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![Structural and functional organization of the liver. A) Anatomy of the liver and its blood supply. The vessel (red) represents the hepatic artery that delivers oxygenated blood from the general circulation. The vessel (blue) represents the hepatic portal vein that delivers deoxygenated blood from the small intestine containing nutrients. The vessel (green) represents the bile duct that carries bile from the liver and gallbladder to the duodenum. B) Schematic of a liver lobule in a hexagonal shape with rows of hepatocytes radiating out from the central vein toward the portal triad. C) Schematic demonstrates the blood flow of the liver via the portal vein and hepatic artery through the sinusoids to the central vein. A lobule could be divided into three zones, zone 1 (periportal), zone 2 (transition zone), and zone 3 (pericentral) based on oxygen gradient from high to low. D) Schematic sinusoids that receive blood from terminal branches of the hepatic artery and portal vein at the periphery of lobules and drain into central veins (red arrow), and the bile ducts that carry bile from the liver and gallbladder to the duodenum (green arrow). Sinusoids are lined with endothelial cells and flanked by plates of hepatocytes. E) Schematic shows the cross‐section of a liver lobule and the flow direction of blood and bile. F) Spatial map to demonstrate flow velocities within the virtual sinusoid network. The red and yellow colors indicate a greater flow velocity while the blue color represents a lower flow velocity. Color bar units indicate µm s⁻¹. (A,B) Reproduced with permission.[³⁵] Copyright 2018, The Authors. Published by De Gruyter; (C) Reproduced with permission.[⁴⁴] Copyright 2010, Nature Publishing Group; (D) Reproduced under terms of the CC‐BY license.[³⁹] Copyright 2005, The Authors. Published by PLOS; (E) Courtesy of Bio Ninja (https://ib.bioninja.com.au/options/option-d-human-physiology/d3-functions-of-the-liver/liver-structure.html) and used with permission; (F) Reproduced under terms of the CC‐BY license.[⁴⁰] Copyright 2018, The Authors. Published by PLOS.](publication/357857717/figure/fig2/AS:11431281173296342@1688826015003/Structural-and-functional-organization-of-the-liver-A-Anatomy-of-the-liver-and-its.png)
Structural and functional organization of the liver. A) Anatomy of the liver and its blood supply. The vessel (red) represents the hepatic artery that delivers oxygenated blood from the general circulation. The vessel (blue) represents the hepatic portal vein that delivers deoxygenated blood from the small intestine containing nutrients. The vessel (green) represents the bile duct that carries bile from the liver and gallbladder to the duodenum. B) Schematic of a liver lobule in a hexagonal shape with rows of hepatocytes radiating out from the central vein toward the portal triad. C) Schematic demonstrates the blood flow of the liver via the portal vein and hepatic artery through the sinusoids to the central vein. A lobule could be divided into three zones, zone 1 (periportal), zone 2 (transition zone), and zone 3 (pericentral) based on oxygen gradient from high to low. D) Schematic sinusoids that receive blood from terminal branches of the hepatic artery and portal vein at the periphery of lobules and drain into central veins (red arrow), and the bile ducts that carry bile from the liver and gallbladder to the duodenum (green arrow). Sinusoids are lined with endothelial cells and flanked by plates of hepatocytes. E) Schematic shows the cross‐section of a liver lobule and the flow direction of blood and bile. F) Spatial map to demonstrate flow velocities within the virtual sinusoid network. The red and yellow colors indicate a greater flow velocity while the blue color represents a lower flow velocity. Color bar units indicate µm s⁻¹. (A,B) Reproduced with permission.[³⁵] Copyright 2018, The Authors. Published by De Gruyter; (C) Reproduced with permission.[⁴⁴] Copyright 2010, Nature Publishing Group; (D) Reproduced under terms of the CC‐BY license.[³⁹] Copyright 2005, The Authors. Published by PLOS; (E) Courtesy of Bio Ninja (https://ib.bioninja.com.au/options/option-d-human-physiology/d3-functions-of-the-liver/liver-structure.html) and used with permission; (F) Reproduced under terms of the CC‐BY license.[⁴⁰] Copyright 2018, The Authors. Published by PLOS.
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Nanomaterials (NMs) are widely used in commercial and medical products, such as cosmetics, vaccines, and drug carriers. Exposure to NMs via various routes such as dermal, inhalation, and ingestion has been shown to gain access to the systemic circulation, resulting in the accumulation of NMs in the liver. The unique organ structures and blood flow...
Citations
... The accumulation in the liver and kidney can be attributed to the unique structural and blood flow features of these organs, which facilitate nanoparticle sequestration. 46,47 Additionally, MPB-3BP@CM NPs exhibit a high affinity to CD47-expressing normal tissue cells owing to the presence of MSIRPα on their surface. However, it is noteworthy that Cy5.5-labeled MPB-3BP@CM NPs exhibited the highest tumor accumulation compared to the other groups. ...
Cell membrane-camouflaged nanoparticles possess inherent advantages derived from their membrane structure and surface antigens, including prolonged circulation in the bloodstream, specific cell recognition and targeting capabilities, and potential for immunotherapy. Herein, we introduce a cell membrane biomimetic nanodrug platform termed MPB-3BP@CM NPs. Comprising microporous Prussian blue nanoparticles (MPB NPs) serving as both a photothermal sensitizer and carrier for 3-bromopyruvate (3BP), these nanoparticles are cloaked in a genetically programmable cell membrane displaying variants of signal regulatory protein α (SIRPα) with enhanced affinity to CD47. As a result, MPB-3BP@CM NPs inherit the characteristics of the original cell membrane, exhibiting an extended circulation time in the bloodstream and effectively targeting CD47 on the cytomembrane of colorectal cancer (CRC) cells. Notably, blocking CD47 with MPB-3BP@CM NPs enhances the phagocytosis of CRC cells by macrophages. Additionally, 3BP, an inhibitor of hexokinase II (HK 2 ), suppresses glycolysis, leading to a reduction in adenosine triphosphate (ATP) levels and lactate production. Besides, it promotes the polarization of tumor-associated macrophages (TAMs) towards an anti-tumor M1 phenotype. Furthermore, integration with MPB NPs-mediated photothermal therapy (PTT) enhances the therapeutic efficacy against tumors. These advantages make MPB-3BP@CM NPs an attractive platform for the future development of innovative therapeutic approaches for CRC. Concurrently, it introduces a universal approach for engineering disease-tailored cell membranes for tumor therapy.
... The reason for the preferential accumulation in the liver could be that liver is the site where detoxification of metabolites takes place and it is here that their interconversion happens. Besides this, the physicochemical properties of nanoparticles such as their size (200-230 nm), negative charge and spherical shape may further facilitate its passive diffusion [26]. The free drug on the other hand is already known to have limited solubility and bioavailability. ...
Sorafenib, a multikinase inhibitor, is used for the treatment of advanced stages of hepatic and renal carcinoma patients. However, sorafenib’s low solubility, low bioavailability, unfavorable pharmacokinetic properties, and undesirable side effects are barriers that restrict its utility. This study aims to overcome these problems by encapsulating sorafenib in a novel camel milk casein nanoparticles. Calcium chloride–linked casein nanoparticles were prepared, lyophilized, and characterized for size distribution, zeta potential, and polydispersity index by using a zeta sizer. Drug encapsulation efficiency and drug loading efficiency of these nanoparticles were also determined by UV spectroscopy. Further, in vivo pharmacokinetic and biodistribution studies were conducted in healthy Swiss albino mice. Bioanalytical method was developed by HPLC for quantitative evaluation of the drug in mice plasma, liver, lungs, kidney, heart, and spleen. Multiple pharmacokinetic parameters like T1/2, AUC, clearance, etc. were analyzed through Phoenix Winolin software. Our pharmacokinetic study showed that sorafenib encapsulation within casein nanoparticles (SFN-CasNPs) significantly increased its bioavailability, as exhibited by an enhanced Cmax (3.8-fold) and AUC (1.42-fold). Also, the half-life (t1/2)) of the encapsulated drug increased by 2 h as compared to free drug. Furthermore, biodistribution study showed an increased accumulation of SFN-CasNPs in the liver and kidney as compared to all other tissues, whereas the free drug showed its maximum accumulation in the heart indicating cardiotoxicity. This accumulation of sorafenib was significantly reduced when it was encapsulated within the camel milk casein nanoparticle. This study has highlighted the significance of using camel milk casein nanoparticles for drug delivery owing to an enhanced bioavailability of the sorafenib in an encapsulated form. The reduced accumulation of sorafenib in an encapsulated form also indicates a reduced risk of cardiotoxicity. In the future, clinical trials may be performed on hepatocellular caricinoma patients, after enhancing the selectivity of the drug towards the liver.
... Metal oxides, including CuO and ZnO nanoparticles, can enter organisms through skin contact, inhalation, and ingestion. [58][59][60] In industrial environments, inhalation is the primary pathway of human exposure to metal oxide nanoparticles. [61] Following inhalation, metal oxide nanoparticles, including CuO and ZnO, enter the alveolar region of the lungs, come into contact with the alveolar epithelium, and penetrate the lung epithelial barrier. ...
Understanding the environmental health and safety of nanomaterials (NanoEHS) is essential for the sustained development of nanotechnology. Although extensive research over the past two decades has elucidated the phenomena, mechanisms, and implications of nanomaterials in cellular and organismal models, the active remediation of the adverse biological and environmental effects of nanomaterials remains largely unexplored. Inspired by recent developments in functional amyloids for biomedical and environmental engineering, this work shows their new utility as metallothionein mimics in the strategically important area of NanoEHS. Specifically, metal ions released from CuO and ZnO nanoparticles are sequestered through cysteine coordination and electrostatic interactions with beta‐lactoglobulin (bLg) amyloid, as revealed by inductively coupled plasma mass spectrometry and molecular dynamics simulations. The toxicity of the metal oxide nanoparticles is subsequently mitigated by functional amyloids, as validated by cell viability and apoptosis assays in vitro and murine survival and biomarker assays in vivo. As bLg amyloid fibrils can be readily produced from whey in large quantities at a low cost, the study offers a crucial strategy for remediating the biological and environmental footprints of transition metal oxide nanomaterials.
... NP sequestration by the liver is one of the main biological barriers, accumulating up to 99% of the injected dose and, thus, preventing the delivery of nanomedicines to the desired target (43,44). Several studies using different kinds of inorganic NPs indicated that these are mostly taken up by hepatic nonparenchymal cells, such as liver macrophages (Kupffer cells) and liver sinusoidal endothelial cells, rather than by the predominant constituents of the liver (parenchymal hepatocytes) (44). ...
... NP sequestration by the liver is one of the main biological barriers, accumulating up to 99% of the injected dose and, thus, preventing the delivery of nanomedicines to the desired target (43,44). Several studies using different kinds of inorganic NPs indicated that these are mostly taken up by hepatic nonparenchymal cells, such as liver macrophages (Kupffer cells) and liver sinusoidal endothelial cells, rather than by the predominant constituents of the liver (parenchymal hepatocytes) (44). Furthermore, the flow dynamics of the liver sinusoid favors the NP uptake (29). ...
Nanoparticles (NPs) are currently developed for drug delivery and molecular imaging. However, they often get intercepted before reaching their target, leading to low targeting efficacy and signal-to-noise ratio. They tend to accumulate in organs like lungs, liver, kidneys, and spleen. The remedy is to iteratively engineer NP surface properties and administration strategies, presently a time-consuming process that includes organ dissection at different time points. To improve this, we propose a rapid iterative approach using whole-animal x-ray fluorescence (XRF) imaging to systematically evaluate NP distribution in vivo. We applied this method to molybdenum-based NPs and clodronate liposomes for tumor targeting with transient macrophage depletion, leading to reduced accumulations in lungs and liver and eventual tumor detection. XRF computed tomography (XFCT) provided 3D insight into NP distribution within the tumor. We validated the results using a multiscale imaging approach with dye-doped NPs and gene expression analysis for nanotoxicological profiling. XRF imaging holds potential for advancing therapeutics and diagnostics in preclinical pharmacokinetic studies.
... NMs have been widely used in commercial and medical products, such as cosmetics, vaccines, diagnostics, and drug carriers. Most studies have reported that exposure to NMs via various routes, such as dermal, inhalation, and ingestion, tends to result in accumulation in the liver after gaining access to the systemic circulation [1,2]. For instance, Fischer et al. found that the liver took up about 40-99% of quantum dots after administration into Sprague Dawley rats [3]. ...
... The effects of the physicochemical properties of GO on the transport and clearance of GO in the lung and kidney have been systematically investigated in our previous work and by others [17][18][19]. Understanding the hepatic clearance of graphene oxide is crucial for its safe medical application [2,20]. However, so far, the final fate of GO in the liver is not yet fully understood. ...
... Understanding the hepatic clearance of nanomaterials (NMs) is crucial for the development of safer NMs in the biomedical field [2]. Previous studies have reported that the unique structures and blood flow features of the liver facilitate the sequestration and accumulation of NMs, potentially leading to adverse effects in the liver [21]. ...
Understanding the final fate of nanomaterials (NMs) in the liver is crucial for their safer application. As a representative two-dimensional (2D) soft nanomaterial, graphene oxide (GO) has shown to have high potential for applications in the biomedical field, including in biosensing, drug delivery, tissue engineering, therapeutics, etc. GO has been shown to accumulate in the liver after entering the body, and thus, understanding the GO–liver interaction will facilitate the development of safer bio-applications. In this study, the hepatic clearance of two types of PEGylated GOs with different lateral sizes (s-GOs: ~70 nm and l-GOs: ~300 nm) was carefully investigated. We found that GO sheets across the hepatic sinusoidal endothelium, which then may be taken up by the hepatocytes via the Disse space. The hepatocytes may degrade GO into dot-like particles, which may be excreted via the hepatobiliary route. In combination with ICP-MS, LA-ICP-MS, and synchrotron radiation FTIR techniques, we found that more s-GO sheets in the liver were prone to be cleared via hepatobiliary excretion than l-GO sheets. A Raman imaging analysis of ID/IG ratios further indicated that both s-GO and l-GO generated more defects in the liver. The liver microsomes may contribute to GO biotransformation into O-containing functional groups, which plays an important role in GO degradation and excretion. In particular, more small-sized GO sheets in the liver were more likely to be cleared via hepatobiliary excretion than l-GO sheets, and a greater clearance of s-GO will mitigate their hepatotoxicity. These results provide a better understanding of the hepatic clearance of soft NMs, which is important in the safer-by-design of GO.
... However, most tumor-targeted modalities exhibit merely limited enhancement of the targeting effect. The possible reasons include that (1) the widely used tumor-targeted ligands are not tumor-specific, and their receptors usually express normal tissues; (2) 30-99 % of intravenously administered NPs will accumulate and sequester in the liver; [134] and (3) dense extracellular matrix (ECM) surrounding the cancer cells prevents the penetration of delivery vehicles. [135] Therefore, it is urgent to explore tumorspecific targets and ligands, reduce liver residence and enhance the tumor penetration of delivery vehicles. ...
Nanodelivery systems (NDSs) provide promising prospects for decreasing drug doses, reducing side effects, and improving therapeutic effects. However, the bioapplications of NDSs are still compromised by their fast clearance, indiscriminate biodistribution, and limited tumor accumulation. Hence, engineering modification of NDSs aiming at promoting tumor‐specific therapy and avoiding systemic toxicity is usually needed. An NDS integrating various functionalities, including flexible camouflage, specific biorecognition, and sensitive stimuli‐responsiveness, into one sequence would be “smart” and highly effective. Herein, we systematically summarize the related principles, methods, and progress. At the end of the review, we predict the obstacles to precise nanoengineering and prospects for the future application of NDSs.
... injection and subsequent increase signal in the tumor can be attributed to the presence of fenestrations in liver sinusoidal endothelial cells, allowing nanoparticles within the 50-200 nm size range to transiently exit hepatocytes and reenter the bloodstream. [49,50] Systemic biodistribution of Hf, analyzed via ICP-MS, showed a 2.9-fold higher in-tratumoral Hf accumulation in the RPB7H group compared to PPB7H nanoparticles at 24 h postinjection, aligning with the ex vivo imaging results (Figure 4d). ...
Radiation therapy (RT) is one of the primary options for clinical cancer therapy, in particular advanced head and neck squamous cell carcinoma (HNSCC). Herein, the crucial role of bromodomain‐containing protein 4 (BRD4)‐RAD51 associated protein 1 (RAD51AP1) axis in sensitizing RT of HNSCC is revealed. A versatile nanosensitizer (RPB7H) is thus innovatively engineered by integrating a PROteolysis TArgeting Chimeras (PROTAC) prodrug (BPA771) and hafnium dioxide (HfO2) nanoparticles to downregulate BRD4‐RAD51AP1 pathway and sensitize HNSCC tumor to RT. Upon intravenous administration, the RPB7H nanoparticles selectively accumulate at the tumor tissue and internalize into tumor cells by recognizing neuropilin‐1 overexpressed in the tumor mass. HfO2 nanoparticles enhance RT effectiveness by amplifying X‐ray deposition, intensifying DNA damage, and boosting oxidative stress. Meanwhile, BPA771 can be activated by RT‐induced H2O2 secretion to degrade BRD4 and inactivate RAD51AP1, thus impeding RT‐induced DNA damage repair. This versatile nanosensitizer, combined with X‐ray irradiation, effectively regresses HNSCC tumor growth in a mouse model. The findings introduce a PROTAC prodrug‐based radiosensitization strategy by targeting the BRD4‐RAD51AP1 axis, may offer a promising avenue to augment RT and more effective HNSCC therapy.
... Of note, other corona ligand-cell receptor interactions have also been shown to promote LNP-mRNA uptake in the liver 95 and, although LDLR-ApoE interactions are not exclusive to the liver, they are further enabled by liver physiology: 10-15% of the total blood volume reaches the liver through the hepatic artery and portal vein, of which 60% is in small capacitance sinusoids 96 . There, decreased blood flow slows down the transport of nanoparticles 97 and allows them to interface with and be taken up by hepatocytes and non-parenchymal cells (for example, Kupffer cells, stellate cells and endothelial cells) 98 . Taken together, hepatic physiology and biomolecular corona-mediated cellular uptake of LNP-mRNA particles enable the passive targeting of the liver at the expense of extrahepatic biodistribution. ...
... When toxicities are observed, investigative in vivo, in vitro and ex vivo experiments aim to understand the underlying mechanisms and ideally improve the design of formulations in development. This section discusses studies on the immunopathogenicity and hepatic or splenic toxicity of LNP-encapsulated IVT mRNA as the main safety concerns with mRNA-based drugs and vaccines in preclinical development 15,98,112 . Unless otherwise noted, only studies on modified and/or dsRNA-purified mRNA are considered. ...
... Owing to pronounced hepatic and splenic biodistribution of LNP-mRNA, microscopic observations and histopathology of the liver and spleen are standard practice during preclinical development. Acute drug-induced liver injury is routinely evaluated by measuring blood plasma levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (APT) 98,113 . Expectedly, most publicly available studies promoting LNP-mRNA therapeutic applications report only minor pathological findings. ...
mRNA formulated with lipid nanoparticles is a transformative
technology that has enabled the rapid development and administration
of billions of coronavirus disease 2019 (COVID-19) vaccine doses
worldwide. However, avoiding unacceptable toxicity with mRNA
drugs and vaccines presents challenges. Lipid nanoparticle structural
components, production methods, route of administration and
proteins produced from complexed mRNAs all present toxicity
concerns. Here, we discuss these concerns, specifically how cell
tropism and tissue distribution of mRNA and lipid nanoparticles can
lead to toxicity, and their possible reactogenicity. We focus on adverse
events from mRNA applications for protein replacement and gene
editing therapies as well as vaccines, tracing common biochemical and
cellular pathways. The potential and limitations of existing models
and tools used to screen for on-target efficacy and de-risk off-target
toxicity, including in vivo and next-generation in vitro models, are also
discussed.
... phase and the results showed that the addition of DSPE-PEG 2k -CS solution made the particle size to be higher than 200 nm and the nanoparticles tended to aggregate, which demonstrated that CS-NPs/VDG prepared by film hydration might not be suitable to deliver drugs to liver. [37] Therefore, ethanol injection method was used to prepare CS-NPs/VDG and good stability was obtained. Moreover, owing to that DSPE-PEG 2k -GA showed poor solubility in aqueous phase and ethanol, we prepared GA-NPs/SIB by film hydration instead of ethanol injection. ...
During liver fibrogenesis, the reciprocal crosstalk among capillarized liver sinusoidal endothelial cells (LSECs), activated hepatic stellate cells (HSCs), and dysfunctional hepatocytes constructs a self‐amplifying vicious cycle, greatly exacerbating the disease condition and weakening therapeutic effect. Limited by the malignant cellular interactions, the previous single‐cell centric treatment approaches show unsatisfactory efficacy and fail to meet clinical demand. Herein, a vicious cycle‐breaking strategy is proposed to target and repair pathological cells separately to terminate the malignant progression of liver fibrosis. Chondroitin sulfate‐modified and vismodegib‐loaded nanoparticles (CS‐NPs/VDG) are designed to efficiently normalize the fenestrae phenotype of LSECs and restore HSCs to quiescent state by inhibiting Hedgehog signaling pathway. In addition, glycyrrhetinic acid‐modified and silybin‐loaded nanoparticles (GA‐NPs/SIB) are prepared to restore hepatocytes function by relieving oxidative stress. The results show successful interruption of vicious cycle as well as distinct fibrosis resolution in two animal models through multiregulation of the pathological cells. This work not only highlights the significance of modulating cellular crosstalk but also provides a promising avenue for developing antifibrotic regimens.
... PROTACs escape the endosome and are released into the cytoplasm, where they function to target and degrade key target proteins. in vivo studies (108,109) and underscores the need for further optimization of in vivo target delivery. ...
PROTACs (proteolysis targeting chimeras) are an emerging precision medicine strategy that targets key proteins for proteolytic degradation to ultimately induce cancer cell killing. These hetero-bifunctional molecules hijack the ubiquitin proteasome system to selectively add polyubiquitin chains onto a specific protein target to induce proteolytic degradation. Importantly, PROTACs have the capacity to target virtually any intracellular and transmembrane protein for degradation, including oncoproteins previously considered undruggable, which strategically positions PROTACs at the crossroads of multiple cancer research areas. In this review, we present normal functions of the ubiquitin regulation proteins and describe the application of PROTACs to improve the efficacy of current broad-spectrum therapeutics. We subsequently present the potential for PROTACs to exploit specific cancer vulnerabilities through synthetic genetic approaches, which may expedite the development, translation and utility of novel synthetic genetic therapies in cancer. Finally, we describe the challenges associated with PROTACs and the ongoing efforts to overcome these issues to streamline clinical translation. Ultimately, these efforts may lead to their routine clinical use, which is expected to revolutionize cancer treatment strategies, delay familial cancer onset and ultimately improve the lives and outcomes of those living with cancer.
