Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA 02115, USA
Tumor therapy, especially in the case of multidrug resistant cancers, could be significantly enhanced by using siRNA down-regulating 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.
 Torchilin VP. Multifunctional, stimuli-sensitive nanoparticulate systems for drug delivery. Nat Rev Drug Discov. 2014;13(11):813-27.
 Jhaveri A, Deshpande P, Torchilin V. Stimuli-sensitive nanopreparations for combination cancer therapy. J Control Release. 2014;190:352-70.
 Zhu L, Perche F, Wang T, Torchilin VP. Matrix metalloproteinase 2-sensitive multifunctional polymeric micelles for tumor-specific co-delivery of siRNA and hydrophobic drugs. Biomaterials. 2014;35(13):4213-22.
 Zhu L, Wang T, Perche F, Taigind A, Torchilin VP. Enhanced anticancer activity of nanopreparation containing an MMP2-sensitive PEG-drug conjugate and cell-penetrating moiety. Proc Natl Acad Sci U S A. 2013;110(42):17047-52.
 Perche F, Biswas S, Wang T, Zhu L, Torchilin VP. Hypoxia-targeted siRNA delivery. Angew Chem Int Ed Engl. 2014;53(13):3362-6.
 Salzano G, Navarro G, Trivedi MS, De Rosa G, Torchilin VP. Multifunctional polymeric micelles co-loaded with anti-survivin siRNA and paclitaxel overcome drug resistance in an animal model of ovarian cancer. Molecular Cancer Therapeutics. 2015;14:1075-1084.
 Essex S, Navarro G, Sabhachandani P, Chordia A, Trivedi M, Movassaghian S, Torchilin VP. Phospholipid-modified PEI-based nanocarriers for in vivo siRNA therapeutics against multidrug-resistant tumors. Gene Therapy. 2015;22:257-266.
 Salzano G, Costa DF, Sarisozen C, Luther E, Mattheolabakis G, Dhargalkar PP, Torchilin VP. Mixed Nanosized Polymeric Micelles as promoter of doxorubicin and miRNA-34a co-delivery triggered by dual stimuli in tumor tissue. Small. 2016;12 4837-4848.