Low molecular weight PEG-PLGA improves optical and photoacoustic properties of PCPDTBT nanoparticles.
The fast evolution of medical micro-and nanorobots in the endeavor to perform non-invasive medical operations in living organisms has boosted the use of diverse medical imaging techniques in the last years. Among those techniques, photoacoustic imaging (PAI), considered a functional technique, has shown to be promising for the visualization of micromotors in deep tissue with high spatiotemporal resolution as it possesses the molecular specificity of optical methods and the penetration depth of ultrasound. However, the precise maneuvering and function's control of medical micromotors, in particular in living organisms, require both anatomical and functional imaging feedback. Therefore, herein, the use of high-frequency ultrasound and PAI is reported to obtain anatomical and molecular information, respectively, of magnetically-driven micromotors in vitro and under ex vivo tissues. Furthermore, the steerability of the micromotors is demonstrated by the action of an external magnetic field into the uterus and bladder of living mice in real-time, being able to discriminate the micromotors' signal from one of the endogenous chromophores by multispectral analysis. Finally, the successful loading and release of a model cargo by the micromotors toward non-invasive in vivo medical interventions is demonstrated.
Multispectral photoacoustic imaging has been widely explored as an emerging tool to visualize and quantify tissue chromophores noninvasively. This modality can capture the spectral absorption signature of prominent tissue chromophores, such as oxygenated, deoxygenated hemoglobin, and other biomarkers in the tissue by using spectral unmixing methods. Currently, most of the reported image processing algorithms use standard unmixing procedures, which include user interaction in the form of providing the expected spectral signatures. For translational research with patients, these types of supervised spectral unmixing can be challenging, as the spectral signature of the tissues can differ with respect to the disease condition. Imaging exogenous contrast agents and accessing their biodistribution can also be problematic, as some of the contrast agents are susceptible to change in spectral properties after the tissue interaction. In this work, we investigated the feasibility of an unsupervised spectral unmixing algorithm to detect and extract the tissue chromophores without any a-priori knowledge and user interaction. The algorithm has been optimized for multispectral photoacoustic imaging in the spectral range of 680–900 nm. The performance of the algorithm has been tested on simulated data, tissue-mimicking phantom, and also on the detection of exogenous contrast agents after the intravenous injection in mice. Our finding shows that the proposed automatic, unsupervised spectral unmixing method has great potential to extract and quantify the tissue chromophores, and this can be used in any wavelength range of the multispectral photoacoustic images.
The fast evolution of medical micro-and nanorobots in the endeavor to perform non-invasive medical operations in living organisms boosted the use of diverse medical imaging techniques in the last years. Among those techniques, photoacoustic (PA) tomography has shown to be promising for the imaging of microrobots in deep-tissue (ex vivo and in vivo), as it possesses the molecular specificity of optical techniques and the penetration depth of ultrasound imaging.However, the precise maneuvering and function control of microrobots, in particular in living organisms, demand the combination of both anatomical and functional imaging methods.Therefore, herein, we report the use of a hybrid High-Frequency Ultrasound (HFUS) and PA imaging system for the real-time tracking of magnetically driven micromotors (single and swarms) in phantoms, ex vivo, and in vivo (in mice bladder and uterus), envisioning their application for targeted drug-delivery.
The π‐conjugated polymer poly[2,6‐(4,4‐bis‐(2‐ethylhexyl)‐4H‐cyclopenta[2,1‐b;3,4‐b0]‐dithiophene)‐alt‐4,7‐(2,1,3‐benzothiadiazole)] (PCPDTBT) with deep‐red/near‐infrared (NIR) absorption and emission has been investigated as a contrast agent for in vivo optical and photoacoustic imaging. PCPDTBT is encapsulated within poly(ethylene glycol) methyl ether‐block‐poly(lactide‐co‐glycolide) (PEG2kDa–PLGA4kDa or PEG5kDa–PLGA55kDa) micelles or enveloped by the phospholipid, 1,2‐dipalmitoyl‐sn‐glycero‐3‐phosphoethanolamine‐N‐[methoxy(polyethylene glycol)‐2000] (PEG2kDa‐DPPE), to investigate the formulation effect on imaging performance, biodistribution, and biocompatibility. Nanoparticles that meet the quality requirements for parenteral administration are generated with similar physicochemical properties. Optical phantom imaging reveals that both PEG‐PLGA systems exhibit a 30% higher signal‐to‐background ratio (SBR) than PEG2kDa‐DPPE. This trend cannot be observed in a murine HeLa xenograft model following intravenous administration since dramatic differences in biodistribution are observed. PEG2kDa–PLGA4kDa systems accumulate more rapidly in the liver compared to other formulations and PEG2kDa‐DPPE demonstrates a higher tumor localization. Protein content in the “hard” corona differs between formulations (PEG2kDa‐DPPE < PEG2kDa–PLGA4kDa < PEG5kDa–PLGA55kDa), although this observation alone does not explain biodistribution patterns. PEG2kDa‐PLGA4kDa systems show the highest photoacoustic amplitude in a phantom, but also a lower signal in the tumor due to differences in biodistribution. This study demonstrates that formulations for conjugated polymer contrast agents can have significant impact on both imaging performance and biodistribution.
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