Pharmacokinetics of intact lipid nanocapsules using new quantitative FRET technique.

The present study investigated the pharmacokinetics of intact lipid nanocapsules (LNCs) after intravenous administration in rats. Six different Förster resonance energy transfer LNCs (FRET-LNCs) have been studied with 2 sizes (50 and 85 nm) and 3 coating types (none, DSPE-mPEG 2000 or stearylamine). A FRET-LNCs blood extraction method was developed to retain an accurate FRET signal. Intact FRET-LNCs were specifically quantified through combination of FRET signal and Nano Tracker Analysis. Pharmacokinetic data were first described by non-compartmental analysis, then used to develop a population pharmacokinetic model. The pharmacokinetic elimination of FRET-LNCs was non-linear and dependent on size and surface modification, while the distribution was dependent on size. The LNCs 85 nm volume of distribution was lower than LNCs 50 nm. As expected, LNCs 85 nm with PEG coating displayed a lower clearance than other formulations. Surprisingly, this study highlighted a faster elimination of LNCs 50 nm with PEG compared to other formulations which could be explained by instability in blood. This first pharmacokinetic model of intact LNCs allowed a thorough understanding of the influence of size and coating on pharmacokinetic properties and paves the way for future mechanistic modeling approaches to predict the fate of LNCs in vivo.

FRET as the tool for in vivo nanomedicine tracking.

Advanced drug delivery system utilizing a nanocarrier is the major application of nanotechnology on pharmacotherapeutics. However, despite the promising benefits and a leading trend in pharmaceutical research, nanomedicine development suffers from a poor clinical translation problem as only a handful of nanomedicine products reach the market yearly. The conventional pharmacokinetic study generally focuses only on monitoring the level of a free drug but ignores the nanocarrier's role in pharmacokinetics. One hurdle is that it is difficult to directly track intact nanocarriers in vivo to explore their pharmacokinetics. Although several imaging techniques such as radiolabeling, nuclear imaging, fluorescence imaging, etc., have been developed over the past few years, currently, one method that can successfully track the intact nanocarriers in vivo directly is by Förster resonance energy transfer (FRET). This review summarizes the application of FRET as the in vivo nanoparticle tracker for studying the in vivo pharmacokinetics of the organic nanocarriers and gives elaborative details on the techniques utilized.

New In Vitro Coculture Model for Evaluating Intestinal Absorption of Different Lipid Nanocapsules.

Standard models used for evaluating the absorption of nanoparticles like Caco-2 ignore the presence of vascular endothelium, which is a part of the intestinal multi-layered barrier structure. Therefore, a coculture between the Caco-2 epithelium and HMEC-1 (Human Microvascular Endothelial Cell type 1) on a Transwell® insert has been developed. The model has been validated for (a) membrane morphology by transmission electron microscope (TEM); (b) ZO-1 and ß-catenin expression by immunoassay; (c) membrane integrity by trans-epithelial electrical resistance (TEER) measurement; and (d) apparent permeability of drugs from different biopharmaceutical classification system (BCS) classes. Lipid nanocapsules (LNCs) were formulated with different sizes (55 and 85 nm) and surface modifications (DSPE-mPEG (2000) and stearylamine). Nanocapsule integrity and particle concentration were monitored using the Förster resonance energy transfer (FRET) technique. The result showed that surface modification by DSPE-mPEG (2000) increased the absorption of 55-nm LNCs in the coculture model but not in the Caco-2. Summarily, the coculture model was validated as a tool for evaluating the intestinal absorption of drugs and nanoparticles. The new coculture model has a different LNCs absorption mechanism suggesting the importance of intestinal endothelium and reveals that the surface modification of LNCs can modify the in vitro oral absorption.