Biocompatible Metal (Core)-Layered Double Hydroxide (Shell) Nanoparticles for siRNA Delivery

Arizona State University, Scottsdale AZ

Investigators

Abstract

CBET-0829128 K. Rege, Arizona State University The overall objective of this collaborative research is the engineering and mechanistic understanding of biocompatible core (gold nanorod)-shell (layered-double hydroxide or LDH) based nanoparticles for selective delivery of siRNA with an eye towards enhancing hyperthermia treatments. Specific segments in the proposed nanoparticle are dedicated to (1) hyperthermic ablation and (2) carrying siRNA for inhibiting heat shock protein response to hyperthermia. The proposed research, therefore, employs bottom-up nanoscale engineering for direct impact in biomedical problems. LDH structures are a class of inorganic ceramic materials with the general formula M2+1(1-x)M3+(OH)2.(An-)x/n.mH2O, where M2+ is a divalent cation, M3+ is a trivalent cation, and An- is the interlayer anion of valence n. The unique LDH structure readily allows the intercalation of anionic molecules (e.g. siRNA) via ion exchange; varying the ratios of metal ions results in the tunable loading of siRNA in these nanoparticles. Nanoscale LDH shells may be generated using physiologically necessary metals (e.g. iron and zinc), thus obviating toxicity-related concerns. Furthermore, the disintegration of the LDH shell at late endosomal / lysozomal (acidic) pH results in an environmentally-responsive platform. The primary objectives are: (1) synthesis and characterization of gold nanorod-LDH nanoparticles with narrow size distribution profiles, (2) generation of siRNA-loaded core-shell nanoparticles, and (3) in-vitro evaluation of siRNA delivery and combination treatment using core-shell nanostructures. Simultaneous siRNA delivery and hyperthermic ablation on a single nanoparticle are unique attributes of the proposed platform, and can significantly enhance therapeutic efficacies for the ablation of cancer cells. Successful completion of the proposed research will result in a platform that can be extended to diverse biomedical applications. The proposed research, at the interface of nanotechnology and biomedical sciences, synergistically combines principles from nanoparticle synthesis, hyperthermia, surface chemistry, biomolecular adsorption, and cell biology, and is intended to have a direct impact on biomedical sciences in the near future. Graduate students will be trained in the application of nanotechnology in the biomedical sciences resulting in well rounded, interdisciplinary training in engineering and biomedical sciences. The educational thrust is also on the recruitment of underrepresented populations and women in graduate studies in engineering as exemplified by the graduate students currently in our respective research groups. In addition, the PI has recently initiated collaboration with Down-to-Earth Science (DES), an NSF-funded GK-12 project at Arizona State University (http://gk12.asu.edu). The PI and Co-PI, and the graduate students will partner with the director, staff, and graduate students of the DES program in bringing the biomedical benefits of nanotechnology into K-12 classrooms through lectures and web-based education tools. The proposed research will also have a significant impact on undergraduate education with a particular emphasis on the biomedical benefits of nanotechnology. Six undergraduate students, including four from the Barrett Honors College, in the PI's laboratory and two undergraduate students in the co-PI's laboratory at ASU exemplify our commitment to encouraging talented students to pursue research opportunities and graduate studies in engineering. All undergraduate students in the PI?s laboratory are recipients of the Fulton Undergraduate Research Initiative (FURI) award from the Ira A. Fulton School of Engineering at ASU which is a unique program that encourages undergraduate research in engineering.