developing the use of a GDNF (glial cell derived neurotrophic factor) gene in their AAV-2 delivery vector for the treatment of Parkinson’s disease. Currently >1300 gene therapy clinical trials are in progress (www.clinicaltrials.gov). In spite of the tremendous progress, a number of challenges remain in realizing the full benefit of this treatment mode. In particular, to achieve the full benefit of gene therapy, it is necessary to develop gene delivery vectors with targeting ability, high transfection efficiency and improved safety. Currently, viruses are the most efficient vectors for DNA delivery, but their use has many disadvantages: high immunogenicity and toxicity, limitations in the size of DNA sequences that can be encapsulated, and potential for mutagenesis. Novel non-viral delivery systems do not present these disadvantages and offer tremendous promise for gene therapy. However, non-viral systems are not yet effective and specific enough for clinical applications. Improvements in both the structure and function of these systems are required. Moreover, in applications where the target site is an externally accessible organ/tissue, such as the eye, skin, nasal/vaginal/oral mucosa, a non-invasive approach to gene therapy, such as topical and oral administration, is highly desirable but not presently feasible due to the lack of effective delivery systems. The research program will focus on both the fundamental and applied aspects of delivery system design for nucleic acids, with specific focus on plasmid DNA and siRNA. In the process of developing new, more advanced non-viral technologies to deliver and target genes and siRNA in the body, the cellular and subcellular pathways of interaction must be fully understood. Induction of the correct and specific therapeutic responses is dependent upon the ‘intelligence’ of the delivery system to arrive to the intended target sites and be activated there. During the design of these systems, visualization of the interaction process and the quantification of the delivery efficiency are required. Nucleic acid-based therapeutic agents are especially difficult molecules to deliver successfully. This is one of the reasons why there is currently only one way administer these compounds: by injection. Development of non-invasive delivery systems that can transport drugs through the skin, cornea, nasal and vaginal mucosa after topical administration could provide an approach to target gene therapies locally and painlessly. In addition, the localized approach could overcome problems related to drug stability during oral and parenteral dosing and absorption, local toxicity and irritation from injection, and multiple dosing because of short drug half-lives. Nanotechnological approaches provide significant potential in the design and development of topical non-invasive delivery and targeting systems for nucleic acids. We propose developing non-invasive drug delivery systems based on composite nanoparticles using self-assembling and targetable biomaterials, including phospholipids, gemini surfactants, acylated amino acids and carbon nanotubes.