Browsing by Author "Lammers, Twan"
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- ItemMultimodal and multiscale optical imaging of nanomedicine delivery across the blood-brain barrier upon sonopermeation(Wyoming, NSW : Ivyspring, 2020) May, Jan-Niklas; Golombek, Susanne K.; Baues, Maike; Dasgupta, Anshuman; Drude, Natascha; Rix, Anne; Rommel, Dirk; Stillfried, Saskia von; Appold, Lia; Pola, Robert; Pechar, Michal; van Bloois, Louis; Storm, Gert; Kuehne, Alexander J.C.; Gremse, Felix; Theek, Benjamin; Kiessling, Fabian; Lammers, TwanRationale: The blood-brain barrier (BBB) is a major obstacle for drug delivery to the brain. Sonopermeation, which relies on the combination of ultrasound and microbubbles, has emerged as a powerful tool to permeate the BBB, enabling the extravasation of drugs and drug delivery systems (DDS) to and into the central nervous system (CNS). When aiming to improve the treatment of high medical need brain disorders, it is important to systematically study nanomedicine translocation across the sonopermeated BBB. To this end, we here employed multimodal and multiscale optical imaging to investigate the impact of DDS size on brain accumulation, extravasation and penetration upon sonopermeation. Methods: Two prototypic DDS, i.e. 10 nm-sized pHPMA polymers and 100 nm-sized PEGylated liposomes, were labeled with fluorophores and intravenously injected in healthy CD-1 nude mice. Upon sonopermeation, computed tomography-fluorescence molecular tomography, fluorescence reflectance imaging, fluorescence microscopy, confocal microscopy and stimulated emission depletion nanoscopy were used to study the effect of DDS size on their translocation across the BBB. Results: Sonopermeation treatment enabled safe and efficient opening of the BBB, which was confirmed by staining extravasated endogenous IgG. No micro-hemorrhages, edema and necrosis were detected in H&E stainings. Multimodal and multiscale optical imaging showed that sonopermeation promoted the accumulation of nanocarriers in mouse brains, and that 10 nm-sized polymeric DDS accumulated more strongly and penetrated deeper into the brain than 100 nm-sized liposomes. Conclusions: BBB opening via sonopermeation enables safe and efficient delivery of nanomedicine formulations to and into the brain. When looking at accumulation and penetration (and when neglecting issues such as drug loading capacity and therapeutic efficacy) smaller-sized DDS are found to be more suitable for drug delivery across the BBB than larger-sized DDS. These findings are valuable for better understanding and further developing nanomedicine-based strategies for the treatment of CNS disorders. © The author(s).
- ItemNoninvasive Assessment of Elimination and Retention using CT-FMT and Kinetic Whole-body Modeling(Wyoming, NSW : Ivyspring, 2017) Al Rawashdeh, Wa'el; Zuo, Simin; Melle, Andrea; Appold, Lia; Koletnik, Susanne; Tsvetkova, Yoanna; Beztsinna, Nataliia; Pich, Andrij; Lammers, Twan; Kiessling, Fabian; Gremse, FelixFluorescence-mediated tomography (FMT) is a quantitative three-dimensional imaging technique for preclinical research applications. The combination with micro-computed tomography (μCT) enables improved reconstruction and analysis. The aim of this study is to assess the potential of μCT-FMT and kinetic modeling to determine elimination and retention of typical model drugs and drug delivery systems. We selected four fluorescent probes with different but well-known biodistribution and elimination routes: Indocyanine green (ICG), hydroxyapatite-binding OsteoSense (OS), biodegradable nanogels (NG) and microbubbles (MB). μCT-FMT scans were performed in twenty BALB/c nude mice (5 per group) at 0.25, 2, 4, 8, 24, 48 and 72 h after intravenous injection. Longitudinal organ curves were determined using interactive organ segmentation software and a pharmacokinetic whole-body model was implemented and applied to compute physiological parameters describing elimination and retention. ICG demonstrated high initial hepatic uptake which decreased rapidly while intestinal accumulation appeared for around 8 hours which is in line with the known direct uptake by hepatocytes followed by hepatobiliary elimination. Complete clearance from the body was observed at 48 h. NG showed similar but slower hepatobiliary elimination because these nanoparticles require degradation before elimination can take place. OS was strongly located in the bones in addition to high signal in the bladder at 0.25 h indicating fast renal excretion. MB showed longest retention in liver and spleen and low signal in the kidneys likely caused by renal elimination or retention of fragments. Furthermore, probe retention was found in liver (MB, NG and OS), spleen (MB) and kidneys (MB and NG) at 72 h which was confirmed by ex vivo data. The kinetic model enabled robust extraction of physiological parameters from the organ curves. In summary, μCT-FMT and kinetic modeling enable differentiation of hepatobiliary and renal elimination routes and allow for the noninvasive assessment of retention sites in relevant organs including liver, kidney, bone and spleen. © Ivyspring International Publisher.
- ItemOptimizing the Geometry of Photoacoustically Active Gold Nanoparticles for Biomedical Imaging(Washington, DC : ACS, 2020) García-Álvarez, Rafaela; Chen, Lisa; Nedilko, Alexander; Sánchez-Iglesias, Ana; Rix, Anne; Lederle, Wiltrud; Pathak, Vertika; Lammers, Twan; von Plessen, Gero; Kostarelos, Kostas; Liz-Marzán, Luis M.; Kuehne, Alexander J.C.; Chigrin, Dmitry N.Photoacoustics is an upcoming modality for biomedical imaging, which promises minimal invasiveness at high penetration depths of several centimeters. For superior photoacoustic contrast, imaging probes with high photothermal conversion efficiency are required. Gold nanoparticles are among the best performing photoacoustic imaging probes. However, the geometry and size of the nanoparticles determine their photothermal efficiency. We present a systematic theoretical analysis to determine the optimum nanoparticle geometry with respect to photoacoustic efficiency in the near-infrared spectral range, for superior photoacoustic contrast. Theoretical predictions are illustrated by experimental results for two of the most promising nanoparticle geometries, namely, high aspect ratio gold nanorods and gold nanostars. Copyright © 2020 American Chemical Society.
- ItemShelf-Life Evaluation and Lyophilization of PBCA-Based Polymeric Microbubbles(Basel : MDPI, 2019) Ojha, Tarun; Pathak, Vertika; Drude, Natascha; Weiler, Marek; Rommel, Dirk; Rütten, Stephan; Geinitz, Bertram; van Steenbergen, Mies J.; Storm, Gert; Kiessling, Fabian; Lammers, TwanPoly(n-butyl cyanoacrylate) microbubbles (PBCA-MB) are extensively employed for functional and molecular ultrasound (US) imaging, as well as for US-mediated drug delivery. To facilitate the use of PBCA-MB as a commercial platform for biomedical applications, it is important to systematically study and improve their stability and shelf-life. In this context, lyophilization (freeze drying) is widely used to increase shelf-life and promote product development. Here, we set out to analyze the stability of standard and rhodamine-B loaded PBCA-MB at three different temperatures (4 °C, 25 °C, and 37 °C), for a period of time of up to 20 weeks. In addition, using sucrose, glucose, polyvinylpyrrolidone (PVP), and polyethylene glycol (PEG) as cryoprotectants, we investigated if PBCA-MB can be lyophilized without affecting their size, concentration, US signal generation properties, and dye retention. Stability assessment showed that PBCA-MB remain largely intact for three and four weeks at 4 °C and 25 °C, respectively, while they disintegrate within one to two weeks at 37 °C, thereby compromising their acoustic properties. Lyophilization analyses demonstrated that PBCA-MB can be efficiently freeze-dried with 5% sucrose and 5% PVP, without changing their size, concentration, and US signal generation properties. Experiments involving rhodamine-B loaded MB indicated that significant dye leakage from the polymeric shell takes place within two to four weeks in case of non-lyophilized PBCA-MB. Lyophilization of rhodamine-loaded PBCA-MB with sucrose and PVP showed that the presence of the dye does not affect the efficiency of freeze-drying, and that the dye is efficiently retained upon MB lyophilization. These findings contribute to the development of PBCA-MB as pharmaceutical products for preclinical and clinical applications.