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Advanced Drug Delivery Reviews (v.64, #15)
Advancing risk assessment of engineered nanomaterials: Application of computational approaches
by Agnieszka Gajewicz; Bakhtiyor Rasulev; Tandabany C. Dinadayalane; Piotr Urbaszek; Tomasz Puzyn; Danuta Leszczynska; Jerzy Leszczynski (pp. 1663-1693).
Nanotechnology that develops novel materials at size of 100nm or less has become one of the most promising areas of human endeavor. Because of their intrinsic properties, nanoparticles are commonly employed in electronics, photovoltaic, catalysis, environmental and space engineering, cosmetic industry and – finally – in medicine and pharmacy. In that sense, nanotechnology creates great opportunities for the progress of modern medicine. However, recent studies have shown evident toxicity of some nanoparticles to living organisms (toxicity), and their potentially negative impact on environmental ecosystems (ecotoxicity). Lack of available data and low adequacy of experimental protocols prevent comprehensive risk assessment. The purpose of this review is to present the current state of knowledge related to the risks of the engineered nanoparticles and to assess the potential of efficient expansion and development of new approaches, which are offered by application of theoretical and computational methods, applicable for evaluation of nanomaterials.Display Omitted
Keywords: Nanomaterials; Nanoparticles; Nanodescriptors; Quantum-chemical methods; Nano-QSAR; Toxicity
Respiratory toxicities of nanomaterials — A focus on carbon nanotubes
by Jorge Boczkowski; Sophie Lanone (pp. 1694-1699).
Carbon nanotubes (CNT) are emblematic nanomaterials, presenting unique physico-chemical properties, such as mechanical, thermal, or electrical conductivity, that have led to a large number of actual applications and uses, as well as (future) developments in aerospace, automobiles, nanoelectronic, or nanomedicine. CNT are currently used in many devices (computers, aircraft airframe, and sporting goods such as tennis rackets, bicycles, golf irons) and have also emerged as efficient drug delivery carriers in the biomedical and drug delivery fields[1]. Because of these actual and future applications, there's an increasing concern regarding the consequences that could result from human exposure to CNT, particularly at the respiratory level, since it represents a major route of exposure to nanomaterials.This review will highlight the advancement in the actual knowledge on lung toxicities of CNT, and try to better understand the underlying biological mechanisms, as well as the importance of physico-chemical determinants directly related to CNT characteristics.Display Omitted
Keywords: Carbon nanotubes; Lung; Oxidative stress; Inflammation; Protein corona; Degradation; Biopersistence; Systemic translocation; Nanomedcine
Perspectives on carbon nanotube-mediated adverse immune effects
by Alina J. Andersen; Peter P. Wibroe; S. Moein Moghimi (pp. 1700-1705).
Carbon nanotubes are entities of different morphology and aspect ratios with anisotropic character. Due to their unique electronic, photonic, mechanical and chemical properties, carbon nanotubes are receiving increasing attention in nanomedicine research where examples include site-specific drug and nucleic acid delivery, photodynamic therapy and photoacoustic molecular imaging. The interaction of carbon nanotubes with the immune system, which plays a key role in the recognition and elimination of foreign materials, and consequential responses, is of central importance for the proposed successful biomedical applications of nanotubes. Research in this avenue, however, is scant and the limited available data are rather contradictory. In this progress article we have collected some of the most important experimental results obtained thus far on carbon nanotube-mediated immune toxicity with an emphasis on cardiovascular exposure, including activation of the complement system, macrophage recognition and clearance, and overall effects on the functionality of different immune cells. Mapping these immune-related risks as well as understanding their molecular mechanisms is a crucial step in the development of any carbon nanotube-containing nanopharmaceuticals.Display Omitted
Keywords: Complement system; Cytokines; Immune cells; Macrophage; Pharmacokinetics; Single-walled carbon nanotubes; Multi-walled carbon nanotubes
A porcine model of complement-mediated infusion reactions to drug carrier nanosystems and other medicines
by János Szebeni; Bedocs Péter Bedőcs; Csukas Domokos Csukás; László Rosivall; Rolf Bünger; Rudolf Urbanics (pp. 1706-1716).
Intravenous administration of low (milligram) doses of nanoparticulate materials in pigs can lead to acute cardiopulmonary, hemodynamic, hematological, biochemical and dermatological changes within minutes, mimicking the human infusion (or anaphylactoid) reactions to many state-of-the‐art (nano)medicines and biologicals. Because of the causal role of complement (C) activation, the phenomenon was called C activation-related pseudoallergy (CARPA). This review summarizes the available information on porcine CARPA caused by different liposomes and polymers. It provides methodical details of the model and addresses the quantitation, sensitivity, specificity, reproducibility and variability of symptoms caused by different reactogenic drugs. We describe a unique feature of the model: the rise of tachyphylaxis (self-induced tolerance) as a function of structural properties of reactogenic agents. For drugs that cause tachyphylactic CARPA, such as liposomal doxorubicin (Doxil), the review recapitulates a recently reported method of desensitization, which may prevent this, as well as many similar hypersensitivity reactions. In explaining the underlying mechanism of tachyphylactic CARPA, a new theory on “double hit” is outlined, wherein the pulmonary intravascular macrophages (PIM cells) of pigs give aggravated response to simultaneous stimulation of their anaphylatoxin and other surface receptors (e.g., toll-like, PAMP, DAMP or mannose) that recognize vesicle surface molecular patterns. The porcine CARPA model might provide unique advantages in studying the mechanism of severe hypersensitivity reactions in man to i.v. drugs, as well as in identifying drugs and drug carriers that may cause such reactions.Display Omitted
Keywords: Adverse drug effects; Anaphylactic shock; Animal models; Circulation; Immune toxicity; Nanomedicines; (Pseudo)allergy; PIM cells
Polycation-based nanoparticle delivery of RNAi therapeutics: Adverse effects and solutions
by Ballarin-Gonzalez Borja Ballarín-González; Kenneth Alan Howard (pp. 1717-1729).
Small interfering RNA (siRNA) that silence genes by the process of RNA interference offers a new therapeutic modality for disease treatment. Polycation-based nanoparticles termed polyplexes have been developed to maximise extracellular and intracellular siRNA delivery, a key requirement for enabling the clinical translation of RNAi-based drugs. Medical applications are dependent on safety; therefore, detailed investigation into potential toxicity to the cell or organism is required. This review addresses potential adverse effects arising from cellular and tissue interactions, immune stimulation and altered gene expression that can be associated with the assembled polyplex or the polycation and siRNA component parts. A greater understanding of the cellular mechanisms involved allows design-based solutions for rationale development of safe, effective and clinically relevant polyplex-based RNAi drugs.Display Omitted
Keywords: RNA interference; siRNA; Polycation; Nanoparticles; Polyplex; Toxicity; Immune stimulation; Chemical modifications; Biodistribution
Safety profile of RNAi nanomedicines
by Scott A. Barros; Jared A. Gollob (pp. 1730-1737).
The emerging class of RNA interference (RNAi) therapeutics is a fundamentally novel approach to treating human disease by enabling the pursuit of molecular targets considered “undruggable” by small molecules and traditional protein therapeutics. A key challenge toward realizing the full potential of this technology is the safe and efficient delivery of siRNA to target tissues. The physical chemical properties of siRNAs preclude passive diffusion across most cell membranes. For systemic administration, novel delivery systems are required to confer “drug-like” pharmacokinetic and pharmacodynamic properties. Engineered nanomaterials and the emerging field of nanomedicine are important drivers of turning the promise of RNAi therapeutics into reality. The current clinical progress of systemically administered siRNA therapeutics is reviewed, with special attention to the toxicity profiles associated with RNAi nanomedicines. As a case study, the preclinical development of ALN-VSP, the first lipid nanoparticle (LNP)-formulated siRNA therapeutic to be tested in cancer patients, is reviewed to broadly highlight some of the preclinical safety challenges and areas of investigation for “next generation” LNP systems.Display Omitted
Keywords: Small interfering RNA; Nanotoxicology; SNALP; Preclinical toxicology; Immunostimulation; Complement activation
Immunotoxicity derived from manipulating leukocytes with lipid-based nanoparticles
by Dan Peer (pp. 1738-1748).
Lipid-based nanoparticles (LNPs) such as liposomes, micelles, and hybrid systems (e.g. lipid-polymer) are prominent delivery vehicles that already made an impact on the lives of millions around the globe. A common denominator of all these LNP‐based platforms is to deliver drugs into specific tissues or cells in a pathological setting with minimal adverse effects on bystander cells. All these platforms must be compatible to the physiological environment and prevent undesirable interactions with the immune system. Avoiding immune stimulation or suppression is an important consideration when developing new strategies in drug and gene delivery, whereas in adjuvants for vaccine therapies, immune activation is desired. Therefore, profound understanding of how LNPs elicit immune responses is essential for the optimization of these systems for various biomedical applications. Herein, I describe general concepts of the immune system and the interaction of subsets of leukocytes with LNPs. Finally, I detail the different immune toxicities reported and propose ways to manipulate leukocytes’ functions using LNPs.Display Omitted
Keywords: Abbreviations; mAb; monoclonal antibody; BD; biodistribution; DOTAP; N; -[1-(2,3-dioleoyloxy)-propyl]-; N; ,; N; ,; N; - trimethylammonium methylsulfate; DOTMA; 3b-[; N; -(; N; ′,; N; ′-dimethy lainin(ethyl) carbamoyl; dsRNA; double stranded ribonucleic acid; EPR; enhanced permeability and retention; I.V; intravenous; miRNA; micro ribonucleic acid; MPS; mononuclear phagocytic system; MW; molecular weight; NLR; Nod‐like receptors; NP; nanoparticle; nt; nucleotide; PEG; polyethylene glycol; PEI; polyethyleneimine; PC; phosphatidylcholine; PK; pharmacokinetics; RES; reticuloendothelial system; RISC; RNA-induced silencing complex; RNA; ribonucleic acid; shRNA; short hairpin ribonucleic acid; siRNA; small interfering RNA; SNALP; stable lipid-nucleic acid particle; T; 1/2; half time; T; H; T helper lymphocytes; TLR; Toll-like receptorLipid-based nanoparticles; Liposomes; Immune response; Leukocytes; RNAi; T cells; Antigen-presenting cells
Cationic lipids activate intracellular signaling pathways
by Caroline Lonez; Michel Vandenbranden; Jean-Marie Ruysschaert (pp. 1749-1758).
Cationic liposomes are commonly used as a transfection reagent for DNA, RNA or proteins and as a co-adjuvant of antigens for vaccination trials. A high density of positive charges close to cell surface is likely to be recognized as a signal of danger by cells or contribute to trigger cascades that are classically activated by endogenous cationic compounds. The present review provides evidence that cationic liposomes activate several cellular pathways like pro-apoptotic and pro-inflammatory cascades. An improved knowledge of the relationship between the cationic lipid properties (nature of the lipid hydrophilic moieties, hydrocarbon tail, mode of organization) and the activation of these pathways opens the way to the use and design of cationic tailored for a specific application (e.g. for gene transport or as adjuvants).Display Omitted
Keywords: Cationic lipids; Signaling; MAPK; Apoptosis; Immunostimulatory; CD14
On the roles of polyvalent binding in immune recognition: Perspectives in the nanoscience of immunology and the immune response to nanomedicines
by Thomas Vorup-Jensen (pp. 1759-1781).
Immunology often conveys the image of large molecules, either in the soluble state or in the membrane of leukocytes, forming multiple contacts with a target for actions of the immune system. Avidity names the ability of a polyvalent molecule to form multiple connections of the same kind with ligands tethered to the same surface. Polyvalent interactions are vastly stronger than their monovalent equivalent. In the present review, the functional consequences of polyvalent interactions are explored in a perspective of recent theoretical advances in understanding the thermodynamics of such binding. From insights on the structural biology of soluble pattern recognition molecules as well as adhesion molecules in the cell membranes or in their proteolytically shed form, this review documents the prominent role of polyvalent interactions in making the immune system a formidable barrier to microbial infection as well as constituting a significant challenge to the application of nanomedicines.Display Omitted
Keywords: Polyvalent binding; Avidity; Adhesion molecules; Integrins; Immunoglobulins; Mannan-binding lectin; Nanotoxicology
Risks and untoward toxicities of antibody-based immunoconjugates
by Dana Litvak-Greenfeld; Itai Benhar (pp. 1782-1799).
Antibody-based immunoconjugates are specifically targeted monoclonal antibodies that deliver a cytotoxic payload to their target. The cytotoxic agents can be highly potent drugs, radionuclides or toxins. Such molecules, referred to as antibody–drug conjugates, radioimmunoconjugates and immunotoxins, respectively, represent a promising approach for enhancing the efficacy of unconjugated (naked) antibodies for improved therapeutic results. Though tremendous progress has been achieved over the last few decades, the safety of these molecules still remains a matter of concern and a careful design is required for achieving a relatively safe toxicity profile along with therapeutic effectiveness. This review focuses on the toxicities arising from the use of these potent agents.Antibody-based conjugates are beneficial when they act on target (tumor) cells. However, they may cause side effects and untoward toxicities when they act off-target.Display Omitted
Keywords: Abbreviations; ADAs; anti-drug antibodies; ADC; antibody–drug conjugate; ADCC; antibody-dependent cellular cytotoxicity; AEs; adverse events; ALCL; anaplastic large cell lymphoma; ALT; alanine transaminase; ALP; alkaline phosphatase; AST; aspartate transaminase; ATL; adult T-cell leukemia; CDC; complement-dependent cytotoxicity; CLL; chronic lymphocytic leukemia; CR; complete remission; CTCL; cutaneous T-cell lymphoma; DLT; dose-limiting toxicity; dsFv; disulfide-stabilized variable fragment; DT; diphtheria toxin; EF2; elongation factor 2; FDA; Food and Drug Administration; Fv; variable fragment; GI; gastrointestinal; GVHD; graft versus-host disease; HAMA; human anti-mouse antibodies; HL; Hodgkin's lymphoma; HUS; hemolytic uremic syndrome; IC; immunoconjugate; IL-2; interleukin-2; IT; immunotoxin; i.v.; intravenous; Le; Y; Lewis-Y; mAb; monoclonal antibody; MDS; myelodysplastic syndrome; MMAE; monomethyl auristatin E; MTD; maximum tolerated dose; NHL; non-Hodgkin's lymphoma; ORR; objective response rate; PE; Pseudomonas; exotoxin A; PR; partial remission; QOD; every other day; RIC; radioimmunoconjugate; RIT; radioimmunotherapy; RTA; ricin toxin A chain; SCT; stem cell transplantation; TCL; T-cell lymphoma; TSH; thyroid stimulating hormone; VOD; veno-occlusive diseaseAntibody–drug conjugates; Radioimmunoconjugates; Immunotoxins; Adverse events; Toxicity; Monoclonal antibody; Targeted therapy
Biocompatibility assessment of Si-based nano- and micro-particles
by Hamsa Jaganathan; Biana Godin (pp. 1800-1819).
Silicon is one of the most abundant chemical elements found on the Earth. Due to its unique chemical and physical properties, silicon based materials and their oxides ( e.g. silica) have been used in several industries such as building and construction, electronics, food industry, consumer products and biomedical engineering/medicine. This review summarizes studies on effects of silicon and silica nano- and micro-particles on cells and organs following four main exposure routes, namely, intravenous, pulmonary, dermal and oral. Further, possible genotoxic effects of silica based nanoparticles are discussed. The review concludes with an outlook on improving and standardizing biocompatibility assessment for nano- and micro-particles.This review summarizes studies on effects of silicon and silica nano- and micro-particles on cells and organs following four main exposure routes: intravenous, pulmonary, dermal and oral.Display Omitted
Keywords: Abbreviations; APTES; 3-Aminopropyltriethoxysilane; ELISA; Enzyme-linked Immunosorbent Assay; GI; Gastrointestinal; HMVEC; Human Micro-Vasculature Endothelial Cells; HUVEC; Human Umbilical Cord Vascular Endothelial Cells; ICP-AES; Inductively Coupled Plasma Atomic Emission Spectroscopy; ICP-OES; Inductively Coupled Plasma Atomic Emission Spectrometry; ICP-MS; Inductively Coupled Plasma Mass Spectrometry; LBL; Layer-by-layer; LDH; Lactate dehydrogenase assay; MSDS; Material Safety Data Sheet; MSV; Multistage Vector; MTS; Cell Viability assay using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium; MTT; Cell Viability assay using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NCI; National Cancer Institute; NIR; Near Infrared; NIST; National Institute of Standards and Technology; NP; Nanoparticles; pSi; Porous Silicon; pSiO; Porous Silica; RBC; Red Blood Cells; RES; Reticuloendothelial system; ROS; Reactive Oxygen Species; SC; Stratum Corneum; Si; Silicon; SiC; Silicon Carbide; SiO; Silica; WST-1 or WST-8; Cell Viability assay using 2-(4-Iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, monosodium salt or 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium; XTT; Cell Viability assay using 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilideSilicon; Silica; Nanomaterials; Biocompatibility; Toxicity; Mesoporous
The influence of nanostructured materials on biointerfacial interactions
by Peter Koegler; Andrew Clayton; Helmut Thissen; Gil Nonato C. Santos; Peter Kingshott (pp. 1820-1839).
Control over biointerfacial interactions in vitro and in vivo is the key to many biomedical applications: from cell culture and diagnostic tools to drug delivery, biomaterials and regenerative medicine. The increasing use of nanostructured materials is placing a greater demand on improving our understanding of how these new materials influence biointerfacial interactions, including protein adsorption and subsequent cellular responses. A range of nanoscale material properties influence these interactions, and material toxicity. The ability to manipulate both material nanochemistry and nanotopography remains challenging in its own right, however, a more in-depth knowledge of the subsequent biological responses to these new materials must occur simultaneously if they are ever to be affective in the clinic. We highlight some of the key technologies used for fabrication of nanostructured materials, examine how nanostructured materials influence the behavior of proteins and cells at surfaces and provide details of important analytical techniques used in this context.Display Omitted
Keywords: Abbreviations; AFFF; asymmetric-flow field flow fraction; ATR-FTIR; attenuated total reflectance‐Fourier transformed infrared spectroscopy; BAECs; bovine aortic endothelial cells; BCEp; bovine corneal epithelial cells; BMP-2; bone morphogenetic protein 2; BSA; bovine serum albumin; CD; circular dichroism; CL; colloidal lithography; DLS; dynamic light scattering; DPN; dip-pen nanolithography; ECM; extra-cellular matrix; EDTA; ethylenediaminetetraacetic acid; ES-DMA; electrospray-differential mobility analysis; FBGC; foreign body giant cells; HCAI; human carbonic anhydrase I; HSA; human serum albumin; IgG; immunoglobulin G; IL-1β; interleukin 1 beta; LSPR; localized surface plasmon resonance; MRI; magnetic resonance imaging; MSC; mesenchymal stem cells; OPN; osteopontin; PCA; principal component analysis; PLGA; poly(lactic-co-glycolic acid); PEG; poly(ethylene glycol); PEGMA; poly(ethylene glycol methacrylate); PDMS; poly(dimethylsiloxane); PEO; poly(ethylene oxide); PLA; poly(; l; -lactic acid); SAM; self‐assembled monolayer; SC; subtilisin Carlsberg; SERS; surface-enhanced Raman scattering/spectroscopy; SPL; scanning probe lithography; SWCNT; single-walled carbon nanotubes; TIRF; total-internal reflection fluorescence; TNF-α; tumor necrosis factor α; ToF-SIMS; time-of-flight secondary ion mass spectrometry; UV; ultra-violet; XPS; X-ray photoelectron spectroscopyProtein adsorption; Cell adhesion; Toxicology; Chemical surface modification; Nanofabrication; Protein conformation; Nanoparticle
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