A5048811821- RNA Interference and Gene Delivery
- Drug Solubulity and Delivery Systems
- Crystallization and Solubility Studies
- Lipid Membrane Structure and Behavior
- Advanced biosensing and bioanalysis techniques
- Nanoparticle-Based Drug Delivery
- Analytical Chemistry and Chromatography
- Drug Transport and Resistance Mechanisms
- Extracellular vesicles in disease
- Surfactants and Colloidal Systems
- Chemical Thermodynamics and Molecular Structure
- Advanced Drug Delivery Systems
- nanoparticles nucleation surface interactions
- Coagulation and Flocculation Studies
- Advanced Fluorescence Microscopy Techniques
- Calcium Carbonate Crystallization and Inhibition
- Thermodynamic properties of mixtures
- Molecular Biology Techniques and Applications
- Spectroscopy and Quantum Chemical Studies
- RNA Research and Splicing
- Electrostatics and Colloid Interactions
- Circular RNAs in diseases
- Virus-based gene therapy research
- Material Dynamics and Properties
- MicroRNA in disease regulation
AstraZeneca (Sweden)
2016-2025
AstraZeneca (Brazil)
2024
University of Gothenburg
2018
AstraZeneca (United Kingdom)
2008-2015
University of Zurich
2012
University of Cagliari
2012
Lund University
2005
The development of safe and efficacious gene vectors has limited greatly the potential for therapeutic treatments based on messenger RNA (mRNA). Lipid nanoparticles (LNPs) formed by an ionizable cationic lipid (here DLin-MC3-DMA), helper lipids (distearoylphosphatidylcholine, DSPC, cholesterol), a poly(ethylene glycol) (PEG) have been identified as very promising delivery short interfering (siRNA) in different clinical phases; however, high-molecular weight proven much more demanding. Herein...
RNA-based therapeutics hold great promise for treating diseases and lipid nanoparticles (LNPs) represent the most advanced platform RNA delivery. However, fate of LNP-mRNA after endosome-engulfing escape from autophagy-lysosomal pathway remains unclear. To investigate this, mRNA (encoding human erythropoietin) was delivered to cells using LNPs, which shows, first time, a link between endocytosis its packaging into extracellular vesicles (endo-EVs: secreted LNP-mRNA). Endosomal is dependent...
Emerging therapeutic treatments based on the production of proteins by delivering mRNA have become increasingly important in recent times. While lipid nanoparticles (LNPs) are approved vehicles for small interfering RNA delivery, there still challenges to use this formulation delivery. LNPs typically a mixture cationic lipid, distearoylphosphatidylcholine (DSPC), cholesterol, and PEG-lipid. The structural characterization mRNA-containing (mRNA-LNPs) is crucial full understanding way which...
The RNA that is packaged into exosomes termed as exosomal-shuttle (esRNA); however, the players, which take this subset of (esRNA) exosomes, remain largely unknown. We hypothesized binding proteins (RBPs) could serve key players in mechanism, by making complexes with RNAs and transporting them during biosynthesis exosomes. Here, we demonstrate presence 30 RBPs were shown to form RNA–RBP both cellular exosomal-RNA species. To assess involvement these RNA-transfer gene transcripts encoding six...
Delivery of exogenous mRNA using lipid nanoparticles (LNPs) is a promising strategy for therapeutics. However, bottleneck remains in the poor understanding parameters that correlate with endosomal escape versus cytotoxicity. To address this problem, we compared distribution six LNP-mRNA formulations diverse chemical composition and efficacy, similar to those used mRNA-based vaccines, primary human adipocytes, fibroblasts, HeLa cells. Surprisingly, found total uptake not sufficient predictor...
Lipid nanoparticles (LNPs) are currently used to transport functional mRNAs, such as COVID-19 mRNA vaccines. The delivery of angiogenic molecules, therapeutic VEGF-A mRNA, ischemic tissues for producing new blood vessels is an emerging strategy the treatment cardiovascular diseases. Here, authors deliver via LNPs and study stoichiometric quantification their uptake kinetics how exogenous LNP-mRNAs between cells functionally extended by cells' own vehicles called extracellular vesicles (EVs)....
Amorphous drug nanosuspensions are prone to particle growth due Ostwald ripening. By incorporating a second component of extremely low aqueous solubility, ripening can be inhibited. These studies indicate that inhibit ripening, the drug/inhibitor mixture (in particles) must form single phase. The characterized by interaction parameter χ using Bragg-Williams theory, in which phase mixtures obtained for < 2. calculated from (crystalline) solubility inhibitor, provided inhibitor is liquid, and...
Abstract Secondary nucleation, wherein crystal seeds are used to induce crystallization, is widely employed in industrial crystallizations. Despite its significance, our understanding of the process, particularly at molecular level, remains rudimentary. An outstanding question why do a few give rise many‐fold increase new crystals? Using simulation coupled with experiments we have uncovered processes that this autocatalytic behavior. The simulations reveal formation aggregates solution,...
Lipid nanoparticles (LNPs) have emerged as potent carriers for mRNA delivery, but several challenges remain before this approach can offer broad clinical translation of therapeutics. To improve their efficacy, a better understanding is required regarding how LNPs are trapped and processed at the anionic endosomal membrane prior to release. We used surface-sensitive fluorescence microscopy with single LNP resolution investigate pH dependency binding kinetics ionizable lipid-containing...
Lipid nanoparticles (LNPs) are advanced core-shell particles for messenger RNA (mRNA) based therapies that made of polyethylene glycol (PEG) lipid, distearoylphosphatidylcholine (DSPC), cationic ionizable lipid (CIL), cholesterol (chol), and mRNA. Yet the mechanism pH-dependent response is believed to cause endosomal release LNPs not well understood. Here, we show eGFP (enhanced green fluorescent protein) protein expression in mouse liver mediated by lipids DLin-MC3-DMA (MC3), DLin-KC2-DMA...
The ionizable-lipid component of RNA-containing nanoparticles controls the pH-dependent behavior necessary for an efficient delivery cargo—the so-called endosomal escape. However, it is still empirical exercise to identify optimally performing lipids. Here, we study two well-known ionizable lipids, DLin-MC3-DMA and DLin-DMA using a combination experiments, multiscale computer simulations, electrostatic theory. All-atom molecular dynamics experimentally measured polar headgroup p K values,...
In the present paper, we have studied particle dissolution and crystal growth of poorly water soluble drug felodipine, using fluorescence as a probe for amount crystalline material. Dissolution kinetics is essentially diffusion-controlled, while rate significantly slower compared to diffusion-controlled limit. The deviation from diffusion control was characterized by effective length, λ, related surface integration process. Amorphous nanoparticles may be highly unstable in presence small...
A simple turbidimetric method was developed to measure the bulk concentration of drug in nanosuspensions. The concentrations measured were range from 1 μM mM. accuracy checked by determination crystalline nanosuspensions, i.e., solubility, which compared favorably solubilities a conventional method. Results obtained for amorphous nanosuspensions agreed with predictions using theory describing relative solubility between supercooled liquid and crystal. Further, it found that Ostwald ripening...
Dissolution models require, at their core, an accurate diffusion model. The accuracy of the model for diffusion-dominated dissolution is particularly important with trend toward micro- and nanoscale drug particles. Often such are based on concept a "diffusion layer." Here framework developed models, we discuss inadequacy classical that unphysical constant layer thickness assumption, or do not correctly modify rate due to "confinement effects": (1) increase in bulk concentration from...
Targeted mRNA transport plays a crucial role in enhancing the therapeutic efficacy of molecule, reducing its side effects, and minimizing off-target effects. Systemic administration through lipid nanoparticles (LNPs) or extracellular vesicles (EVs) predominantly results accumulation liver. We hypothesized that cardiac-specific EVs could more effectively target to heart, comparison non-cardiac-specific LNPs. In mice, after intravenous administration, from cardiac progenitor cells (CPC-EVs)...
Ostwald ripening of crystalline and amorphous nanoparticle dispersions a model organic compound are compared. While nanoparticles show rapid on the time scale minutes, crystalline...
As a first step in the computational prediction of drug solubility free energy hydration, DeltaG*(vw) TIP4P water has been computed for data set 48 molecules using perturbation method and optimized potential liquid simulations all-atom force field. The were performed two steps, where Coulomb then Lennard-Jones interactions between solute scaled down from full to zero strength provide physical understanding simpler predictive models. results have interpreted theory assuming = A(MS)gamma +...
The purpose of this study was to investigate in vivo intestinal precipitation a model drug mebendazole, basic BCS class II drug, using dogs with stomas for administration or sampling. After oral solution an expected supersaturation approximately 20 times the solubility, measured dog fluid (DIF) up 10 and, on average, only 11% given dose retrieved as solid collected from stoma. rapidly absorbed >90% total systemic exposure reached within three hours after duodenal solution. In silico...