Establishing the effects of mesoporous silica nanoparticle properties on in vivo disposition using imaging-based pharmacokinetics
- DOI
- Language of the publication
- English
- Date
- 2018-10-31
- Type
- Article
- Author(s)
- Dogra, Prashant
- Adolphi, Natalie L.
- Wang, Zhihui
- Lin, Yu-Shen
- Butler, Kimberly S.
- Durfee, Paul N.
- Croissant, Jonas G.
- Noureddine, Achraf
- Coker, Eric N.
- Bearer, Elaine L.
- Cristini, Vittorio
- Brinker, Jeffrey C.
- Publisher
- Nature Research
Abstract
The progress of nanoparticle (NP)-based drug delivery has been hindered by an inability to establish structure-activity relationships in vivo. Here, using stable, monosized, radiolabeled, mesoporous silica nanoparticles (MSNs), we apply an integrated SPECT/CT imaging and mathematical modeling approach to understand the combined effects of MSN size, surface chemistry and routes of administration on biodistribution and clearance kinetics in healthy rats. We show that increased particle size from ~32- to ~142-nm results in a monotonic decrease in systemic bioavailability, irrespective of route of administration, with corresponding accumulation in liver and spleen. Cationic MSNs with surface exposed amines (PEI) have reduced circulation, compared to MSNs of identical size and charge but with shielded amines (QA), due to rapid sequestration into liver and spleen. However, QA show greater total excretion than PEI and their size-matched neutral counterparts (TMS). Overall, we provide important predictive functional correlations to support the rational design of nanomedicines.
Plain language summary
Health Canada is responsible for conducting safety assessments of new materials such as silica nanoparticles. Mesoporous silica nanoparticles (mSiNPs) with ordered, large pores are finding use in drug delivery, medical imaging and industrial applications, increasing the likelihood of environmental and health impacts of these materials. Developing reliable safety assessments requires an understanding of the influence of physicochemical and biological factors on toxicity of nanomaterials. In this work, Health Canada scientists investigated the toxic and inflammatory potential of a panel of mesoporous SiNPs that vary in size and surface modification in human and mouse-derived cells which serve different functions in the body, using a set of assays. The biological potency and the nanoparticle properties were interrogated for associations using statistical tools. The results showed that toxicity of the mSiNPs was similar across the different cell types, while the inflammatory potential was more cell type-specific. Physicochemical properties including surface area and the size of nanoparticle clusters were the most important determinants of the overall biological activity of the mSiNPs. The combination of size, surface modification and mSiNP properties influenced the cellular responses to this set of SiNPs. The work provides essential data to aid in the evidence-based assessment and management of nanomaterials for their effective regulation.
Subject
- Health,
- Health and safety