Optimization-by-design of hepatotropic lipid nanoparticles targeting the sodium-taurocholate cotransporting polypeptide

Witzigmann, Dominik; Uhl, Philipp; Sieber, Sandro; Kaufman, Christina L.; Einfalt, Tomaz; Schöneweis, Katrin; Grossen, Philip; Buck, Jonas; Ni, Yi; Schenk, Susanne; Hußner, Janine; Schwabedissen, Henriette E. Meyer zu; Québatte, Gabriela; Mier, Walter; Urban, Stephan; Huwyler, Jörg

doi:10.7554/elife.42276

Cited by 26 publications

(34 citation statements)

References 76 publications

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“…To this end, the embryonic zebrafish has provided an invaluable pre-clinical in vivo screening platform, offering unprecedented opportunities to assess, analyse and optimise nanoparticle behaviour over an entire live organism (i.e. visualising total injected doses), at cellular resolution and in real time 42,60,61 . Furthermore, the presence and conserved function of key RES cell types enables predictive assessment of fundamentally important in vivo clearance mechanisms of nanoparticles 25,43 .…”

Section: Discussionmentioning

confidence: 99%

Light-triggered switching of liposome surface charge directs delivery of membrane impermeable payloads in vivo

et al. 2020

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Surface charge plays a fundamental role in determining the fate of a nanoparticle, and any encapsulated contents, in vivo. Herein, we describe, and visualise in real time, light-triggered switching of liposome surface charge, from neutral to cationic, in situ and in vivo (embryonic zebrafish). Prior to light activation, intravenously administered liposomes, composed of just two lipid reagents, freely circulate and successfully evade innate immune cells present in the fish. Upon in situ irradiation and surface charge switching, however, liposomes rapidly adsorb to, and are taken up by, endothelial cells and/or are phagocytosed by blood resident macrophages. Coupling complete external control of nanoparticle targeting together with the intracellular delivery of encapsulated (and membrane impermeable) cargos, these compositionally simple liposomes are proof that advanced nanoparticle function in vivo does not require increased design complexity but rather a thorough understanding of the fundamental nano-bio interactions involved.

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Section: Discussionmentioning

confidence: 99%

Light-triggered switching of liposome surface charge directs delivery of membrane impermeable payloads in vivo

et al. 2020

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“…Dox was excited at 488 nm argon laser and CellMask was excited with a 633 nm. [42] Zebrafish Pharmacokinetic Studies: Embryos from Tg(kdrl:eGFP) and Tg(AB/Tübingen) adult zebrafish (Danio rerio) were breaded at 28 °C in zebrafish culture media containing 30.4 ug mL −1 1-phenyl-2-thiourea (PTU) and maintained according to Swiss animal welfare regulations. Embryos were embedded in 0.3% agarose containing tricaine and PTU and injected with a calibrated volume of 1 nL into Duct of Cuvier (48 h post fertilization, hpf) and cardinal vein (72 hpf) using a micromanipulator (Wagner Instrumentenbau KG), a pneumatic Pico Pump PV830 (WPI) and a Leica S8APO microscope (Leica).…”

Section: Methodsmentioning

confidence: 99%

“…Quantitative image analysis was performed as previously described. [34,42] Dox Release Studies in Zebrafish Embryos: 48 hpf embryos from Tg(abc/ tu) were injected with 2 nL of 3 mg mL −1 Dox containing LNPs into the duct of Cuvier and incubated at 28 °C in PTU containing zebrafish culture media. 24 hpi, one set of zebrafish was irradiated with pulsedlight for additional 24 h. For quantitative analysis, confocal images of five fishes were processed applying a defined threshold, followed by area calculation in Fiji (ImageJ) 2.1.0.…”

Section: Methodsmentioning

confidence: 99%

Optimized Photoactivatable Lipid Nanoparticles Enable Red Light Triggered Drug Release

Chander

Bolten

Shemet

et al. 2021

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Encapsulation of small molecule drugs in long‐circulating lipid nanoparticles (LNPs) can reduce toxic side effects and enhance accumulation at tumor sites. A fundamental problem, however, is the slow release of encapsulated drugs from these liposomal systems at the disease site resulting in limited therapeutic benefit. Methods to trigger release at specific sites are highly warranted. Here, it is demonstrated that incorporation of ultraviolet (UV‐A) or red‐light photoswitchable‐phosphatidylcholine analogs (AzoPC and redAzoPC) in conventional LNPs generates photoactivatable LNPs (paLNPs) having comparable structural integrity, drug loading capacity, and size distribution to the parent DSPC‐cholesterol liposomes. It is shown that 65–70% drug release (doxorubicin) can be induced from these systems by irradiation with pulsed light based on trans‐to‐cis azobenzene isomerization. In vitro it is confirmed that paLNPs are non‐toxic in the dark but convey cytotoxicity upon irradiation in a human cancer cell line. In vivo studies in zebrafish embryos demonstrate prolonged blood circulation and extravasation of paLNPs comparable to clinically approved formulations, with enhanced drug release following irradiation with pulsed light. Conclusively, paLNPs closely mimic the properties of clinically approved LNPs with the added benefit of light‐induced drug release making them promising candidates for clinical development.

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“…For decades, the specific target of HBV on the sinusoidal membrane of hepatocytes was unknown until the interaction of the virus with the human sodium-taurocholate cotransporting polypeptide (NTCP/SLC10A1) was identified [ 137 ]. Witzigmann et al modified synthetic lipid-based nanoparticles with targeting peptides derived from the hepatitis B virus large envelope protein (HBVpreS) to specifically target NTCP/SLC10A1 on the sinusoidal membrane of hepatocytes [ 138 ]. NTCP-specific, ligand-dependent binding and internalization were confirmed in vitro.…”

Section: Transporter-targeted Ndds For Other Indicationsmentioning

confidence: 99%

Transporter-Targeted Nano-Sized Vehicles for Enhanced and Site-Specific Drug Delivery

Kou

Yao

Zhang

et al. 2020

Cancers

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Nano-devices are recognized as increasingly attractive to deliver therapeutics to target cells. The specificity of this approach can be improved by modifying the surface of the delivery vehicles such that they are recognized by the target cells. In the past, cell-surface receptors were exploited for this purpose, but plasma membrane transporters also hold similar potential. Selective transporters are often highly expressed in biological barriers (e.g., intestinal barrier, blood–brain barrier, and blood–retinal barrier) in a site-specific manner, and play a key role in the vectorial transfer of nutrients. Similarly, selective transporters are also overexpressed in the plasma membrane of specific cell types under pathological states to meet the biological needs demanded by such conditions. Nano-drug delivery systems could be strategically modified to make them recognizable by these transporters to enhance the transfer of drugs across the biological barriers or to selectively expose specific cell types to therapeutic drugs. Here, we provide a comprehensive review and detailed evaluation of the recent advances in the field of transporter-targeted nano-drug delivery systems. We specifically focus on areas related to intestinal absorption, transfer across blood–brain barrier, tumor-cell selective targeting, ocular drug delivery, identification of the transporters appropriate for this purpose, and details of the rationale for the approach.

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Optimization-by-design of hepatotropic lipid nanoparticles targeting the sodium-taurocholate cotransporting polypeptide

Cited by 26 publications

References 76 publications

Light-triggered switching of liposome surface charge directs delivery of membrane impermeable payloads in vivo

Light-triggered switching of liposome surface charge directs delivery of membrane impermeable payloads in vivo

Optimized Photoactivatable Lipid Nanoparticles Enable Red Light Triggered Drug Release

Transporter-Targeted Nano-Sized Vehicles for Enhanced and Site-Specific Drug Delivery

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