N. Wijewantha, M.M. Eikanger, R.M. Antony, R.A. Potts, K. Rezvani, G. Sereda
University of South Dakota,
Keywords: colorectal cancer, drug delivery, mesoporous silica nanoparticles, metastasis, veratridine
Summary:Colorectal cancer (CRC) is one of the most widely diagnosed cancer worldwide. Despite the notable improvement in therapeutic strategies, one-third of patients with advanced CRC will ultimately die from the disease. A 5-year survival rate of 91% for localized tumors in the intestine can be attributed to the success of surgical resection, but this rate drops to 12% for patients diagnosed with a metastatic form of the disease because of a lack of effective therapies. The development of therapeutic strategies that use nanoparticles as a drug delivery system has become one of the most promising potential approaches for cancer therapy. A nanoparticle encapsulated with anti-cancer drugs can be designed to possess a particular affinity toward cancer cells based on the unique characteristics of those cells. The so-called smart nanoparticles can release an effective dosage of small molecules next to tumor tissues while the surrounding normal organ tissues are exposed to a lower concentration of drugs and remain functional. Previous studies have shown that a natural plant alkaloid, veratridine (VTD), suppresses colon cancer cell migration and invasion, two essential factors in tumor metastasis, through activation of the gene that encodes the tumor-suppressor protein UBXN2A. However, it has been reported that the accumulation of veratridine in an animal model can induce neurotoxicity since VTD also binds to and activates sodium receptors. We hypothesized that encapsulation of VTD in nanoparticles with a high affinity to cancer cells is an effective method for elevating the anti-cancer effectiveness of VTD while significantly lowering the permeabilization of VTD through the blood-brain barrier (BBB). The goal of this study is to design gated VTD drug delivery methods by mesoporous silica-based nanoassemblies (MSNs). An enzymatically cleavable protein seals MSNs to deliver a VTD molecule to the colon cancer cells. An enzyme overproduced by the cancer cells cleaves a gate-keeping component of the nanoassembly and releases the drug precisely. The drug is sealed inside the core of mesoporous silica with gatekeeping MMP-7 substrate casein conjugated with the core. We have proven the selective affinity of two types of VTD-carrying particles to CRC cells and enzyme- or acid-triggered VTD release. Besides that, the MSNs demonstrated a much higher affinity to CRC cells than to healthy colon fibroblasts. Coupled with the significant internalization of the particles by CRC versus healthy cells, making VTD-MSNs a promising anti-cancer drugs with minimal side effects.