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

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• 作者：Nicolas Darville^a ; Jukka Saarinen^b ; Antti Isomä ; ki^c ; Leonid Khriachtchev^d ; Dirk Cleeren^e ; Patrick Sterkens^f ; Marjolein van Heerden^f ; Pieter Annaert^a ; Leena Peltonen^b ; Hé ; lder A. Santos^b ; Clare J. Strachan^b ; Guy Van den Mooter^a ; ^{Guy.VandenMooter@pharm.kuleuven.be" class="auth_mail" title="E-mail the corresponding author}
• 关键词：位p ; wavelength of the pump/probe laser beam ; 位s ; wavelength of the Stokes laser beam ; 蠅p ; vibrational frequency of the pump/probe beam ; 蠅s ; vibrational frequency of the Stokes beam ; BF ; bright field ; CARS ; coherent anti-Stokes Raman scattering ; DMEM ; Dulbecco&rsquo ; s modified Eagle medium ; E- ; epi-directed ; backward ; EDTA ; ethylenediaminetetraacetic acid disodium salt dehydrate ; F- ; forward-directed ; FWHM ; full width at half maximum lateral resolution ; H&E ; haematoxylin and eosin ; HBSS ; Hank&rsq
• 刊名：European Journal of Pharmaceutics and Biopharmaceutics
• 出版年：2015
• 出版时间：October 2015
• 年：2015
• 卷：96
• 期：Complete
• 页码：338-348
• 全文大小：2881 K

文摘

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 400 nm, 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.