Nanoparticle Delivery of siRNA for Cancer Therapy

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  • March 22, 2019
Creator
  • Chen, Yunching
    • Affiliation: Eshelman School of Pharmacy
Abstract
  • We have developed lipid-polycation-DNA (LPD) nanoparticles containing DOTAP and targeted with polyethylene glycol (PEG) tethered with a targeting ligand such as anisamide (AA) to specifically deliver siRNA to cancer cells. Two novel non-glycerol based cationic lipids which contain both a guanidinium and a lysine or an arginine residue as the cationic headgroup are synthesized to replace DOTAP and form nanoparticles. DSGLA, which contains a lysine residue, down-regulated pERK more efficiently in H460 cells than DOTAP. DSAA, which contains an arginine residue, induced reactive oxygen species (ROS), triggered apoptosis and down-regulated anti-apoptotic protein Bcl-2 in B16F10 melanoma cells. A significant improvement in tumor growth inhibition was observed after dosing with targeted nanoparticles containing DSGLA or DSAA. We further designed a LPD nanoparticle modification with NGR (aspargine-glycine-arginine) peptide, targeting aminopeptidase N (CD13) expressed in the tumor cells or tumor vascular endothelium. The targeted nanoparticles efficiently delivered c-myc siRNA into the cytoplasm of HT-1080 xenograft tumor and effectively suppressed c-myc expression and triggered cellular apoptosis in the tumor, resulting in a partial tumor growth inhibition. When doxorubicin (Dox) and siRNA were co-formulated in the multi-functional nanoparticles, an enhanced therapeutic effect was observed. Furthermore, we explored the application of the multi-functional nanoparticles in multi-drug resistant cells which are new targets for cancer therapy. In this study, we have used a multi-functional anionic LPD (LPD-II) nanoparticle for efficient systemic co-delivery of siRNA against c-myc and Dox, into P-gp-positive NCI/ADR-RES tumors in a xenograft model. c-Myc siRNA delivered by the targeted nanoparticles significantly down-regulated both c-myc and P-gp expressions in the tumor, caused enhanced Dox uptake and sensitized tumor cells to the co-delivered Dox. Three daily intravenous injections of c-myc siRNA and Dox co-formulated in the targeted nanoparticles showed a significant improvement in tumor growth inhibition. We have further developed a LPH (liposome-polycation-hyaluronic acid) nanoparticle formulation modified with tumor specific scFv (single chain variable fragment) for systemic delivery of small interfering RNA (siRNA) and microRNA (miRNA) into lung metastasis of murine B16F10 melanoma. When miR-34a and therapeutic siRNAs were co-formulated in C4-targeted nanoparticles, an enhanced anti-cancer effect was observed.
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  • ... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Eshelman School of Pharmacy.
Advisor
  • Huang, Leaf
Degree granting institution
  • University of North Carolina at Chapel Hill
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