University of Science and Technology of China  South China University of Technology 中文|English

Nanomedicine for siRNA Delivery

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Small interfering RNA (siRNA), also referred to as short interfering RNA or silencing RNA, is a class of double-stranded RNA molecules with 20-25 base pairs in length. siRNA plays multiple biological roles through interfering with the expression of specific genes via having the mRNA of targeted gene degraded after transcription, consequently retarding its translation in interested cells. siRNA drugs for systemic application in vivo face a series of hurdles before reaching into the cytoplasm of target cells. Post-injection, the siRNA drug must navigate host circulatory system while avoiding kidney filtration, uptake by phagocytes, aggregation with serum proteins, and enzymatic degradation by endogenous nucleases followed by internalization into cells.

To develop efficient nanoparticle-based siRNA drug in vivo delivery systems

We took the lead in the research on siRNA drug delivery in China, and developed micelleplex system based on biocompatible and biodegradable polymers, lipid-polymer hybrid nanoparticle drug delivery system, and single segment fusion protein (ScFv-protamine peptide fusion protein, or F5-P) for siRNA drug delivery in vivo. In addition, to develop a hybrid nanoparticle system that integrates the desirable characteristics of both biodegradable polymer nanoparticles and cationic liposomes for systemic delivery of siRNA, we prepared cationic lipidpolymer hybrid nanoparticles by a single-step nanoprecipitation of a cationic lipid with either amphiphilic poly (ethylene glycol)-block-polylactide (mPEG-PLA) or a mixture of mPEG-PLA and poly-lactide (PLA) (ACS Nano, 2012, 6, 4955-4965).

Potent antitumor effects of diverse nanoparticle-based siRNA drug delivery platforms in vivo

1. We designed and synthesized a novel amphiphilic and cationic triblock copolymer consisting of poly(ethylene glycol), poly(3-caprolactone) (PCL) and poly (2-aminoethyl ethylene phosphate) for siRNA delivery (Biomaterials,2008, 29, 4348-4355). We successfully in vivo targeted the acid ceramidase with the micelleplex delivering siRNA for breast cancer therapy (Biomaterials,2011, 32 3124-3133). Notably, we further examined the antitumor effects of the micelleplex to simultaneously deliver Polo-like kinase 1 (PLK1) specific siRNA (siPlk1) and paclitaxel in vivo. Our convincing data illustrated that this “two-in-one” micelleplex system including specific siRNA and a chemotherapeutic drug inhibited tumor growth in a synergistic fashion (ACS Nano, 2011, 5, 1483-1494).

2.Using cationic lipid assisted poly (ethylene glycol)-b-poly (d,l-lactide) (PEG-PLA) nanoparticles as the siPlk1 carrier, we confirmed the therapeutic effects of the nano-drug on targeting breast cancer (Journal of Controlled Release, 2011, 156, 203–211).

3. Single segment fusion protein (ScFv-protamine peptide fusion protein, or F5-P) for efficient siRNA drug delivery in vivo:

A.We succeeded in establishment of the ScFv-protamine peptide fusion protein (F5-P) E. coli expression system, then tested and confirmed that PLK1-siRNA complexed with a Her2-ScFv-protamine peptide fusion protein (F5-P/PLK1-siRNA) can suppress Her2+ breast cancer cell lines and primary human cancer cells in orthotopic breast cancer models. Intravenously-administered F5-P/PLK1-siRNA complexes were enriched in orthotopic Her2+ breast cancer xenografts and persisted for at least 72 hours, leading to suppressed PLK1 gene expression, tumor cell apoptosis, retarded Her2+ breast tumor growth, reduced metastasis, and prolonged survival without evident toxicity (Science Translational Medicine, 2012, 4, 130-148; this work was highly commented by Nature Reviews Cancer) .

B. F5-P-mediated delivery of a cocktail of PLK1, CCND1, and AKT siRNAs was more effective than an equivalent dose of PLK1-siRNA alone. These data suggest that F5-P may be used to deliver siRNAs to treat Her2+ breast cancers (Science Translational Medicine, 2012, 4, 130-148).

C. We further applied this F5-P delivery system to targeting the DNMTs gene and found that the fusion protein was able to deliver siDnmts to Her2+ cancer cells, effectively silence DNMTs gene expression, activate the tumor suppressor gene RASSF1A with methylated promoter region, and therefore inhibit cancer cell proliferation (Journal of Controlled Release, 2012, 161, 875–883).