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Eur J Pharm Biopharm. 2015 Oct;96:338-48. doi: 10.1016/j.ejpb.2015.09.003. Epub 2015 Sep 5.

Multimodal non-linear optical imaging for the investigation of drug nano-/microcrystal-cell interactions.

Author information

1
Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Leuven, Belgium.
2
Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
3
Institute of Biomedicine, Anatomy, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
4
Department of Chemistry, University of Helsinki, Helsinki, Finland.
5
Pharmaceutical Development and Manufacturing Sciences, A Division of Janssen Pharmaceutica NV, Beerse, Belgium.
6
Preclinical Development and Safety, Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium.
7
Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Leuven, Belgium. Electronic address: Guy.VandenMooter@pharm.kuleuven.be.

Abstract

Drug nano-/microcrystals are being used for sustained parenteral drug release, but safety and efficacy concerns persist as the knowledge of the in vivo fate of long-living particulates is limited. There is a need for techniques enabling the visualization of drug nano-/microcrystals in biological matrices. The aim of this work was to explore the potential of coherent anti-Stokes Raman scattering (CARS) microscopy, supported by other non-linear optical methods, as an emerging tool for the investigation of cellular and tissue interactions of unlabeled and non-fluorescent nano-/microcrystals. Raman and CARS spectra of the prodrug paliperidone palmitate (PP), paliperidone (PAL) and several suspension stabilizers were recorded. PP nano-/microcrystals were incubated with RAW 264.7 macrophages in vitro and their cellular disposition was investigated using a fully-integrated multimodal non-linear optical imaging platform. Suitable anti-Stokes shifts (CH stretching) were identified for selective CARS imaging. CARS microscopy was successfully applied for the selective three-dimensional, non-perturbative and real-time imaging of unlabeled PP nano-/microcrystals having dimensions larger than the optical lateral resolution of approximately 400nm, in relation to the cellular framework in cell cultures and ex vivo in histological sections. In conclusion, CARS microscopy enables the non-invasive and label-free imaging of (sub)micron-sized (pro-)drug crystals in complex biological matrices and could provide vital information on poorly understood nano-/microcrystal-cell interactions in future.

KEYWORDS:

CARS microscopy; Drug nano-/microcrystal; Long-acting injectable; Non-linear imaging; Paliperidone palmitate; RAW 264.7 macrophages; Sustained-release

PMID:
26347923
DOI:
10.1016/j.ejpb.2015.09.003
[Indexed for MEDLINE]

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