Exploring uptake mechanisms of oral nanomedicines using multimodal nonlinear optical microscopy

Abstract

Advances in pharmaceutical nanotechnology have yielded ever increasingly sophisticated nanoparticles for medicine delivery. When administered via oral, intravenous, ocular and transcutaneous delivery routes, these nanoparticles can elicit enhanced drug performance. In spite of this, little is known about the mechanistic processes underlying interactions between nanoparticles and tissues, or how these correlate with improved pharmaceutical effects. These mechanisms must be fully understood before nanomedicines can be rationally engineered to optimise their performance. Methods to directly visualise these particulates within tissue samples have traditionally involved imaging modalities requiring covalent labelling of fluorescent or radioisotope contrast agents. We present CARS, second harmonic generation and two photon fluorescence microscopy combined as a multi‐modal label‐free method for pinpointing polymeric nanoparticles within the stomach, intestine, gall bladder and liver. We demonstrate for the first time that orally administered chitosan nanoparticles follow a recirculation pathway from the GI tract via enterocytes, to the liver hepatocytes and intercellular spaces and then to the gall bladder, before being re‐released into the gut together with bile. (© 2012 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)

Utility of models of the gastrointestinal tract for assessment of the digestion and absorption of engineered nanomaterials released from food matrices

“…In vivo, fluorescence detection of administered NMs can include not only post-mortem analysis of tissues, but also noninvasive imaging. For example, multimodal multiphoton optical microscopy imaging in mice can qualitatively localize fluorescent NPs such as chitosan in organs (Garrett et al, 2012). X-ray computed tomography and NIR fluorescent imaging can also detect NPs such as fluorescent silica-coated gold nanorods (Luo et al, 2011).…”

Accumulating advantages, reducing limitations: Multimodal nonlinear imaging in biomedical sciences – The synergy of multiple contrast mechanisms

“…On the other hand, processes relying on very general optical properties, e.g., refractive index changes in FWM and THG, are powerful for label-free visualization of the overall tissue structure, but provide only unspecific molecular information [19]. Here coherent Raman processes are very powerful enabling both the visualization of the tissue structure, e.g., by utilizing abundant vibrational resonances for imaging, but also highly selective visualization, when a molecule or structure specific vibrational resonance is probed, e.g., for drug delivery studies with isotope labeling [28,29].…”

“…All these exogenous labels generate significantly brighter nonlinear signals than endogenous molecular markers, which is key for increasing the image acquisition or allows detecting very low concentrations of marker molecules. For CRS based techniques, isotope labelling with deuterium shifts the signal to a silent region of the vibrational spectrum, allowing for drug delivery investigations [28,29]. Alternatively the high specificity of antibodies routinely used in immunohistochemistry can be combined with vibrational detection.…”

“…The visualization Figure 5 Multimodal nonlinear microscopy for imaging of tissue structure and composition. (A) the uptake of deuterated nanoparticles is monitored by CARS microscopy (2100 cm À1 , green) while the tissue is depicted by 2PF, red, autofluorescence, GC-goblet cell [28]. (B) engineered tissue made of cellulose fibers (blue, SHG) is seeded with smooth muscle cells (CARS 2845 cm À1 , yellow), which develop into different cell phenotypes (1, 2) and produce collagen as an extracellular matrix element by themselves (2, arrow) [109].…”

CARS based label‐free assay for assessment of drugs by monitoring lipid droplets in tumour cells

“…Furthermore, an emerging area of applications for CARS microscopy is the imaging of drugs and drug delivery. Apart from being able to track penetrating oil-rich ointments applied to skin [17] CARS has also been used to track deuterated drug particles in mouse tissue [18].…”