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Lung cancer is the leading cancer killer in the United States, accounting for over 160,000 deaths in 2006. Tobacco smoking or "second-hand" exposure to tobacco smoke is directly linked to lung cancer. Approximately 80% of all lung cancer cases are classified as non-small cell lung cancers (NSCLC) based on the histology of the tumor, and the five-year survival rate of NSCLC is typically below 15% One of the major factors that contribute to the high mortality rate associated with NSCLC is that the majority of NSCLC patients are at an advanced disease stage at the time of diagnosis, precluding surgical removal of the tumor as a viable treatment option. Moreover, the efficacy of current chemotherapeutic drugs is unsatisfactory in the treatment of NSCLC. There is clearly a strong need for the development of novel treatment option for this highly deadly disease. A recently discovered cellular defense mechanism known as RNA interference, or RNAi for short, presents great potential in the treatment of cancers. In RNAi, small pieces of double-stranded RNA (also known as siRNA) can be delivered into cells, where they can undergo sequence-specific binding to a target gene and lead to subsequent degradation (turn off) of the gene. This "gene-silencing" effect is highly specific and potent, and RNAi has become one of the most important tools in studying gene functions in the laboratory. In NSCLC, several proteins, including the epidermal growth factor receptor (EGFR), have been shown to exist at an abnormally high level due to the hyperactivity of the EGFR gene. It has also been shown in cell culture that RNAi can be used to reduce the activity level of the EGFR gene, which consequently leads to the retardation of tumor cell proliferation. The possibility of using RNAi as a novel treatment for lung cancer certainly exists; however, a major determinant for its use in the clinic is the efficient, systemic delivery for it inside the human body. The delivery method for gene-based therapeutics has been the bottleneck for the development of gene therapy. Although viruses can be used as an efficient vehicle for the delivery of genetic materials (DNA and RNA), there are safety concerns associated with their cancer-inducing properties and ability to illicit undesirable immune responses. The use of synthetic polymers as gene delivery reagent is therefore an attractive alternative. Although significant progress has been made, an ideal polymeric vector that is biodegradable, nontoxic, non-immunogenic, and allows high gene delivery efficiency is still elusive. Given the complicated mechanism involved in gene delivery, it is critical to have a system that is inherently safe while offering structural flexibility in the design of new vectors. Our research group has recently reported the design of a novel class of carbohydrate-peptide cationic polymers that show significantly-reduced toxicity and comparable DNA delivery efficiency compared to an existing popular gene delivery reagent, poly-L-lysine. By combining the use of natural building blocks and a modular design, we gain biocompatibility as well as synthetic flexibility that will allow facile permutation of our existing design to improve the properties of these polymers. Taking one step further, we propose here the evaluation of our first-generation hybrid polymers for use in siRNA delivery (which is different from DNA both in size and structure), as well as the design of second and third generation polymers with structural features that are devised to improve the siRNA-delivery efficiency by taking advantage of cellular properties, namely, change in pH and the reductive intracellular environment. By using a systematic approach in changing the properties and the detailed characterization of our polymers, we hope to obtain insights on the parameters that define an efficient and non-toxic siRNA delivery vehicle. The information obtained in this study will help guide future design in gene delivery vehicles, which can be used in the treatment of a variety of diseases that are currently difficult to treat such as NSCLC. |
