Solid tumors appear in over 85% of human cancers. The tumor environment differs dramatically from normal tissues in the body. In tumors, the cell density and the extracellular matrix are abnormally dense and are opaque to drug transport. Diffusion and convection of drugs therefore are extremely slow and theoretically can take months instead of minutes. High levels of collagen and hyaluronan were found to be a major contributor to diffusive hindrance in tumors. Moreover, biological effects including binding of drugs to cells and degradation of the drug molecules can further reduce the amount of drug reaching and affecting the malignant cells in the entire tumor volume. In addition, the rapid proliferating cancer cells compress lymphatic vessels and reduce lymphatic drainage. As the core of a tumor is nearly avascular and lacks a functioning blood vessel network, the overall result is elevation of the fluid pressure. The interstitial fluid pressure (IFP) in tumor cores measured to elevate by ~10-20 mm mercury compared to normal tissue. Such a high-pressure gradiant is diminishing the inward transfer of fluid from the tumor’s peripheral arteries into the inner core.
Most of the drug-delivery strategies to reach tumors rely on systemic methods, aiming to solve penetration and distribution of molecules from the peripheral vasculature into the tumor core. After more than three decades of research, the general view is that transport in the tumor interstitial space of small molecules occurs mainly by diffusion, whereas transport of large molecules, such as siRNA and proteins, is extremely slow, ineffective and highly dependent on conditions that affect convection. Altogether, such abnormal physiological conditions in solid tumors present a strong barrier for effective nano-particle based and systemic drug delivery strategies to treat solid tumors. Moreover, part of the recent anti-tumor drugs are developed against the tumor conditions, and not directly against the tumor cells.
We have developed our LODER platform to solve such challenges, by combining a local and prolonged delivery of the drug within the tumor core, utilizing our novel siRNA drugs. Our next generation LODER aims to further improve the distribution of drugs in the tumor by incorporating our proprietary nano technology with the LODER platform. Results from our studies in animals have shown early evidence of improvement in drug transport to tumors, as well as control of pancreatic cell line proliferation.
Silenseed’s LODER platform enables harnessing of the advantages of siRNA technology to a therapeutic modality for pancreatic cancer. Utilizing siRNA against mutated KRAS can lead to apoptosis of cancer cells in vitro and in-vivo in mice and reduce tumor growth. In the cells, the siRNA is loaded into a protein complex called the RNA-induced silencing complex (RISC), which unwinds the siRNA, retaining the antisense strand, thus silencing the target gene and preventing protein production. Moreover, anti-mutated KRAS treatment can potentially slow epithelial-to-mesenchymal transition (EMT), thereby slowing the progression of PC disease from local to metastasis. Local and prolonged delivery of siRNA-based drugs can overcome the many existing challenges of systemic delivery, including enzymatic degradation and renal clearance of the siRNA, while enabling targeting of previously non-druggable targets, dramatic dose reduction, and reduction/elimination of toxicity effects including stimulation of the immune system.