Assorted challenges in physicochemical characterization, sterilization, depyrogenation, and in the assessment of pharmacology, safety, and efficacy profiles accompany pre-clinical development of ...nanotechnology-formulated drugs. Some of these challenges are not unique to nanotechnology and are common in the development of other pharmaceutical products. However, nanoparticle-formulated drugs are biochemically sophisticated, which causes their translation into the clinic to be particularly complex. An understanding of both the immune compatibility of nanoformulations and their effects on hematological parameters is now recognized as an important step in the (pre)clinical development of nanomedicines. An evaluation of nanoparticle immunotoxicity is usually performed as a part of a traditional toxicological assessment; however, it often requires additional in vitro and in vivo specialized immuno- and hematotoxicity tests. Herein, I review literature examples and share the experience with the NCI Nanotechnology Characterization Laboratory assay cascade used in the early (discovery-level) phase of pre-clinical development to summarize common challenges in the immunotoxicological assessment of nanomaterials, highlight considerations and discuss solutions to overcome problems that commonly slow or halt the translation of nanoparticle-formulated drugs toward clinical trials. Special attention will be paid to the grand-challenge related to detection, quantification and removal of endotoxin from nanoformulations, and practical considerations related to this challenge.
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Nanoparticle immunogenicity and antigenicity have been under investigation for many years. During the past decade, significant progress has been made in understanding what makes a nanoparticle ...immunogenic, how immune cells respond to nanoparticles, what consequences of nanoparticle-specific antibody formation exist and how they challenge the application of nanoparticles for drug delivery. Moreover, it has been recognized that accidental contamination of therapeutic protein formulations with nanosized particulate materials may contribute to the immunogenicity of this type of biotechnology products. While the immunological properties of engineered nanomaterials and their application as vaccine carriers and adjuvants have been given substantial consideration in the current literature, little attention has been paid to nanoparticle immuno- and antigenicity. To fill in this gap, we herein provide an overview of this subject to highlight the current state of the field, review past and present research, and discuss future research directions.
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•Most engineered nanomaterials are not immunogenic per se.•Generation of nanoparticle-specific antibody can be T-cell dependent or independent.•Antibodies can be generated to particle core, terminal groups or surface coatings.•Engineered and accidental nanomaterials have distinct contribution to immunogenicity.•Tunable physicochemical properties make each nanoparticle unique.
Preclinical characterization of novel nanotechnology-based formulations is often challenged by physicochemical characteristics, sterility/sterilization issues, safety and efficacy. Such challenges ...are not unique to nanomedicine, as they are common in the development of small and macromolecular drugs. However, due to the lack of a general consensus on critical characterization parameters, a shortage of harmonized protocols to support testing, and the vast variety of engineered nanomaterials, the translation of nanomedicines into clinic is particularly complex. Understanding the immune compatibility of nanoformulations has been identified as one of the important factors in (pre)clinical development and requires reliable in vitro and in vivo immunotoxicity tests. The generally low sensitivity of standard in vivo toxicity tests to immunotoxicities, inter-species variability in the structure and function of the immune system, high costs and relatively low throughput of in vivo tests, and ethical concerns about animal use underscore the need for trustworthy in vitro assays. Here, we consider the correlation (or lack thereof) between in vitro and in vivo immunotoxicity tests as a mean to identify useful in vitro assays. We review literature examples and case studies from the experience of the NCI Nanotechnology Characterization Lab, and highlight assays where predictability has been demonstrated for a variety of nanomaterials and assays with high potential for predictability in vivo.
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The delivery of drugs, antigens, and imaging agents benefits from using nanotechnology-based carriers. The successful translation of nanoformulations to the clinic involves thorough assessment of ...their safety profiles, which, among other end-points, includes evaluation of immunotoxicity. The past decade of research focusing on nanoparticle interaction with the immune system has been fruitful in terms of understanding the basics of nanoparticle immunocompatibility, developing a bioanalytical infrastructure to screen for nanoparticle-mediated immune reactions, beginning to uncover the mechanisms of nanoparticle immunotoxicity, and utilizing current knowledge about the structure–activity relationship between nanoparticles' physicochemical properties and their effects on the immune system to guide safe drug delivery. In the present review, we focus on the most prominent pieces of the nanoparticle–immune system puzzle and discuss the achievements, disappointments, and lessons learned over the past 15years of research on the immunotoxicity of engineered nanomaterials.
API — active pharmaceutical ingredient; NP — nanoparticles; PCP — physicochemical properties, CARPA — complement activation-related pseudoallergy, ICH — International Conference on Harmonization. Display omitted
•Achievements, disappointments and lessons learned over past decade are reviewed.•Areas in focus include characterization, immunotoxicity and utility in drug delivery.•Future direction focusing on mechanistic immunotoxicity studies is proposed.
Nanotechnology offers several advantages for drug delivery. However, there is the need for addressing potential safety concerns regarding the adverse health effects of these unique materials. Some ...such effects may occur due to undesirable interactions between nanoparticles and the immune system, and they may include hypersensitivity reactions, immunosuppression, and immunostimulation. While strategies, models, and approaches for studying the immunological safety of various engineered nanoparticles, including metal oxides, have been covered in the current literature, little attention has been given to the interactions between iron oxide-based nanomaterials and various components of the immune system. Here we provide a comprehensive review of studies investigating the effects of iron oxides and iron-based nanoparticles on various types of immune cells, highlight current gaps in the understanding of the structure–activity relationships of these materials, and propose a framework for capturing their immunotoxicity to streamline comparative studies between various types of iron-based formulations.
Strategy for developing an experimental framework to assess immunotoxicity of IONPs. IONPs have variety of effects on the immune system. Clinical translation of these formulations is often delayed or even halted due to the immunotoxicity. Here we review the literature and suggest translational considerations. The key recommendation of the review is the strategy for developing experimental framework to assess IONPs immunotoxicity. The framework can be applied to compare between different types of IONPs, as well as between brand and generic version of the same type of iron-based complex drug formulation. Display omitted
•This manuscript provides review of the literature regarding immunotoxicity of iron oxide nanoparticles (IONPs). A considerable body of literature suggests that IONPs induce immune dysfunction. However, most available studies focus on monocytes and macrophages and use cytotoxicity as the main end point of evaluation. The effects of these materials on the other types of immune cells and the mechanisms of toxicity are incompletely understood.•The available literature contains evidence for both immunosuppressive and immunostimulatory properties of IONPs. However, nanoparticle physicochemical parameters, route of administration, dose, or any other critical parameters for determining these toxicities are not well-established.•Therefore, a better understanding of the immunotoxicity of IONPs with different surface properties, size, hydrophobicity, and release of iron ions is needed. It is also essential to distinguish between toxicities specific to the iron core, the released iron ions, and the coating materials.•Systematic studies, which not only evaluate the cytotoxicity of IONPs on the immune cells but also include a broad spectrum of both structural and functional changes in various types of immune cells under physiologically relevant conditions, are also required to fill the current gap.•To inform the safe design of IONPs and other iron-based nanomedicines, we propose an experimental framework, which could assist with evaluation of the critical mechanistic components of IONPs’ effects on the immune system. Such a framework could be used to compare brand and generic formulations of IONPs and assist with bio(nano)similarity evaluation of these products.
Nanotechnology carriers have become common in pharmaceutical products because of their benefits to drug delivery, including reduced toxicities and improved efficacy of active pharmaceutical ...ingredients due to targeted delivery, prolonged circulation time, and controlled payload release. While available examples of reduced drug toxicity through formulation using a nanocarrier are encouraging, current data also demonstrate that nanoparticles may change a drug’s biodistribution and alter its toxicity profile. Moreover, individual components of nanoparticles and excipients commonly used in formulations are often not immunologically inert and contribute to the overall immune responses to nanotechnology-formulated products. Said immune responses may be beneficial or adverse depending on the indication, dose, dose regimen, and route of administration. Therefore, comprehensive toxicology studies are of paramount importance even when previously known drugs, components, and excipients are used in nanoformulations. Recent data also suggest that, despite decades of research directed at hiding nanocarriers from the immune recognition, the immune system’s inherent property of clearing particulate materials can be leveraged to improve the therapeutic efficacy of drugs formulated using nanoparticles. Herein, I review current knowledge about nanoparticles’ interaction with the immune system and how these interactions contribute to nanotechnology-formulated drug products’ safety and efficacy through the lens of over a decade of nanoparticle characterization at the Nanotechnology Characterization Laboratory.
Recent clinical successes using therapeutic nucleic acids (TNAs) have accelerated the transition of nucleic acid nanotechnology toward therapeutic applications. Significant progress in the ...development, production, and characterization of nucleic acid nanomaterials and nucleic acid nanoparticles (NANPs), as well as abundant proof-of-concept data, are paving the way toward biomedical applications of these materials. This recent progress has catalyzed the development of new strategies for biosensing, imaging, drug delivery, and immunotherapies with previously unrecognized opportunities and identified some barriers that may impede the broader clinical translation of NANP technologies. A recent workshop sponsored by the Kavli Foundation and the Materials Research Society discussed the future directions and current challenges for the development of therapeutic nucleic acid nanotechnology. Herein, we communicate discussions on the opportunities, barriers, and strategies for realizing the clinical grand challenge of TNA nanotechnology, with a focus on ways to overcome barriers to advance NANPs to the clinic.
Infusion reactions (IRs) are complex, immune-mediated side effects that mainly occur within minutes to hours of receiving a therapeutic dose of intravenously administered pharmaceutical products. ...These products are diverse and include both traditional pharmaceuticals (for example biological agents and small molecules) and new ones (for example nanotechnology-based products). Although IRs are not unique to nanomedicines, they represent a hurdle for the translation of nanotechnology-based drug products. This Perspective offers a big picture of the pharmaceutical field and examines current understanding of mechanisms responsible for IRs to nanomedicines. We outline outstanding questions, review currently available experimental evidence to provide some answers and highlight the gaps. We review advantages and limitations of the in vitro tests and animal models used for studying IRs to nanomedicines. Finally, we propose a roadmap to improve current understanding, and we recommend a strategy for overcoming the problem.
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Polyethylene glycol or PEG has a long history of use in medicine. Many conventional formulations utilize PEG as either an active ingredient or an excipient. PEG found its use in ...biotechnology therapeutics as a tool to slow down drug clearance and shield protein therapeutics from undesirable immunogenicity. Nanotechnology field applies PEG to create stealth drug carriers with prolonged circulation time and decreased recognition and clearance by the mononuclear phagocyte system (MPS). Most nanomedicines approved for clinical use and experimental nanotherapeutics contain PEG. Among the most recent successful examples are two mRNA-based COVID-19 vaccines that are delivered by PEGylated lipid nanoparticles. The breadth of PEG use in a wide variety of over the counter (OTC) medications as well as in drug products and vaccines stimulated research which uncovered that PEG is not as immunologically inert as it was initially expected. Herein, we review the current understanding of PEG’s immunological properties and discuss them in the context of synthesis, biodistribution, safety, efficacy, and characterization of PEGylated nanomedicines. We also review the current knowledge about immunological compatibility of other polymers that are being actively investigated as PEG alternatives.
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