Vladimir P Torchilin
Title: Next generation of smart stimuli-sensitive siRNA/drug nanopreparations for cancer
Biography
Biography: Vladimir P Torchilin
Abstract
Tumor therapy, especially in the case of multidrug resistant cancers, could be significantly enhanced by using siRNA downregulating
the production of proteins, which are involved in cancer cell resistance, such as Pgp or survivin. Even better
response could be achieved is such siRNA could be delivered to tumors together with chemotherapeutic agent. This task is
complicated by low stability of siRNA in biological surrounding. Thus, the delivery system should simultaneously protect
siRNA from degradation. We have developed several types of lipid-core polymeric micelles based on PEG-phospholipid or
PEI-phospholipid conjugates, which are biologically inert, demonstrate prolonged circulation in the blood and can firmly
bind non-modified or reversibly-modified siRNA. Additionally, these nanopreparations can be loaded into their lipidic core
with poorly water soluble chemotherapeutic agents, such as paclitaxel or camptothecin. In experiments with cancer cell
monolayers, cancer cell 3D spheroids, and in animals with implanted tumors, it was shown that such co-loaded preparations
can significantly down-regulate target proteins in cancer cells, enhance drug activity, and reverse multidrug resistance. In order
to specifically unload such nanopreparations inside tumors, we made them sensitive to local tumor-specific stimuli, such as
lowered pH, hypoxia, or overexpressed certain enzymes, such as matrix metalloproteases. Using pH-, hypoxia-, or MMP2-
sensitive bonds between different components of nanopreparations co-loaded with siRNA and drugs, we were able to make
the systems specifically delivering biologically active agents in tumors, which resulted in significantly improved therapeutic
response.