Clearance Of Nanoparticles Research Articles

Accelerated Blood Clearance of Lipid Nanoparticles Entails a Biphasic Humoral Response of B-1 Followed by B-2 Lymphocytes to Distinct Antigenic Moieties.

Accelerated blood clearance (ABC) is a phenomenon in which certain pharmaceutical agents are rapidly cleared from the blood upon second and subsequent administrations. ABC has been observed for many lipid-delivery vehicles, including liposomes and lipid nanoparticles (LNP). Previous studies have demonstrated a role for humoral responses against the polyethylene glycol motifs in clearance, but significant gaps remain in our understanding of the mechanism of ABC, and strategies for limiting the impact of ABC in a clinical setting have been elusive. mRNA therapeutics have great promise, but require chronic administration in encapsulating delivery systems, of which LNP are the most clinically advanced. In this study, we investigate the mechanisms of ABC for mRNA-formulated LNP in vivo and in vitro. We present evidence that ABC of mRNA-formulated LNP is dramatic and proceeds rapidly, based on a previously unrecognized ability of LNP to directly activate B-1 lymphocytes, resulting in the production of antiphosphorylcholine IgM Abs in response to initial injection. Upon repeated injections, B-2 lymphocytes also become activated and generate a classic anti-polyethylene glycol adaptive humoral response. The ABC response to phosphorylcholine/LNP-encapsulated mRNA is therefore a combination of early B-1 lymphocyte and later B-2 lymphocyte responses.

On measuring nanoparticle toxicity and clearance with Paramecium caudatum

As the extent to which aquatic environments are polluted with nano-scale objects is becoming known, we are presented with an urgent need to study their effects on various forms of life and to clear and/or detoxify them. A range of methods exist to these ends, but a lack of inter-study comparability arising from an absence of experimental standardisation impedes progress. Here we present experiments that demonstrate measurement of orchestrated uptake and clearance of two environmentally-relevant nano- and micromaterials by a model aquatic microoraganism, Paramecium caudatum. Experiments were based on a simple, modular, multi-chamber platform that permits standardised control of organism behaviour and measurement of variables relevant to the study of nanotoxicology, including nanomaterial chemotaxis assays, bioaccumulation and deleterious effects on cell motility systems. Uptake of internalised materials may be estimated through the addition of a low-cost fluorescence spectrometer. P. caudatum cells can clear an estimated 0.7 fg of contaminant materials (or 161 of the particles used) per cell over a 5 mm distance per 6 hour experiment, whilst suffering few short-term adverse effects, suggesting that the organism and the platform used to investigate their properties are well-suited to a range of laboratory and field-based nanotoxicological studies.

Multifunctional low-temperature photothermal nanodrug with in vivo clearance, ROS-Scavenging and anti-inflammatory abilities

Harsh photothermal temperatures, long-term body retention of nanoagents, elevated ROS and inflammation induction all threaten the normal tissues, thus hindering the translation of photothermal therapy (PTT) from bench to clinical practice. To resolve these problems, we have developed a disassembled theranostic nanodrug Qu-FeIIP based on the quercetin coordination. Herein, quercetin is not only the heat shock protein (Hsp 70) inhibitor but also the skeleton of Qu-FeIIP, realizing near-infrared light induced low-temperature PTT (45 °C) to ablate tumor completely without heat stress to normal tissues. Owing to the ROS scavenging ability of quercetin, Qu-FeIIP effectively reduces intracellular ROS and in vivo inflammatory factors (TNF-α, IL-6, IFN-γ) levels. Simultaneously, quercetin-Fe coordination is weakened when scavenging ROS, which triggers the Qu-FeIIP disassembling, resulting in effective clearance of nanoparticles from main organs 168 h post intravenous injection. Additionally, the photoacoustic and magnetic resonance dual-imaging capability of Qu-FeIIP offers excellent spatial resolution and imaging depth not only for precise tumor diagnosis but also for monitoring the nanodrug disassembling in vivo. Thus, Qu-FeIIP intrinsically integrates precise diagnosis, excellent low-temperature PTT efficacy, ROS elimination and anti-inflammatory action, dynamic disassembly and renal clearance ability into a single nanodrug, which is very promising for future clinical cancer treatment.

Copper Sulfide Facilitates Hepatobiliary Clearance of Gold Nanoparticles through the Copper-Transporting ATPase ATP7B.

Metallic gold (Au) nanoparticles have great potential for a wide variety of biomedical applications. Yet, slow clearance of Au nanoparticles significantly hinders their clinical translation. Herein, we describe a strategy of utilizing the endogenous copper (Cu) clearance to improve the elimination of Au nanoparticles. Our mechanistic study reveals that a Cu-transporting P-type ATPase, ATP7B, mediates the exocytosis of CuS nanoparticles into bile canaliculi for their rapid hepatobiliary excretion. The efflux of CuS nanoparticles is adopted to facilitate the hepatobiliary clearance of Au nanoparticles through CuS-Au conjugation. Using two different CuS-Au nanoconjugates, we demonstrate that CuS increases the biliary Au excretion of CuS-Au nanospheres or CuS-Au nanorods in mice or rats in comparison to that of their respective unconjugated Au nanoparticles postintravenous injection. The current CuS-Au conjugation approach provides a feasible strategy to enhance the hepatobiliary clearance of Au nanoparticles that may be applicable to various structures.

Protein Nanoparticle Fabrication for Optimized Reticuloendothelial System Evasion and Tumor Accumulation.

Nanoparticles (NPs) of protein-based materials have become one of the most promising candidates for drug carriers in drug-delivery systems because of their in vivo nontoxicity, biodegradability, compatibility with hydrophilic drugs, and adaptability to the human body. Many studies have investigated the fabrication of protein NPs from human serum albumin (HSA) as a new drug carrier. It is important for these NPs to remain in the blood until they reach their therapeutic target to achieve the desired effect; the quicker the clearance of drugs from the body, the shorter is the residence time of drugs in the body, which eventually reduces drug efficacy. Macrophage uptake is a major mechanism for clearance of NPs from the body, so, reducing the degree of macrophage uptake is a major challenge in drug-delivery systems. Original studies of HSA NP uptake by macrophages showed that denatured HSA and HSA NPs synthesized with 80% (v/v) ethanol showed a high degree of macrophage uptake. We found that HSA NPs synthesized with lower ethanol content at pH 7 showed lower macrophage uptake in in vitro macrophage cellular uptake experiments. The effects of the preparation parameters of ethanol concentration, pH, and glutaraldehyde on the macrophage uptake of NPs were thoroughly studied. This newly developed protein NP with lower macrophage uptake has potential application as a drug carrier for many delivery systems.

Magnetometry based method for investigation of nanoparticle clearance from circulation in a liver perfusion model

Nanoparticles (NPs) are among the most promising agents for advanced theranostics. However, their functioning in vivo is severely inhibited by the mononuclear phagocyte system (MPS), which rapidly removes all foreign entities from blood circulation. Little is known about the sequestration mechanisms and the ways to counteract them. New methods are highly demanded for investigation with high scrutiny of each aspect of NP clearance from blood. For example, while liver macrophages capture the majority of the administered particles, reliable investigation of this process in absence of other MPS components is hard to implement in vivo. Here, we demonstrate a novel method for real-time investigation hepatic uptake of NPs in an isolated perfused liver based on an extremely accurate magnetometric registration technique. The signal is obtained solely from the magnetic NPs without any ‘background’ from blood or tissues, which is a significant advantage over other techniques, e.g. optical ones. We illustrate the method capacity by investigation of behavior of different particles and show good correlation with in vivo studies. We also demonstrate notable suitability of the method for studying the NP clearance from the flow in the user-defined mediums, e.g. those containing specific serum components. Finally, the method was applied to reveal an interesting effect of short-term decrease of liver macrophage activity after the first interaction with small amounts of NPs. The developed perfusion model based on the high-performance magnetometry can be used for finding new mechanisms of NP sequestration and for development of novel ‘stealth’ nanoagents.

Degradability and Clearance of Inorganic Nanoparticles for Biomedical Applications.

Inorganic nanoparticles with tunable and diverse properties hold tremendous potential in the field of nanomedicine, while having non-negligible toxicity concerns in healthy tissues/organs that have resulted in their restricted clinical translation to date. In the past decade, the emergence of biodegradable or clearable inorganic nanoparticles has made it possible to completely solve this long-standing conundrum. A comprehensive understanding of the design of these inorganic nanoparticles with their metabolic performance in the body is of crucial importance to advance clinical trials and expand their biological applications in disease diagnosis. Here, a diverse variety of biodegradable or clearable inorganic nanoparticles regarding considerations of the size, morphology, surface chemistry, and doping strategy are highlighted. Their pharmacokinetics, pathways of metabolism in the body, and time required for excretion are discussed. Some inorganic materials intrinsically responsive to various conditions in the tumor microenvironment are also introduced. Finally, an overview of the encountered challenges is provided along with an outlook for applying these inorganic nanoparticles toward future clinical translations.

Radiolabeled Molecular Imaging Probes for the In Vivo Evaluation of Cellulose Nanocrystals for Biomedical Applications.

Cellulose nanocrystals (CNCs) have remarkable potential to improve the delivery of diagnostic and therapeutic agents to tumors; however, the in vivo studies on CNC biodistribution are still limited. We developed CNC-based imaging probes for the in vitro and in vivo evaluation using two labeling strategies: site-specific hydrazone linkage to the terminal aldehyde of the CNC and nonsite-specific activation using 1,1'-carbonyldiimidazole (CDI). The in vivo behavior of unmodified CNC, DOTA-CNC (ald.), and DOTA-CNC (OH) was investigated in healthy and 4T1 breast cancer mouse models. They displayed good biocompatibility in cell models. Moreover, the biodistribution profile and SPECT/CT imaging confirmed that the accumulation of 111In-labeled DOTA-CNC (ald.) and 111In-DOTA-CNC (OH) was primarily in hepatic, splenic, and pulmonary ducts in accordance with the clearance of nontargeted nanoparticles. The developed CNC imaging probes can be used to obtain information with noninvasive imaging on the behavior in vivo to guide structural optimization for targeted delivery.

Cloaking nanoparticles with protein corona shield for targeted drug delivery

Targeted drug delivery using nanoparticles can minimize the side effects of conventional pharmaceutical agents and enhance their efficacy. However, translating nanoparticle-based agents into clinical applications still remains a challenge due to the difficulty in regulating interactions on the interfaces between nanoparticles and biological systems. Here, we present a targeting strategy for nanoparticles incorporated with a supramolecularly pre-coated recombinant fusion protein in which HER2-binding affibody combines with glutathione-S-transferase. Once thermodynamically stabilized in preferred orientations on the nanoparticles, the adsorbed fusion proteins as a corona minimize interactions with serum proteins to prevent the clearance of nanoparticles by macrophages, while ensuring systematic targeting functions in vitro and in vivo. This study provides insight into the use of the supramolecularly built protein corona shield as a targeting agent through regulating the interfaces between nanoparticles and biological systems.

Accumulation of gold nano-rods in the failing heart of transgenic mice with the cardiac-specific expression of TNF-α.

Gold nano-rods, rod-shaped gold nanoparticles, act as contrast agents for in vivo bioimaging, drug delivery vehicles and thermal converters for photothermal therapy. Pro-inflammatory cytokines play critical roles in the development of heart failure. We examined the delivery of GNRs into the failing heart of a transgenic (TG) mouse model of inflammatory cardiomyopathy with the cardiac-specific overexpression of TNF-α. We modified GNRs with polyethylene glycol (PEG) to avoid cytotoxicity and reduce the rapid clearance of nanoparticles from blood. PEG-modified GNRs (4.5mM as gold atoms, 200 μL) were administered intravenously to TG (n = 7) and wild-type (WT) mice (n = 5). These were killed 24h later, and the heart, lung, liver, kidney and spleen were excised. A quantitative analysis of gold was performed using inductively coupled plasma mass or optical emission spectrometry. The amount of gold (ng) in the TG heart (3.24 ± 1.56ng/mg heart weight) was significantly greater than that in the WT heart (1.01 ± 0.19; p < 0.05). No significant differences were observed among the other organs of TG and WT mice. The amount of gold in the TG heart was significantly and positively correlated with the ratio of the ventricular weight to body weight, which is known to be an index of ventricular hypertrophy. In conclusion, PEG-modified GNRs accumulated in the inflammatory TG heart in proportion with the severity of ventricular hypertrophy.

Transport and interactions of nanoparticles in the kidneys

Kidneys are a major organ for blood filtration and waste elimination and thus play a key role in the transport and clearance of nanoparticles in vivo. The interactions of nanoparticles with different kidney compartments can be precisely regulated by modulating their size, shape and surface chemistry. The quantitative understanding of nanoparticle–kidney interactions at the molecular level is important for improving disease targeting, precisely controlling nanoparticle transport and clearance, and minimizing the potential health hazards of nanomedicines. In this Review, we summarize the glomerular filtration of macromolecules and nanoparticles in the kidney and survey kidney imaging techniques for the study of nanoparticle–kidney interactions ex vivo and in vivo. We investigate the different transport mechanisms of nanoparticles in the kidneys and discuss size, charge and shape dependencies in renal clearance. Nanoparticles are then investigated for the preclinical and clinical detection and treatment of diseases such as kidney dysfunction and cancer. Finally, challenges and opportunities for renal-clearable nanoparticles are highlighted. Interactions of nanoparticles with the kidneys affect their transport, clearance, targeting, therapeutic efficacy and biosafety in the body. This Review discusses nano–bio interactions of nanoparticles in the kidneys and highlights their potential for the detection and treatment of disease.

Nanotechnological foundations of a “new” Nephrology

After contextualizing the generic frameworks of nanotechnology and nanomedicine, the 2 disciplines are discussed in the field of Nephrology. The potential downside to nanonephrology is the renal clearance of nanoparticles, the use of which is ever-increasing both for nanomedicinal purposes and in nanofoods. The positive impact of nanotechnology in Nephrology is centered on the development of renal nanodiagnostics for basic renal function studies, the early diagnosis of acute kidney injury, reliable and simple follow-up of chronic kidney disease and the improvement of magnetic resonance imaging. Renal drug nanotherapies comprise an important and dual-faceted area: the protection of drugs and nephrotoxic agents (e.g. antibiotics, antiretrovirals, contrast media, etc.) on the one hand, and the development of new kidney disease medications on the other. Renal ‘nanotheranostics’ is a promising but little-studied area. The impact of nanostructured supports on renal tissue regeneration is also discussed. The article concludes with a brief analysis of the various nanonephrology perspectives.

Chloroquine and nanoparticle drug delivery: A promising combination.

Clinically approved cancer therapies include small molecules, antibodies, and nanoparticles. There has been major progress in the treatment of several cancer types over recent decades. However, many challenges remain for optimal use of conventional and nanoparticle-based therapies in oncology including poor drug delivery, rapid clearance, and drug resistance. The antimalarial agent chloroquine has been found to mitigate some of these challenges by modulating cancer cells and the tissue microenvironment. Particularly, chloroquine was recently found to reduce immunological clearance of nanoparticles by resident macrophages in the liver, leading to increased tumor accumulation of nanodrugs. Additionally, chloroquine has been shown to improve drug delivery and efficacy through normalization of tumor vasculature and suppression of several oncogenic and stress-tolerance pathways, such as autophagy, that protect cancer cells from cytotoxic agents. This review will discuss the use of chloroquine as combination therapy to improve cancer treatment.

Factors relating to the biodistribution & clearance of nanoparticles & their effects on in vivo application.

Nanoparticles have promising biomedical applications for drug delivery, tumor imaging and tumor treatment. Pharmacokinetics are important for the in vivo application of nanoparticles. Biodistribution and clearance are largely defined as the key points of pharmacokinetics to maximize therapeutic efficacy and to minimize side effects. Different engineered nanoparticles have different biodistribution and clearance processes. The interactions of organs with nanoparticles, which are determined by the characteristics of the organs and the biochemical/physical properties of the nanoparticles, are a major factor influencing biodistribution and clearance. In this review, the clearance functions of organs and the properties related to pharmacokinetics, including nanoparticle size, shape, biodegradation and surface modifications are discussed.

Bases nanotecnológicas de una «nueva» Nefrología

After contextualising the generic frameworks of nanotechnology and nanomedicine, the 2disciplines are discussed in the field of Nephrology. The potential downside to nanonephrology is the renal clearance of nanoparticles, the use of which is ever-increasing both for nanomedicinal purposes and in nanofoods. The positive impact of nanotechnology in Nephrology is centred on the development of renal nanodiagnostics for basic renal function studies, the early diagnosis of acute kidney injury, reliable and simple follow-up of chronic kidney disease and the improvement of magnetic resonance imaging. Renal drug nanotherapies comprise an important and dual-faceted area: The protection of drugs and nephrotoxic agents (e.g. antibiotics, antiretrovirals, contrast media, etc.) on the one hand, and the development of new kidney disease medications on the other. Renal ‘nanotheranostics’ is a promising but little-studied area. The impact of nanostructured supports on renal tissue regeneration is also discussed. The article concludes with a brief analysis of the various nanonephrology perspectives.

Silver nanoparticles promote the emergence of heterogeneic human neutrophil sub-populations

Neutrophil surveillance is central to nanoparticle clearance. Silver nanoparticles (AgNP) have numerous uses, however conflicting evidence exists as to their impact on neutrophils and whether they trigger damaging inflammation. Neutrophil’s importance in innate defence and regulating immune networks mean it’s essential we understand AgNP’s impact on neutrophil function. Human neutrophil viability following AgNP or Ag Bulk treatment was analysed by flow cytometry and AnV/PI staining. Whilst AgNP exposure did not increase the total number of apoptotic neutrophils, the number of late apoptotic neutrophils was increased, suggesting AgNP increase transit through apoptosis. Mature (CD16bright/CD62Lbright), immature (CD16dim/CD62Lbright) and apoptotic (CD16dim/CD62Ldim) neutrophil populations were evident within isolated neutrophil preparations. AgNP exposure significantly reduced CD62L staining of CD16bright/CD62Lbright neutrophils, and increased CD16 staining of CD16dim/CD62Lbright populations, suggesting AgNPs trigger neutrophil activation and maturation, respectively. AgNP exposure dramatically increased IL-8, yet not classical pro-inflammatory cytokine release, suggesting AgNP triggers neutrophil activation, without pro-inflammation or damaging, necrotic cell death. For the first time, we show AgNPs differentially affect distinct sub-populations of circulating human neutrophils; activating mature neutrophils with the emergence of CD16bright/CD62Ldim neutrophils. This may stimulate particle clearance without harmful inflammation, challenging previous assumptions that silver nanomaterials induce neutrophil toxicity and damaging inflammatory responses.

Cell membrane coating for reducing nanoparticle-induced inflammatory responses to scaffold constructs.

The controlled release of therapeutics from micro or nanoparticles has been well-studied. Incorporation of these particles inside biomaterial scaffolds is promising for tissue regeneration and immune modulation. However, these particles may induce inflammatory and foreign body responses to scaffold constructs, limiting their applications. Here we show that widely used poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs) formed by double emulsion dramatically increased neutrophil infiltration and pro-inflammatory cytokines in alginate scaffolds 1 day after the subcutaneous injection of the scaffolds into mice. The coating of red blood cell (RBC) membranes on PLGA NPs completely eliminated these short-term inflammatory responses. For a longer term of 10 days, neither PLGA NPs nor RBC membrane-coated nanoparticles exerted a significant effect on the infiltration of neutrophils or macrophages in alginate scaffolds possibly due to the degradation and/or clearance of nanoparticles by infiltrating cells by that time. Despite the extensive exploration of cell membrane-coated nanoparticles, our study is the first to investigate the effects of cell membrane coating on foreign body reaction to nanoparticles. Harnessing the natural biocompatibility of cell membranes, our strategy of anti-inflammatory protection for scaffolds may be pivotal for many applications, such as those relying on the recruitment of stem cells and/or progenitor cells to scaffolds.

New Avenues for Nanoparticle-Related Therapies

Development of nanoparticle-based drug delivery systems has been attempted for the treatment of cancer over the past decade. The enhanced permeability and retention (EPR) effect is the major mechanism to passively deliver nanodrugs to tumor tissue. However, a recent systematic review demonstrated limited success of these studies, with the clearance of nanoparticles by the mononuclear phagocytic system (MPS) being a major hurdle. Herein, we propose that nanotechnologists should reconsider their research focuses, aiming for therapeutic targets other than cancer. Treatments for diseases that do not (or less) rely on EPR should be considered, such as active targeting or MPS evasion systems. For example, systemic delivery of drugs through intravenous injection can be used to treat sepsis, multi-organ failure, metabolic disorders, blood diseases, immune and autoimmune diseases, etc. Local delivery of nanodrugs to organs such as the lung, rectum, or bladder may enhance the local drug concentration with less clearance via MPS. In transplant settings, ex vivo organ perfusion provides a new route to repair injury of isolated organs in the absence of MPS. Based on a similar concept, chemotherapy with in vivo lung perfusion techniques and other isolated organ perfusion provides opportunities for cancer therapy.

Precision Nanomedicine Volume 1 Issue 1 Table of Contents

The inaugural issue is introduced by several editorials: "The Story of Precision Nanomedicine-the Journal", "Balancing Interests of Science, Scientists, and the Publishing Business", and "Improving Innovation in Nano-Healthcare Funding". The Clinical Editor's comments on research papers: Prec. Nanomed. 2018, Apr; 1(1):18-42. Extracellular vesicles (EVs) are involved in various biological processes such as cargo trafficking, cell-cell communication, and signal transduction. The advances in nanotechnology have enabled researchers to utilize EVs for potential use in clinical applications, within the so-called precision medicine approach. In this review article, the authors discuss the techniques used in EV isolation in length, together with their applications in clinical diagnosis and therapeutics. Prec. Nanomed. 2018 Apr;1(1):63-75. Due to potential hypersensitivity reactions to nanodrugs, thorough testing is required before these drugs can be used in the clinical setting. Here the authors provide a succinct review on the use of pigs as a reliable in-vivo model for pre-clinical drug testing. Prec. Nanomed. 2018 Apr;1(1):76-85. One of the ways that nanoparticles are cleared in the body is via Kupffer cells. The authors of the next paper tested the role of scavenger receptor SR-AI/II in the clearance of dextran superparamagnetic iron oxide (SPIO) Feridex-IV® and dextran-coated SPIO nanoworms (SPIO NWs). Results here show that multiple pathways and mechanisms exist in nanoparticle clearance. Thus, further understanding of nanoparticle clearance would be required to prolong in vivo half-life. Prec. Nanomed. 2018 Apr;1(1):43-62. Liposomes have been used in clinical practice for some years, this delivery system often result in significant systemic effects due to hypersensitivity reactions, via the activation of the complement system. The authors here show good biocompatibility of Rad-PC-Rad liposomes in terms of complement activation and pro-inflammatory cytokines production in-vitro.

Translational gaps in animal models of human infusion reactions to nanomedicines.

Adverse infusion reactions to regulatory approved nanomedicines in human subjects are idiosyncratic, but outwardly reproducible in pigs. A large body of evidence suggests that the porcine reactions are related to robust nanoparticle clearance by pulmonary intravascular macrophages (PIMs), and rapid release of arachidonate metabolites from these cells. Similar to pigs, other animals that have resident PIMs in their lungs also respond to intravenously injected particles, where rapid particle clearance by PIMs correlate with peak periods of cardiopulmonary distress. Normal human lungs, however, do not have PIMs, but 'induced' PIMs have been identified in pulmonary circulation under certain pathological conditions. We question suitability, and limitation of these preclinical models for global assessment of nanomedicine safety, and discuss alternative models and approaches.