#2 RNA nanoparticles and RNA/DNA chimeric nanoparticles comprising one or more functionalities for multiple disorders including cancer
NIH Title: Multifunctional RNA Nanoparticles as Therapeutic Agents
NIH Reference Number: E-765-2013
Executive Summary:
General Description:
RNA nanoparticles have been shown to trigger improved cellular targeting and cell uptake, long retention time, and low immune response because of its small size and the ability to carry multiple components. However, the unmet need for RNA nano scaffolds remains the accurate cell targeting, the ease of synthesis, the on-demand triggering of therapeutic functions, as well as the safe and efficient delivery of siRNAs.
The NIH researchers dedicated to creating the algorithms for design and modeling RNA nanoparticles, as well as in vitro experiment design, synthesis, and delivery of RNA nanoparticles. They experimentally self-assemble and functionalize several RNA-based nanoparticles. Moreover, the researchers explored the RNA/DNA hybrid nanoconstructs that contain split functionalities. The hybrid nanoconstruct reassembles into DNA duplex and a Diceable siRNA when injected into the cell, allowing for controlled activation of the functions.
Scientific Progress:
In the previous report the researchers developed a class of cationic lipids called "bolaamphiphiles" or "bolas" that can efficiently carry siRNA to cancer cells. In their study the micelles of the bolas GLH-19 and GLH-20 (derived from vernonia oil) efficiently deliver siRNAs, while having relatively low toxicities in vitro and in vivo. Both computer prediction and in vitro analysis showed that the hydrophobic head groups of GLH-19 protruded further from the micelle surface and is more flexible than those of the GLH-20. Consequently, they validated the tumor uptake of GLH-19 associated with siRNA in tumor-bearing nude mice.
In more recent study the researchers developed new bolas GLH-58 and GLH-60 (derived from jojoba oil) that contains similar hydrophobic domains. GLH-58 is more stable, and GLH-58/siRNA complexes demonstrated better efficiency in silencing the expression of the GFP gene in human breast cancer cells at concentrations of 5μg/mL, well below the toxic dose. In addition, they proved that HIV viral production could be inhibited by delivery of siRNAs targeting HIV genomes.
In another project the researchers evaluated the structure-activity relationship of modified oxime ether lipids (OELs) with siRNA molecules and the siRNA delivery efficiency of lipid-siRNA complexes to MDA-MB-231, a human breast cancer cell line. They discovered that introducing hydroxyl groups to the polar domain of the OELs and the unsaturation into the hydrophobic domain favor higher transfection and gene silencing in a cell culture system.
These preliminary studies showed that the modified nanoparticles could be used for siRNA delivery to target a variety of diseases.
Future Direction:
Strength:
Weakness:
Patent Status:
US Application No. 61/878,758
PCT Application No. PCT/US2014/056007
Filed Sept. 17th, 2014
Publications:
Gupta K et al. PMID: 26151705
Gupta et al. PMID: 26107486
Afonin KA et al. PMID: 25267559
Afonin KA et al. PMID: 25521794
Kim T et al. PMID: 23511334
Inventor Bio:
Dr. Shapiro received his Ph.D. in computer science from the University of Maryland in 1978, with undergraduate work in mathematics and physics. During his association with the NIH, Dr. Shapiro has done extensive work in image processing, nucleic acid structure prediction and analysis, and computational and experimental nanobiology, leading to several novel algorithms, computer systems, experimental techniques and discoveries in RNA biology. His latest interests include RNA nanobiology, understanding the relationships between RNA structure and function, and the use of parallel high performance computer architectures to solve problems related to RNA computational and experimental biology and molecular modeling.
NIH Reference Number: E-765-2013
Executive Summary:
- Invention Type: Therapeutic or diagnostic
- Patent Status: Patent pending
- Link: https://www.ott.nih.gov/technology/e-765-2013
- NIH Institute or Center: National Cancer Institute (NCI)
- Disease Focus: Cancer, viral infection, other infectious diseases
- Basis of Invention: Treating or diagnose a subject with DNA/RNA hybrid nanoparticles or RNA nanoparticles which carries both cell-targeting agents and anti-cancer/anti-pathogen components
- How it works: Modified lipids efficiently deliver small interfering RNAs to cancer cells directed by cell-targeting agents
- Lead Inventor: Bruce Shapiro (NCI), Kirill Afonin (NCI), Viard Mathias (NCI), Angelica Martins (NCI)
- Development Stage: Pre-clinical, in silico and in vitro assays, in vivo siRNA delivery in animal models
-
Novelty:
- Modified cationic lipids consist of a hydrophobic chain and one or more positively charged head groups at each end form micelles in vitro and in vivo
- Relatively low toxicities
- Modified cationic lipids consist of a hydrophobic chain and one or more positively charged head groups at each end form micelles in vitro and in vivo
-
Clinical Applications:
- Targeted drug delivery to treat cancer, HIV, and other diseases
General Description:
RNA nanoparticles have been shown to trigger improved cellular targeting and cell uptake, long retention time, and low immune response because of its small size and the ability to carry multiple components. However, the unmet need for RNA nano scaffolds remains the accurate cell targeting, the ease of synthesis, the on-demand triggering of therapeutic functions, as well as the safe and efficient delivery of siRNAs.
The NIH researchers dedicated to creating the algorithms for design and modeling RNA nanoparticles, as well as in vitro experiment design, synthesis, and delivery of RNA nanoparticles. They experimentally self-assemble and functionalize several RNA-based nanoparticles. Moreover, the researchers explored the RNA/DNA hybrid nanoconstructs that contain split functionalities. The hybrid nanoconstruct reassembles into DNA duplex and a Diceable siRNA when injected into the cell, allowing for controlled activation of the functions.
Scientific Progress:
In the previous report the researchers developed a class of cationic lipids called "bolaamphiphiles" or "bolas" that can efficiently carry siRNA to cancer cells. In their study the micelles of the bolas GLH-19 and GLH-20 (derived from vernonia oil) efficiently deliver siRNAs, while having relatively low toxicities in vitro and in vivo. Both computer prediction and in vitro analysis showed that the hydrophobic head groups of GLH-19 protruded further from the micelle surface and is more flexible than those of the GLH-20. Consequently, they validated the tumor uptake of GLH-19 associated with siRNA in tumor-bearing nude mice.
In more recent study the researchers developed new bolas GLH-58 and GLH-60 (derived from jojoba oil) that contains similar hydrophobic domains. GLH-58 is more stable, and GLH-58/siRNA complexes demonstrated better efficiency in silencing the expression of the GFP gene in human breast cancer cells at concentrations of 5μg/mL, well below the toxic dose. In addition, they proved that HIV viral production could be inhibited by delivery of siRNAs targeting HIV genomes.
In another project the researchers evaluated the structure-activity relationship of modified oxime ether lipids (OELs) with siRNA molecules and the siRNA delivery efficiency of lipid-siRNA complexes to MDA-MB-231, a human breast cancer cell line. They discovered that introducing hydroxyl groups to the polar domain of the OELs and the unsaturation into the hydrophobic domain favor higher transfection and gene silencing in a cell culture system.
These preliminary studies showed that the modified nanoparticles could be used for siRNA delivery to target a variety of diseases.
Future Direction:
- Investigate the anti-cancer activity of RNA nanoparticles in preclinical animal models
- Clinical research to study the toxicity and effectiveness of RNA nanoparticles in human subjects
- Basic research using engineered RNA nanoparticles
Strength:
- More detection sensitivity
- Higher silencing efficiency
- Low cytotoxicity
- Multiple functionality
- Multiple targets including cancer, virus, etc
- Visualization application
- Controlled activation
Weakness:
- Requires further validation of RNA complex on its anti-cancer activity in vivo
- Treatment efficiency is dependent on the specificity and effectiveness of siRNA cargo
Patent Status:
US Application No. 61/878,758
PCT Application No. PCT/US2014/056007
Filed Sept. 17th, 2014
Publications:
Gupta K et al. PMID: 26151705
Gupta et al. PMID: 26107486
Afonin KA et al. PMID: 25267559
Afonin KA et al. PMID: 25521794
Kim T et al. PMID: 23511334
Inventor Bio:
Dr. Shapiro received his Ph.D. in computer science from the University of Maryland in 1978, with undergraduate work in mathematics and physics. During his association with the NIH, Dr. Shapiro has done extensive work in image processing, nucleic acid structure prediction and analysis, and computational and experimental nanobiology, leading to several novel algorithms, computer systems, experimental techniques and discoveries in RNA biology. His latest interests include RNA nanobiology, understanding the relationships between RNA structure and function, and the use of parallel high performance computer architectures to solve problems related to RNA computational and experimental biology and molecular modeling.
