Establishing the effects of mesoporous silica nanoparticle properties on in vivo disposition using imaging-based pharmacokinetics

Prashant Dogra,Vittorio Cristini,Paul N Durfee,Eric N Coker,Elaine L Bearer,Natalie L Adolphi,Zhihui Wang,C Jeffrey Brinker,Jonas G Croissant,Kimberly S Butler,Achraf Noureddine,Yu-Shen Lin

doi:10.1038/s41467-018-06730-z

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.

Highlights

The progress of nanoparticle (NP)-based drug delivery has been hindered by an inability to establish structure-activity relationships in vivo
To avoid confounding effects of particle size polydispersity and hydrodynamic instability, we employed well-characterized, monosized (defined as hydrodynamic diameter polydispersity index (PdI)
The selection of MSNs as the NP of choice for the current investigation is based on their ability to undergo surface functionalization and precise synthesis control that allows for selection of particle size, shape, and pore size

Summary

Introduction

The progress of nanoparticle (NP)-based drug delivery has been hindered by an inability to establish structure-activity relationships in vivo. To date, based on the ten-year survey of NP delivery to solid tumors[3], several trends have been observed with respect to NP physicochemical properties: inorganic NPs have higher delivery efficiencies than organic NPs, NPs smaller than 100 nm in hydrodynamic diameter have higher delivery efficiencies than larger particles, nearly neutrally charged NPs (defined as having zeta potentials −10 to +10 mV) have higher delivery efficiencies than more positively or negatively charged particles, and rod-shaped particles are more efficient than spherical or plate-like particles These trends presumably reflect the in vivo stabilities of the NPs, differential uptake by the MPS, and differences in renal clearance; this survey did not establish unambiguously the stability or size polydispersity of the NPs nor their biodistribution, and there appeared to be no systematic studies to isolate the effects of size or charge or surface chemistry for NPs of comparable composition and shape. Noteworthy in this regard, we have recently demonstrated for mesoporous silica NPs (MSNs) of identical size and charge that the spatial arrangement and accessibility of charged molecules on the MSN surface (i.e. surface chemistry) is another critical, but to date unrecognized, factor governing biological behavior of NPs16

Methods

Results

Conclusion