4^th European Biopharma Congress

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.