Novel Hybrid Nanoparticles for Therapeutics Delivery
Background & Summary
Medicines of the 21st century are becoming increasingly targeted to the specific molecular pathway in the particular cells of the tissue or organ that is diseased. Broad acting drugs are giving way to precision medicines that show disease specificity, strong efficacy and reduced side effects or toxicities. While siRNA and other nucleotides have proven to be therapeutically effective, there is currently no non-viral delivery system on the market yet for administering these to successfully achieve gene knockdown. The research team at Thomas Jefferson University, led by Dr. Sunday Shoyele, has developed a novel, proprietary hybrid nanoparticle delivery system to efficiently and safely deliver nucleic acids to targeted cells. Non-small cell lung cancer represents an early target indication among others, as the KRAS mutation has been implicated in the resistance of lung cancers to certain targeted therapies, such as EGFR tyrosine kinase inhibitors.
Applications and Advantages
• Specifically targets diseased cells/tissues enabling stronger drug efficacy with reduced side effects and toxicities
• Protects payload nucleic acids from degradation by the nuclease enzymes in blood
• Can incorporate additional targeting moieties for delivery preferential to diseased cells or tissues
Detailed Description
RNA interference (RNAi) therapeutics such as siRNAs and microRNAs have a high potential to silence critical molecular pathways that are pathogenic. However, the clinical application of RNAi in cancer therapy has been limited by a lack of efficient nanotechnology-based delivery systems to ensure an efficient and safe delivery of this unique technology to specific cells/tissues while avoiding healthy cells in the process. While viral vectors have been known to transduce cells efficiently, their use is limited by the possibility of viral toxicity and immunogenic and inflammatory reactions. Non-viral vectors such as lipid-based nanoparticles, polymer-based nanoparticles, mesoporous silica, and protein based nanoparticles are currently being investigated as possible vectors for RNAi. None of these nanotechnologies have proven to be effective without eliciting systemic immunogenic/inflammatory reactions. Furthermore, nucleic acids encapsulated in these vectors are often destroyed by endonucleases.
Jefferson researchers reported the use of a novel hybrid nanoparticle delivery system for the safe and efficient delivery of RNAi. This nanoparticle technology takes advantage of the benefits derived from the human IgG antibody and poloxamer-188 for stable and efficient RNAi delivery. The hybrid capsule protects payload nucleic acids from the nuclease enzymes in blood. Human IgG reduces/eliminates well documented inflammation/immunogenic reactions that are seen with most other nanoparticle formulations. Because IgG antibodies are so ubiquitous in circulation, the immune system is tricked into seeing the nanoparticles as natural components of the blood. Poloxamer-188 is a nonionic triblock copolymer used as a stealth polymer to prevent macrophage uptake of nanoparticles during circulation. These nanoparticles are then functionalized with a targeting ligand for selective delivery to diseased tissues. A further proprietary innovation enables these nanoparticles to release their nucleic acid payload only upon arrival in the cytoplasm by taking advantage of the higher acidity of the intracellular shuttle vesicles that transport particles from the cell membrane to the intracellular environment.
Selected Publications:
• Perepelyuk M et al. (2016) Biodistribution and Pharmacokinetic study of siRNA-Ioaded anti-
NTSR1-mAb-functionalized novel hybrid nanoparticles in metastatic orthotopic murine lung cancer model. Molecular Therapy-Nucleic Acid. 5, e282.
• Dim N et al. (2015) Novel Targeted siRNA-Loaded Hybrid Nanoparticles: Preparation, Characterization and in vitro Evaluation. J. Nanobiotechnol. 13:61.
•Lakshmikuttyamma, A et al. (2014). Stable and Efficient Transfection of siRNA for Mutated
KRAS Silencing using Novel Hybrid Nanoparticles. Mol. Pharmaceutics 11 (12), 4415-4424.
Relevant Patent Filings:
WO2018071864 Delivery Compositions and Methods of Making Using the Same
US2016213777 Novel Delivery Compositions and Methods Using the Same