Abstract Macrophage recognition of nanoparticles is highly influenced by particle size and surface modification. Due to the lack of appropriate in vivo screening models, it is still challenging and time-consuming to characterize and optimize nanomedicines regarding this undesired clearance mechanism. Therefore, we validate zebrafish embryos as an emerging vertebrate screening tool to assess the macrophage sequestration of surface modified particulate formulations with varying particle size under realistic biological conditions. Liposomes with different PEG molecular weights (PEG350-PEG5000) at different PEG densities (3.0-10.0 mol%) and particle sizes between 60 and 120 nm were used as a well-established reference system showing various degrees of macrophage uptake. The results of in vitro experiments, zebrafish embryos, and in vivo rodent biodistribution studies were consistent, highlighting the validity of the newly introduced zebrafish macrophage clearance model. We hereby present a strategy for efficient, systematic and rapid nanomedicine optimization in order to facilitate the preclinical development of nanotherapeutics.
Liposomes have attracted much attention as the first nanoformulations entering the clinic. The optimization of physicochemical properties of liposomes during nanomedicine development however is time-consuming and challenging despite great advances in formulation development. Here, we present a systematic approach for the rapid size optimization of liposomes. The combination of microfluidics with a design-of-experiment (DoE) approach offers a strategy to rapidly screen and optimize various liposo...
The enhanced permeability and retention (EPR) effect is the only described mechanism enabling nanoparticles (NPs) flowing in blood to reach tumors by a passive targeting mechanism. Here, using the transparent zebrafish model infected with Mycobacterium marinum we show that an EPR-like process also occurs allowing different types of NPs to extravasate from the vasculature to reach granulomas that assemble during tuberculosis (TB) infection. PEGylated liposomes and other NP types cross endothelial...
Up to 99% of systemically administered nanoparticles are cleared through the liver. Within the liver, most nanoparticles are thought to be sequestered by macrophages (Kupffer cells), although significant nanoparticle interactions with other hepatic cells have also been observed. To achieve effective cell-specific targeting of drugs through nanoparticle encapsulation, improved mechanistic understanding of nanoparticle–liver interactions is required. Here, we show the caudal vein of the embryonic ...
Last. Jörg Huwyler(University of Basel)H-Index: 49
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Abstract Nanomedicines have gained much attention for the delivery of small molecules or nucleic acids as treatment options for many diseases. However, the transfer from experimental systems to in vivo applications remains a challenge since it is difficult to assess their circulation behavior in the body at an early stage of drug discovery. Thus, innovative and improved concepts are urgently needed to overcome this issue and to close the gap between empiric nanoparticle design, in vitro assessme...
Last. Joy Wolfram(Houston Methodist Hospital)H-Index: 30
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Abstract The liver is a major barrier for site-specific delivery of systemically injected nanoparticles, as up to 90% of the dose is usually captured by this organ. Kupffer cells are thought to be the main cellular component responsible for nanoparticle accumulation in the liver. These resident macrophages form part of the mononuclear phagocyte system, which recognizes and engulfs foreign bodies in the circulatory system. In this study, we have compared two strategies for reducing nanoparticle a...
Last. Jörg Huwyler(University of Basel)H-Index: 49
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Enzyme immobilization is of high interest for industrial applications. However, immobilization may compromise enzyme activity or stability due to the harsh conditions which have to be applied. The authors therefore present a new and improved crosslinked layer-by-layer (cLbL) approach. Two different model enzymes (acid phosphatase and beta-galactosidase) are immobilized under mild conditions on biocompatible, monodisperse, sub-micrometer poly(lactide-coglycolide) (PLGA) particles. The resulting P...
#1Shahed Behzadi(Brigham and Women's Hospital)H-Index: 13
#2Vahid Serpooshan(Cardiovascular Institute of the South)H-Index: 25
Last. Morteza Mahmoudi(Tehran University of Medical Sciences)H-Index: 85
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Nanoscale materials are increasingly found in consumer goods, electronics, and pharmaceuticals. While these particles interact with the body in myriad ways, their beneficial and/or deleterious effects ultimately arise from interactions at the cellular and subcellular level. Nanoparticles (NPs) can modulate cell fate, induce or prevent mutations, initiate cell–cell communication, and modulate cell structure in a manner dictated largely by phenomena at the nano–bio interface. Recent advances in ch...
Last. Morteza Mahmoudi(Tehran University of Medical Sciences)H-Index: 85
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Despite the advances in biomedical applications of nanoparticle (NP) and numerous publications, few NPs have made it to clinical trials and even fewer have reached clinical practice. This wide gap between bench discoveries and clinical applications is mainly because of our limited understanding of the biological identity of NPs. In physiological environments, NPs are coated by a ‘protein corona' (PC), critically affecting physiological and therapeutic responses. To date, nearly all studies attem...
Summary Liver sinusoidal endothelial cells (LSECs) are highly specialized endothelial cells representing the interface between blood cells on the one side and hepatocytes and hepatic stellate cells on the other side. LSECs represent a permeable barrier. Indeed, the association of ‘fenestrae', absence of diaphragm and lack of basement membrane make them the most permeable endothelial cells of the mammalian body. They also have the highest endocytosis capacity of human cells. In physiological cond...
Delivering drugs to the brain has always remained a challenge for the research community and physicians. The blood-brain barrier (BBB) acts as a major hurdle for delivering drugs to specific parts of the brain and the central nervous system. It is physiologically comprised of complex network of capillaries to protect the brain from any invasive agents or foreign particles. Therefore, there is an absolute need for understanding of the BBB for successful therapeutic interventions. Recent research ...
New nanoparticles and biomaterials are increasingly being used in biomedical research for drug delivery, diagnostic applications, or vaccines, and they are also present in numerous commercial products, in the environment and workplaces. Thus, the evaluation of the safety and possible therapeutic application of these nanomaterials has become of foremost importance for the proper progress of nanotechnology. Due to economical and ethical issues, in vitro and in vivo methods are encouraged for the t...
Last. Jörg Huwyler(University of Basel)H-Index: 49
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Recently, a lipopeptide derived from the hepatitis B virus (HBV) large surface protein has been developed as an HBV entry inhibitor. This lipopeptide, called MyrcludexB (MyrB), selectively binds to the sodium taurocholate cotransporting polypeptide (NTCP) on the basolateral membrane of hepatocytes. Here, the feasibility of coupling therapeutic enzymes to MyrB was investigated for the development of enzyme delivery strategies. Hepatotropic targeting shall enable enzyme prodrug therapies and detox...
#1Julian Vogler(UBC: University of British Columbia)H-Index: 1
#2Roland Böttger(UBC: University of British Columbia)H-Index: 3
Last. Shyh-Dar Li(UBC: University of British Columbia)H-Index: 32
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We demonstrated that phospholipid-free small unilamellar vesicles (PFSUVs) composed of TWEEN 80 and cholesterol (25/75, mol%) could be fabricated using a staggered herringbone micromixer with precise controlling of their mean size between 54 nm and 147 nm. Increasing the temperature or decreasing the flow rate led to an increase in the resulting particle diameter. In zebrafish embryos, 120-nm PFSUVs showed 3-fold higher macrophage clearance compared to the 60-nm particles, which exhibited prolon...
Last. Bernard Verrier(CNRS: Centre national de la recherche scientifique)H-Index: 47
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Abstract In the development of therapeutic nanoparticles (NP), there is a large gap between in vitro testing and in vivo experimentation. Despite its prominence as a model, the mouse shows severe limitations for imaging NP and the cells with which they interact. Recently, the transparent zebrafish larva, which is well suited for high-resolution live-imaging, has emerged as a powerful alternative model to investigate the in vivo behavior of NP. Poly(D,L lactic acid) (PLA) is widely accepted as a ...
Last. Ying Zheng(UM: University of Macau)H-Index: 28
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Understanding the behaviors of nanomedicines in vivo is one of the most important prerequisites for the design and optimization of nanomedicines. However, the in vivo tracking of nanomedicines in rodents is severely limited by the restricted imaging possibilities within these animals. To meet these needs, the FRET (fluorescence or Forster resonance energy transfer) imaging combined with visual zebrafish larvae model (7 dpf) was used to study the behaviors of polymeric micelles in vivo at high sp...
Cellular delivery of DNA vectors for the expression of therapeutic proteins is a promising approach to treat monogenic disorders or cancer. Significant efforts in a preclinical and clinical setting have been made to develop potent nonviral gene delivery systems based on lipoplexes composed of permanently cationic lipids. However, transfection efficiency and tolerability of such systems are in most cases not satisfactory. Here, we present a one-pot combinatorial method based on double-reductive a...
#1Giulia Anderluzzi(Strathclyde Institute of Pharmacy and Biomedical Sciences)H-Index: 5
#2Yvonne Perrie(Strathclyde Institute of Pharmacy and Biomedical Sciences)H-Index: 43
Solid lipid nanoparticles are lipid-based carriers and that can be used for a range of drugs and biomolecules. However, most manufacturing methods currently used do not offer easy translation from laboratory to scale-independent production. Within this study, we have investigated the use of microfluidics to produce solid lipid nanoparticles and investigated their protein loading capability. In the development of the process we have investigated and identified the critical process parameters that...
Last. Jörg Huwyler(University of Basel)H-Index: 49
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Metal-based nanoparticles are clinically used for diagnostic and therapeutic applications. After parenteral administration, they will distribute throughout different organs. Quantification of their distribution within tissues in the 3D space, however, remains a challenge owing to the small particle diameter. In this study, synchrotron radiation-based hard X-ray tomography (SRμCT) in absorption and phase contrast modes is evaluated for the localization of superparamagnetic iron oxide nanoparticle...