Multimodal non-linear optical imaging for the investigation of drug nano-/microcrystal-cell interactions.
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.
Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Leuven, Belgium.
Nicolas
N
Darville
Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
Jukka
J
Saarinen
Institute of Biomedicine, Anatomy, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Antti
A
Isomäki
Department of Chemistry, University of Helsinki, Helsinki, Finland.
Leonid
L
Khriachtchev
Pharmaceutical Development and Manufacturing Sciences, A Division of Janssen Pharmaceutica NV, Beerse, Belgium.
Dirk
D
Cleeren
Preclinical Development and Safety, Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium.
Patrick
P
Sterkens
Preclinical Development and Safety, Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium.
Marjolein
M
van Heerden
Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Leuven, Belgium.
Pieter
P
Annaert
Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
Leena
L
Peltonen
Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
Hélder A
HA
Santos
Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
Clare J
CJ
Strachan
Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Leuven, Belgium. Electronic address: Guy.VandenMooter@pharm.kuleuven.be.
Guy
G
Van den Mooter
D065567:Absorption, Physiological / Q000187:drug effects; D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004337:Drug Carriers; D004339:Drug Compounding; D004355:Drug Stability; D021621:Imaging, Three-Dimensional; D007273:Injections, Intramuscular; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D064847:Multimodal Imaging; D053758:Nanoparticles / Q000009:adverse effects / Q000737:chemistry*; D061848:Optical Imaging; D000068882:Paliperidone Palmitate / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010316:Particle Size; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000067996:RAW 264.7 Cells; D051381:Rats; D013059:Spectrum Analysis, Raman; D013535:Suspensions
D014150:Antipsychotic Agents; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D011355:Prodrugs; D013535:Suspensions; D000068882:Paliperidone Palmitate
CARS microscopy; Drug nano-/microcrystal; Long-acting injectable; Non-linear imaging; Paliperidone palmitate; RAW 264.7 macrophages; Sustained-release