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Nanoparticulate drug delivery is known to greatly improve the efficacy of pharmaceuticals and has found a wide range of applications with different administration methods including oral, intravenous, transcutaneous and ocular routes. However, the mechanisms by which these nanoparticles travel through, interact with, and modify tissues and how this relates to the improved drug performance are still unclear. These are critical questions that need to be answered to optimise the properties of future pharmaceuticals, dose rates and frequencies, and reduce potential side effects. Our ability to answer these questions is greatly hindered by the fact that there is currently no imaging modality available to directly visualise such small particles and the structure and function of the surrounding tissue, without the aid of contrast agents or highly invasive methods. Current imaging modalities derive image contrast of the nanoparticles and/or the surrounding tissues by means of external labels. We present coherent antistokes Raman scattering microscopy as a novel tool for imaging nanoparticle drug carriers against a background of biological tissues and cells.

The ability to map microvascular morphology and hemodynamic parameters, such as blood volume, is desirable for many biomedical studies and will lead to a deeper understanding of the mechanisms of angiogenesis and vascular disease. Capillary networks can be delineated in three dimensions with two-photon excited fluorescence microscopy; however, this requires the intravenous infusion of a fluorescent dye into the blood plasma, which often complicates in vivo imaging and only provides an indirect estimate of local haematocrit volume. Moreover, visualising the spatial distribution of capillaries is often insufficient; ideally, one would wish to correlate the proximity of the blood vessels with the surrounding local tissue structure. We present in this study a novel multimodal approach that combines stimulated Raman scattering and two-photon photothermal lensing to provide simultaneous visualisation of cortical microvasular morphology and surrounding cellular structures. We show that volumetric analysis of the nonlinear photothermal contrast of erythrocytes allows a direct quantification of local haematocrit volume rather than relying upon average plasma volume-to-haematocrit ratios. Copyright © 2012 John Wiley & Sons, Ltd.

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.

Nanotechnology involves manipulating matter at the nanoscale (

The blood-brain barrier (BBB) limits the bioavailability of most bioactive molecules and drugs in the CNS, leaving clinicians with only a few options for pharmacotherapy. In this issue Regina et al. demonstrate that a 'Trojan horse' drug conjugate, acting as a substrate of a physiological BBB receptor that facilitates transcytosis, significantly improves drug transport into the CNS. Specifically, the low-density lipoprotein receptor-related protein (LRP) is used to carry a conjugate of paclitaxel and Angiopep-2, an aprotinin-derived peptide, across the BBB. Interestingly, in its conjugated form paclitaxel circumvents the efflux pumps at the BBB but still retains its activity against microtubules. Importantly, the authors were able to demonstrate improved therapeutic efficacy of this approach in orthotopic models of primary and metastatic brain cancer. This proof-of-principle study thus represents a milestone for drug delivery across the BBB but also a starting point for studies exploring wider applicability and potential limitations of the approach.

Packaging drugs and genes into nanoparticles enables drug or gene biodistribution to be favourably altered, with an ultimate therapeutic benefit [1–3]. To acquire such control on the in vivo fate of drugs and genes requires that such particles be precision engineered and electron microscopy is one of the techniques used to visualise and confirm the results of such engineering.