Targeting distinct myeloid cell populations in vivo using polymers, liposomes and microbubbles

Ergen, Can; Heymann, Felix; Rawashdeh, Wa’el Al; Gremse, Felix; Bartneck, Matthias; Panzer, Ulf; Pola, Robert; Pechar, Michal; Storm, Gert; Mohr, Nicole; Barz, Matthias; Zentel, Rudolf; Kießling, Fabian; Trautwein, Christian; Lammers, Twan; Tacke, Frank

doi:10.1016/j.biomaterials.2016.11.009

Cited by 66 publications

(83 citation statements)

References 76 publications

(93 reference statements)

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“…PBCA-based MB have a short blood-half-life and accumulate in the lungs, liver and spleen within minutes as determined using radio-labeling 29. While the retention in the lungs is temporary (a few minutes), MB remain in the liver and spleen for several days due to their slow degradation 28-30. Degradation products are soluble in water and can be eliminated through kidney filtration 28.…”

Section: Methodsmentioning

confidence: 99%

Noninvasive Assessment of Elimination and Retention using CT-FMT and Kinetic Whole-body Modeling

et al. 2017

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Fluorescence-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.

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Section: Methodsmentioning

confidence: 99%

Noninvasive Assessment of Elimination and Retention using CT-FMT and Kinetic Whole-body Modeling

et al. 2017

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“…Thus, mannosylated core crosslinked particles are easily accessible. This was done because mannose is a target for the mannose receptor, which is characteristic for immune cells like dendritic cells or macrophages …”

Section: Resultsmentioning

confidence: 99%

Size Tunable Core Crosslinked Micelles from HPMA‐Based Amphiphilic Block Copolymers

Krämer

Kim

Zentel

2017

Macro Chemistry & Physics

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A variety of core crosslinkable hydroxypropylmethacrylamide‐based block copolymers are synthesized by reversible addition‐fragmentation chain transfer (RAFT) polymerization, which are composed of hydroxypropyl‐methacrylate as hydrophilic block combined with a statistical hydrophobic block from laurylmethacrylate and the photo crosslinkable monomer. It is discovered that the self‐assembled micellar aggregates from these systems vary strongly in size depending not only on the velocity of the polarity switch (nanoprecipitation or slow dialysis) but also on the solvent from which they were dialyzed. In this way micellar aggregates with an Rh varying between 15 and 80 nm can be prepared from the same block copolymer. In addition, a new hydrophobic crosslinkable hymecromone moiety is introduced. In this way the differently sized nanoparticles can be effectively stabilized by photo‐crosslinking, leading to a high stability of the photo crosslinkable polymeric micelles against disintegration by detergents.

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“…Further modifications via mono primary amines are possible at this stage, like the incorporation of fluorescent dyes for labeling or mannose linkage for improved cell targeting . Even peptide or drug functionalization is possible like the introduction of TLR 7/8 agonists for immune stimulation (Figure A) .…”

Section: Synthesis Of Cationic Nanohydrogel Particlesmentioning

confidence: 99%

“…First in vitro studies on HeLa cells revealed that cationic nanohydrogel particles undergo size‐dependent intracellular distributions shown in Figure 8 . Bigger NPs with hydrodynamic diameters ( D h ) of 100 nm were directed to lysosomal compartments where degradation of the cargo siRNA probably occurs instantaneously.…”

Section: Knockdown Potential Of Sirna‐loaded Cationic Nanohydrogel Pamentioning

confidence: 99%

“…Thus, during self‐assembly of the block copolymers into micelles followed by transformation into cationic nanohydrogels, these functionalities will always remain accessible at the outer shell for the recognition of its targets. This approach has already been used successfully to immobilize peptide antigens for vaccination (see below), but further synthetic attempts are currently in progress to target M2 macrophages for alternative liver fibrosis therapeutics or antigen‐presenting cells (e.g., dendritic cells) for vaccination …”

Section: Sirna‐loaded Cationic Nanohydrogel Particles For Liver Fibromentioning

confidence: 99%

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Cationic Nanohydrogel Particles for Therapeutic Oligonucleotide Delivery

Leber

Nuhn

Zentel

2017

Macromolecular Bioscience

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Short pharmaceutical active oligonucleotides such as small interfering RNA (siRNA) or cytidine‐phosphate‐guanosine (CpG) are considered as powerful therapeutic alternatives, especially to medicate hard‐to‐treat diseases (e.g., liver fibrosis or cancer). Unfortunately, these molecules are equipped with poor pharmacokinetic properties that prevent them from translation. Well‐defined nanosized carriers can provide opportunities to optimize their delivery and guide them to their site of action. Among several concepts, this Feature Article focuses on cationic nanohydrogel particles as a universal delivery system for small anionic molecules including siRNA and CpG. Cationic nanohydrogels are derived from preaggregated precursor block copolymers, which are further cross‐linked to obtain well‐defined nanoparticles of tunable sizes and with (degradable) cationic cores. Novel opportunities for oligonucleotide delivery in vitro and in vivo with respect to liver fibrosis therapies will be highlighted as well as perspectives toward modulating the immune system. In general, the approach of covalently stabilized cationic carrier systems can contribute to find advanced oligonucleotide therapeutics.

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Targeting distinct myeloid cell populations in vivo using polymers, liposomes and microbubbles

Cited by 66 publications

References 76 publications

Noninvasive Assessment of Elimination and Retention using CT-FMT and Kinetic Whole-body Modeling

Noninvasive Assessment of Elimination and Retention using CT-FMT and Kinetic Whole-body Modeling

Size Tunable Core Crosslinked Micelles from HPMA‐Based Amphiphilic Block Copolymers

Cationic Nanohydrogel Particles for Therapeutic Oligonucleotide Delivery

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