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

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.

Size‐Optimized Ultrasmall Porous Silica Nanoparticles Depict Vasculature‐Based Differential Targeting in Triple Negative Breast Cancer

“…Unlike our previous modeling approaches to study tissue disposition kinetics and tumor delivery efficacy of NPs, here we developed a multicompartment, semimechanistic model, which is a reduced physiologically based PK (PBPK) model, comprising a systemic blood pool, RES (i.e., liver and spleen), muscle, and a facultative tumor compartment (applicable for tumor‐bearing groups only), which represent the dominant distribution sites of the UPSNs in vivo, connected in an anatomical fashion via plasma (red arrows) and lymph (blue arrows) flow (Figure C and Figure S7, Supporting Information). In traditional PK modeling, organs are modeled as well‐stirred, black‐box like compartments with homogenous, time‐dependent exposure to administered drugs . This approximation often leads to a limited understanding of the pharmacological behavior of the administered agent, thus resulting in partial or heterogenous responses in the clinic.…”

Multidisciplinary Role of Mesoporous Silica Nanoparticles in Brain Regeneration and Cancers: From Crossing the Blood–Brain Barrier to Treatment

“…The degradation products of both types of nanoparticles were excreted in urine for a period of up to 1 month post administration of the nanoparticles . Also, Dogra et al demonstrated that MSNs are excreted through the urinary and fecal routes using an in vivo model of healthy female rats . It was also found that silica nanoparticles were excreted mainly through the urinary and fecal routes after administration using different routes; this may happen due to kidney and hepatobiliary excretion processes …”

“…The discovery of MCM‐41 was recognized as a major breakthrough in materials science and since then mesoporous silica nanoparticles (MSNs), thanks to their superior physiochemical properties such as large porosity, high surface areas, low toxicity, controllable sizes, and wide range of morphologies compared to conventional nanoparticles (NPs) have emerged as favorable tools in biomedical applications as nanocarriers for encapsulation and delivery of therapeutic medicines . Designing biocompatible MSNs and their multifunctional derivatives for drug transport as well as theranostics is one of the hottest areas of research in the field of nanobiotechnology and nanomedicine . High loading capacity, acceptable biocompatibility, and limitless possibilities of surface functionalization for specific cellular recognition undoubtedly make MSNs also suitable for detection, diagnosis, and treatment of neurodegenerative disorders, brain cancers, and in brain regeneration.…”

Propranolol‐Loaded Mesoporous Silica Nanoparticles for Treatment of Infantile Hemangiomas

“…The possible reasons can be that the sustained and prolonged release of PRN and apoptosis induced by PVA‐MSN‐PRN resulted in a better therapeutic outcome at rather low medication frequency and drug doses. Compared with free PRN that would be immediately released into the systemic circulation, PVA‐MSN‐PRN could release the PRN drug in a controlled and slow way, which could enhance circulation time and direct the biodistribution of the drug by passive targeting through permeability and retention (EPR) effect, wherein MSNs passively accumulate in the tumor microenvironment due to its leaky vasculature . Considering the characteristic features of hemangiomas with irregular and immature vascular structures, the EPR effect by PVA‐MSN‐PRNs might be greatly promoted, although premature released still could occur before the particle reaches the target cells.…”