A5009024719- RNA Interference and Gene Delivery
- Lipid Membrane Structure and Behavior
- Advanced biosensing and bioanalysis techniques
- Nanoparticle-Based Drug Delivery
- Virus-based gene therapy research
- CRISPR and Genetic Engineering
- MicroRNA in disease regulation
- RNA Research and Splicing
- Immunotherapy and Immune Responses
- Advanced Drug Delivery Systems
- Pediatric health and respiratory diseases
- SARS-CoV-2 and COVID-19 Research
- Nanoplatforms for cancer theranostics
- Chronic Obstructive Pulmonary Disease (COPD) Research
- Extracellular vesicles in disease
- Chromatography in Natural Products
- Supramolecular Self-Assembly in Materials
- Lignin and Wood Chemistry
- Food Chemistry and Fat Analysis
- Genetic Neurodegenerative Diseases
- Platelet Disorders and Treatments
- Molecular Communication and Nanonetworks
- Protein purification and stability
- Nanopore and Nanochannel Transport Studies
- Advancements in Transdermal Drug Delivery
University of British Columbia
2016-2024
iCo Therapeutics (Canada)
2023-2024
BC Innovation Council
2022
NanoMedicines Innovation Network
2020-2021
British Columbia Children's Hospital
2019-2021
Evonik (Canada)
2020
Vancouver Biotech (Canada)
2017-2019
Lipid nanoparticles (LNPs) containing short interfering RNA (LNP-siRNA) and optimized ionizable cationic lipids are now clinically validated systems for silencing disease-causing genes in hepatocytes following intravenous administration. However, the mechanism of formation certain structural features LNP-siRNA remain obscure. These formed from lipid mixtures (cationic lipid, distearoylphosphatidylcholine, cholesterol, PEG-lipid) dissolved ethanol that is rapidly mixed with siRNA aqueous...
In empty LNP formulations, DSPC–cholesterol resides in outer layers, whereas loaded systems some of the is internalized together with siRNA.
Abstract Lipid nanoparticles (LNPs) are currently the most clinically advanced nonviral carriers for delivery of small interfering RNA (siRNA). Free siRNA molecules suffer from unfavorable physicochemical characteristics and rapid clearance mechanisms, hampering ability to reach cytoplasm target cells when administered intravenously. As a result, therapeutic use is crucially dependent on strategies. LNPs can encapsulate protect it degradative endonucleases in circulation, prevent kidney...
The transfection potency of lipid nanoparticle (LNP) mRNA systems is critically dependent on the ionizable cationic component. LNP composed optimized lipids often display distinctive mRNA-rich "bleb" structures. Here, it shown that such structures can also be induced for LNPs containing nominally less active by formulating them in presence high concentrations pH 4 buffers as sodium citrate, leading to improved potencies both vitro and vivo. Induction bleb structure type buffer employed, with...
Neutralization of the pH (and ionizable lipid) drives fusion precursor vesicles into electron-dense core structures attributed to lipid nanoparticles.
Lipid nanoparticles (LNPs) containing short-interfering RNA (LNP-siRNA systems) are a promising approach for silencing disease-causing genes in hepatocytes following intravenous administration. LNP-siRNA systems generated by rapid mixing of lipids ethanol with siRNA aqueous buffer (pH 4.0) where the ionizable lipid is positively charged, followed dialysis to remove and raise pH 7.4. Ionizable cationic critical excipient LNP as they drive entrapment intracellular delivery. A recent study on...
Lignin, the second most abundant biopolymer, is a promising renewable energy source and chemical feedstock. A key element of lignin biosynthesis unknown: how do precursors (monolignols) get from inside cell out to wall where they are polymerized? Modeling indicates that monolignols can passively diffuse through lipid bilayers, but this has not been tested experimentally. We demonstrate significant monolignol diffusion occurs when laccases, which consume monolignols, present on one side...
Lipid nanoparticles (LNPs) composed of ionizable cationic lipids are currently the leading systems for siRNA delivery in liver disease, with major limitation low release efficacy into cytoplasm. Ionizable known to be critical importance LNP structure and stability, entrapment, endosomal disruption. However, their distribution inside LNPs exact role cytoplasmic remain unclear. A recent study [Kulkarni et al., On formation morphology lipid containing siRNA, ACS Nano, 2018, 12(5), 4787-4795] on...
Curcumin exhibits potent anticancer activity via various mechanisms, but its in vivo efficacy has been hampered by poor solubility. Nanotechnology employed to deliver curcumin, most of the reported systems suffered from low drug loading capacity and stability. Here, we report development optimization a liposomal formulation for curcumin (Lipo-Cur) using an automated microfluidic technology. Lipo-Cur exhibited mean diameter 120 nm with polydispersity index (<0.2) superior (17 wt %) compared...
Abstract Successfully employing small interfering RNA (siRNA) therapeutics requires the use of nanotechnology for efficient intracellular delivery. Lipid nanoparticles (LNPs) have enabled approval various nucleic acid therapeutics. A major advantage LNPs is interchangeability its building blocks and payload, which allow it to be a highly modular system. In addition, drug derivatization approaches can used synthesize lipophilic molecule prodrugs that stably incorporate in LNPs. This provides...
DNA damage repair genes are modifiers of disease onset in Huntington's (HD), but how this process intersects with associated pathways remains unclear. Here we evaluated the mechanistic contributions protein inhibitor activated STAT-1 (PIAS1) HD mice and patient-derived induced pluripotent stem cells (iPSCs) find a link between PIAS1 pathways. We show that is component transcription-coupled complex, includes end processing enzyme polynucleotide kinase-phosphatase (PNKP), SUMO E3 ligase for...
We describe a facile and highly efficient rapid-mixing technique to entrap hydrophobic inorganic nanoparticles within lipid nanoparticles.
We show that siRNA encapsulation within a lipid nanoparticle (LNP) can occur in the absence of organic solvent and use these studies to propose mechanism by which is entrapped during LNP formulation process.
Previous work suggested that lipid nanoparticle (LNP) formulations, encapsulating nucleic acids, display electron-dense morphology when examined by cryogenic-transmission electron microscopy (cryo-TEM). Critically, the employed cryo-TEM method cannot differentiate between loaded and empty LNP formulations. Clinically relevant formulations contain high lipid-to-nucleic acid ratios (10-25 (w/w)), for systems mRNA or DNA, it is anticipated a substantial fraction of population does not payload....