Ensysce Biosciences Inc. is a biotechnology company located in Houston, TX, exploiting the pionering nanotechnology studies of the late 1996 Nobel Laureate, Dr. Richard Smalley of Rice University. The rights to Dr. Smalley's work on carbon nanotube technology in the area of therapeutics, as well as other critical carbon nanotube patents, have been in-licensed or applied for by Ensysce and the company has initiated a number of research programs to utilize carbon nanotubes to treat cancer including that described herein to deliver short interfering RNAs (siRNA). Ensysce's interest in the single-walled carbon nanotubes (SWCNT) delivery system spans a number of therapeutic modalities including the delivery of RNAis. siRNA, are a type of small segments of double- stranded RNA that are being explored to control cancer growth in a highly specific fashion. However, efficient means are needed to deliver the RNAi into tumor cells. Ensysce's data show that the solubilized SWCNT/siRNA complexes delivered to mice intravenously cause little to no toxicity, accumulate in tumor and produce tumor target-protein knockdown and antitumor activity. Ensysce is now exploring means to optimize the tumor accumulation and produce robust antitumor activity. Ensysce data has also shown that circulating the half-life of SWCNT/siRNA complex affect its biodistribution, although complexes with even short t1/2 were found to produce god antitumor activity in human tumor xengrafts in animal models. This proposal will undertake a comprehensive examination of a number of formulations of SWCNT/siRNA to determine their tumor and tissue distribution following intravenous administration. The preparation with the most promising tumor versus tissue distribution will be further examined for antitumor eficacy using siRNA for KRAS. Mutant KRAS (mut-KRAS) is the prototypical undruggable cancer target. It is found in 25% of patient tumors across many cancer types and an estimated 320,000 individuals who will be diagnosed with mut-KRAS in the US in 2012 most of who will die of their disease. There is no treatment for KRAS and finding effective therapies for KRAS is arguably the single most important unmet medical need in cancer today. Therefore reducing its presence with siRNA delivered by SWCNT provides approach to this deadly problem. Hence, this project will extensively evaluate the biodistribution properties of a number of SWCNT complexes delivered systemically and will provide data on the efficacy of SWCNT/siRNA complexes in tumors. Ultimately, this work will pave the way for the use of a powerful new siRNA delivery system with the potential for inhibiting many different cancer causing targets in a clinical setting for the treatment of cancer.
Novel selective cancer therapies are still needed to improve outcome for patients without unnecessary toxic side effects. Short interfering RNA (siRNA) is one such potential modality as it can block the activity of genes that are essential for the cancer growth but not for normal tissue. However, the major barrier to the development of clinical siRNA therapies is the lack of an effective delivery mechanism to administer it to a patient and carry it into the tumor cell. Ensysce's research has shown that single-walled carbon nanotubes (SWCNT) can complex with siRNA and act as a delivery vehicle to carry siRNA into cancer cells hence providing a selective therapeutic outcome. To ensure delivery of the siRNA to tumors it has been found that the circulation time (half-life) of the complexes is important. This proposal will undertake a comprehensive examination of a number of SWCNT preparations with a range of circulation half-lives to determine the tumor and tissue distribution following intravenous administration. The preparation with the most promising tumor versus tissue distribution will be further examined for antitumor activity in combination with another cancer therapy. These critical studies will move this novel technology one step closer to full pre-clinical development and eventually to a clinical trial study.