Time-resolved small-angle neutron scattering for characterization of molecular exchange in lipid nanoparticle therapeutics

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dc.contributor.authorHilburg, SLen_AU
dc.contributor.authorSokolova, AVen_AU
dc.contributor.authorCagnes, MPen_AU
dc.contributor.authorPozzo, LDen_AU
dc.date.accessioned2024-09-16T23:57:06Zen_AU
dc.date.available2024-09-16T23:57:06Zen_AU
dc.date.issued2025-01en_AU
dc.date.statistics2024-08-23en_AU
dc.description.abstractHypothesis: Nano-scale dynamics of self-assembled therapeutics play a large role in their biological function. However, assessment of such dynamics remains absent from conventional pharmaceutical characterization. We hypothesize that time-resolved small-angle neutron scattering (TR-SANS) can reveal their kinetic properties. For lipid nanoparticles (LNP), limited molecular motion is important for avoiding degradation prior to entering cells while, intracellularly, enhanced molecular motion is then vital for effective endosomal escape. We propose TRSANS for quantifying molecular exchange in LNPs and, therefore, enabling optimization of opposing molecular behaviors of a pharmaceutical in two distinct environments. Experiments: We use TR-SANS in combination with traditional SANS and small-angle x-ray scattering (SAXS) to experimentally quantify nano-scale dynamics and provided unprecedented insight to molecular behavior of LNPs. Findings: LNPs have molecular exchange dynamics relevant to storage and delivery which can be captured using TR-SANS. Cholesterol exchanges on the time-scale of hours even at neutral pH. As pH drops below the effective pKa of the ionizable lipid, molecular exchange occurs faster. The results give insight into behavior enabling delivery and provide a quantifiable metric by which to compare formulations. Successful analysis of this multicomponent system also expands the opportunities for using TR-SANS to characterize complex therapeutics. © 2024 Elsevier Inc.en_AU
dc.description.sponsorshipWe acknowledge the support of the Australian Centre for Neutron Scattering (ACNS), Australian Nuclear Science and Technology Organisation (ANSTO) and the Australian Government through the National Collaborative Research Infrastructure Strategy, in supporting this work via ACNS Proposal 15396. The National Deuteration Facility is partly funded by the National Collaborative Research Infrastructure Strategy (NCRIS) – an Australian Government initiative. Thanks to Sage Scheiwiller and Karen Li for assistance during experimentation. We acknowledge the use of SAXS facilities and instrumentation supported by the U.S. National Science Foundation (NSF) through the Major Research Instrumentation (MRI) program (DMR-2116265) and by the UW Molecular Engineering Materials Center, a Materials Research Science and Engineering Center (Grant No. DMR-2308979). This work benefited from the use of the SasView application, [42] originally developed under NSF award DMR-0520547. SasView contains code developed with funding from the European Union's Horizon 2020 research and innovation programme under the SINE2020 project, grant agreement No 654000. This material is based upon work supported by the NSF under Grant EEC-2127509 to the American Society for Engineering Education.en_AU
dc.identifier.citationHilburg, S. L., Sokolova, A., Cagnes, M., & Pozzo, L. D. (2025). Time-resolved small-angle neutron scattering for characterization of molecular exchange in lipid nanoparticle therapeutics. Journal of Colloid and Interface Science, 677, 387-395. doi:10.1016/j.jcis.2024.08.061en_AU
dc.identifier.issn0021-9797en_AU
dc.identifier.issueBen_AU
dc.identifier.journaltitleJournal of Colloid and Interface Scienceen_AU
dc.identifier.pagination387-395en_AU
dc.identifier.urihttps://apo.ansto.gov.au/handle/10238/15679en_AU
dc.identifier.volume677en_AU
dc.language.isoenen_AU
dc.publisherElsevieren_AU
dc.relation.urihttps://doi.org/10.1016/j.jcis.2024.08.061en_AU
dc.subjectLipidsen_AU
dc.subjectNanoparticlesen_AU
dc.subjectSmall angle scatteringen_AU
dc.subjectScatteringen_AU
dc.subjectVaccinesen_AU
dc.subjectCold storageen_AU
dc.subjectGlycolsen_AU
dc.subjectToxicityen_AU
dc.subjectCholesterolen_AU
dc.titleTime-resolved small-angle neutron scattering for characterization of molecular exchange in lipid nanoparticle therapeuticsen_AU
dc.typeJournal Articleen_AU
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