Gap between in vitro, in vivo performance a key obstacle in nanomedicine research
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One of the major challenges in the field of nanomedicine is translating in vitro performance of nanoparticles to in vivo studies, a factor that may hinder the development of nanoparticles as drug delivery vehicles.
In early stages of development of drug nanocarriers, this problem was not evident, because evaluation of the nanoparticles occurred mainly within standard cell culture. As research evolves in this area to include advanced pharmacologic in vivo studies in mice or humans, the poor reliability and validity of cell culture testing for therapeutic purposes has become evident, according to a paper published earlier this year in Biophysics Reviews.
Researchers in Germany reviewed in detail the different challenges for nanoparticles in cell culture in contrast to those in pharmacological models or patients, and suggested options for better predictive future experiments.
“We have good performance in the in vitro assays, the cell culture, and sometimes the behavior is the same in vivo but often it is not,” Simone Berger, PhD student in the department of pharmacy at Ludwig-Maximilians-University of Munich and an author of the study, told Healio | HemOnc Today. “We are just looking at some better predictions in vitro so that this gap between in vitro and in vivo will be closed a bit.”
The in vivo use of nanoparticles is hindered by several conditions that differ from those encountered in vitro. One is the interaction with blood components, Berger said.
“When [nanoparticles] get into the bloodstream and have contact with a lot of blood components, like serum proteins and blood cells, they frequently are covered with proteins and other biomolecules, and this is called the protein corona or the biomolecular multilayer,” Berger said. “This, of course, alters the particles’ properties and has an impact on their pharmacokinetics and toxicity profile in mice or humans. So, we have a different situation in vivo than what we are characterizing in vitro, so if we test the nanoparticles in cell culture, we will face different properties.”
The choice of the biofluid — whether serum, plasma or full blood — and the creation of standardized protocols will be key to more reliable, robust and comprehensive preclinical studies to understand structure-activity relationships and correlations between in vitro and in vivo performance, Berger said.
In vitro studies currently cannot capture information that is observed in vivo, such as biodistribution and off-target effects. However, new high-throughput screening methods such as cellular barcoding can improve the efficacy, cost and ethical integrity of in vivo analysis, Berger and colleagues wrote.
Berger said there is still uncertainty about translatability from small to large animals and humans, adding that bioinformatics could be harnessed to identify the best animal models for certain diseases.
Ultimately, animal models may be replaced by alternative methods, such as microfluidic human “organ-on-a-chip” technology or computational predictions, Berger said.
“’Microfluidic ‘human-organ-on-a-chip’ represents 3D cell culture in a flow model recapitulating the in vivo situation to a greater extent compared with standard 2D cell monolayers, as such systems display heterogeneous cell populations, cell-to-cell and cell-to-extracellular matrix interactions. It enables us to create organoid in vitro test models,” she said. “Computational predictions can help to predict in vivo performance of nanoparticles by simulating nanoparticle interaction with blood components in silico. With the rapid progress in electronic development and improvement of computing power, this will gain more importance in the future.”
Berger maintains that nanoparticles have a valuable role in the future development of cancer therapeutics.
“We truly believe that nanomedicine has great potential to revolutionize the therapeutic landscape, especially in cancer treatments but also, for example, in the treatment of genetic disorders,” Berger said. “Nanomedicine has the potential to provide some very personalized, patient-specific treatments.”
- Reference:
- Berger S, et al. Biophysics Rev. 2022;doi:10.1063/5.0073494.
- For more information:
- Simone Berger can be reached at Department of Pharmacy, University of Munich, Butenandtstraße 5-13. Building D 81377 München, Germany; email: simone.berger@cup.uni-muenchen.de.
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