A set of biomedically relevant iron oxide nanoparticles with systematically modified polymer surfaces was investigated regarding their interaction with the first contact partners after systemic administration such as blood cells, blood proteins, and the endothelial blood vessels, to establish structure-activity relationships. All nanoparticles were intensively characterized regarding their physicochemical parameters. Cyto- and hemocompatibility tests showed that (1) the properties of the core material itself were not relevant in short-term incubation studies, and (2) toxicities increased with higher polymer mass, neutral = anionic < cationic surface charge and charge density, as well as agglomeration. Based on this, it was possible to classify the nanoparticles in three groups, to establish structure-activity relationships and to predict nanosafety. While the results between cyto- and hemotoxicity tests correlated well for the polymers, data were not fully transferable for the nanoparticles, especially in case of cationic low molar mass polymer coatings. To evaluate the prediction efficacy of the static in vitro models, the results were compared to those obtained in an ex ovo shell-less hen's egg test after microinjection under dynamic flow conditions. While the polymers demonstrated hemotoxicity profiles comparable to the in vitro tests, the size-dependent risks of nanoparticles could be more efficiently simulated in the more complex ex ovo environment, making the shell-less egg model an efficient alternative to animal studies according to the 3R concept.
The coronavirus disease of 2019 (COVID-19) pandemic launched an unprecedented global
effort to rapidly develop vaccines to stem the spread of the novel severe acute
respiratory syndrome coronavirus (SARS-CoV-2). Messenger ribonucleic acid (mRNA)
vaccines were developed quickly by companies that were actively developing mRNA
therapeutics and vaccines for other indications, leading to two mRNA vaccines being not
only the first SARS-CoV-2 vaccines to be approved for emergency use but also the first
mRNA drugs to gain emergency use authorization and to eventually gain full approval.
This was possible partly because mRNA sequences can be altered to encode nearly any
protein without significantly altering its chemical properties, allowing the drug
substance to be a modular component of the drug product. Lipid nanoparticle (LNP)
technology required to protect the ribonucleic acid (RNA) and mediate delivery into the
cytoplasm of cells is likewise modular, as are technologies and infrastructure required
to encapsulate the RNA into the LNP. This enabled the rapid adaptation of the technology
to a new target. Upon the coattails of the clinical success of mRNA vaccines, this
modularity will pave the way for future RNA medicines for cancer, gene therapy, and RNA
engineered cell therapies. In this review, trends in the publication records and
clinical trial registrations are tallied to show the sharp intensification in
preclinical and clinical research for RNA medicines. Demand for the manufacturing of
both the RNA drug substance (DS) and the LNP drug product (DP) has already been
strained, causing shortages of the vaccine, and the rise in development and translation
of other mRNA drugs in the coming years will exacerbate this strain. To estimate demand
for DP manufacturing, the dosing requirements for the preclinical and clinical studies
of the two approved mRNA vaccines were examined. To understand the current state of
mRNA-LNP production, current methods and technologies are reviewed, as are current and
announced global capacities for commercial manufacturing. Finally, a vision is
rationalized for how emerging technologies such as self-amplifying mRNA, microfluidic
production, and trends toward integrated and distributed manufacturing will shape the
future of RNA manufacturing and unlock the potential for an RNA medicine revolution.
Aim: To simulate the stability and degradation of superparamagnetic iron oxide nanoparticles (MNP) in vitro as part of their life cycle using complex simulated biological fluids. Materials & methods: A set of 13 MNP with different polymeric or inorganic shell materials was synthesized and characterized regarding stability and degradation of core and shell in simulated biological fluids. Results: All MNP formulations showed excellent stability during storage and in simulated body fluid. In endosomal/lysosomal media the degradation behavior depended on shell characteristics (e.g., charge, acid-base character) and temperature enabling the development of an accelerated stress test protocol. Conclusion: Kinetics of transformations depending on the MNP type could be established to define structure-activity relationships as prediction model for rational particle design.
Aim: In this study, the influence of a serum albumin (SA) and human plasma (HP) derived protein- and lipid molecule corona on the toxicity and biodegradability of different iron oxide...
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