//Background//---
What
kinds of materials are used as the cell-to-cell communication biomaterial in
our body? The tremendous kinds of proteins(amino acids) and nucleic acids
exist. On the other hand, in the communicative-trait materials, there are
several subtypes of extracellular-vesicle(EV), including exosomes, ectosomes,
microvesicles, membrane vesicles and apoptotic bodies(2). One of the
characteristics in these materials is to have closed space. Therefore, we can
add variety functions as a drug delivery carrier, such as creating surface
protein specific to the target cells and tissues(the cell-specific delivery
system), entering the drugs into this EV, and conjugate system on surface.
Inge
Katrin Herrmann, Matthew John Andrew Wood & Gregor Fuhrmann et al. review
extracellular vesicles as a next-generation drug delivery platform including
the perspectives of loading methods, in-depth characterization, large-scale
manufacturing, challenge and advantage for the clinical application, and
ongoing clinical examples. These contents are highly related to “the
cell-specific delivery system”, so I hope to share this review with the global
important reader especially related to the drug development and that the
discussion arises from my letter.
//The challenging and risk matters//---
*The methodologies for investigation of
drug efficacy and biocompatibility in EVs, (but) which is extensively evaluated
in liposome, are lacking(1).
*Due to material limitation such as complex
mixture of various lipids, specific cell targeting is difficult.
*The associated risk-benefit ration remain
matters of debates(13).
*Single vesicle level analysis, which is
purification and sort, is difficult, resulting analytical challenge. Currently,
there is no consensus on an appropriate EV isolation technique. Magnetic
immunoaffinity purification has been considered against this challenge.
*Half-life of EVs is considerably shorter
than that of liposomes.(at most 60 minutes(13))
*Negative immune reaction, such as
anaphylaxis, cytokine release syndrome, neutralization of important biological
activity, cross-reactivity, chronic immune reaction and the production of
unnecessary or excess biologicals(26) could be emerged in an inappropriate
condition.
*Stable manufacturing is difficult, such as
batch-to-batch variation, size heterogeneity. Quality-by-design approach is
needed.
*Virus entry risk: Manufacturing control,
appropriate testing, clearance method are needed.
*Cold storage condition (-80 degC) is
needed to prevent quality degradation(34).
*Quality change over time even in
autologous EVs.
//Guidelines about EVs//---
*The general definition of “the
extracellular vesicle(EV)” have not been made in the guideline. However, the
minimal information about EV is written in MISEV guidelines(14). However,
careful discrimination of EVs from contaminant, such as protein aggregate,
conjugated materials and viruses, is important. Currently, there are no typical
EV makers. This MISEV guideline was updated in 2018 by 382 researchers(14).
*Listing MISEV guideline is following(1)(See
Box1):
Size
/ Yield / Morphology / Presence of a bilayer / Cell debris / Purity / Avoid
misuse of nomenclature
*In unapproved cases, serious adverse
effect has been confirmed(15), so comprehensive approval guideline needs to be
set, and transparent reporting of data, including manufacturing process,
provider information, and characterization in multi-phases, is mandatory in
order to ensure safety and clinical benefit for the patient.
*The separate approval guideline, such as each
vesicle, each functional property and infused drug may be needed.
//The advantages//---
*EVs has little limitation on the drug
delivery in the places, such as brain (through brain blood barrier(21)),
stromal penetration in the situation where extracellular matrix intricately
formed, infiltration into tissues from the circulating system. In these
characteristics, EVs may be superior to cell-based vesicle.
*Native EVs shows substantial accumulation
in tumor tissue(24,25), so the cancer treatment using EVs as a drug delivery
carrier may be suitable.
//The methods//---
Drug loading, in-depth characterization,
large-scale manufacturing
(Drug loading)-
@Endogenous approach-
EV-producing
cells also equip vesicles with drug cargo(29,30). This approach is relatively
simple, but the generable drug may be limited.
@Exogenous approach-
The drugs
are loaded into EVs after isolation. Electroporation(31), Saponin treatment(32)
of EVs and Extrusion to EVs can be candidate process, but cost is high(1)(See
Fig.4c). In saponin treatment, >200kDa large enzyme roading is
succeeded(32,33).
(In-depth characterization)-
We
need to analysis EV through multi-omics study(3), and understand systemic
characterization about it as following(1)(See Fig 1):
*Exchange
among cells in the both proximal and distal manner, including endocytosis.
*The
function in vascular system, such as circulation.
*The
metabolism in the organ, especially liver, heart, and kidney.
*The
interaction of immune system.
*The
interaction and cross-talk among EVs.
*The
detection of disease specific EVs such as cancer(4-6)
Analysis
measure is following:
*Flow
cytometry(18)
*Cryoelectron transmission microscopy(19)
*Mass
spectrometory(20)
(Large-scale manufacturing)-
*EVs from non-pathogenic and probiotic
bacterial sources may also be taken advantage, because their production could
be scalable in small fermenters(7-10). However, immunogenicity, which could
lead severe side effects, needs to be scrutinized for bacterial vesicles due to
the potential presence of lipopolysaccharides(11).
*The refinement of manufacturing process is
ongoing. (EVs from MSCs(16,17).)
*Suggested methods: Multilayered culture
flasks / Bioreactors / Hollow fibre cartridges.
*Feasible study on using Milk EVs is under
development(27), but needs to be optimized due to complexity(28).
//Cinical application(1)(See Table 1)//---
Drug-resistant
infections / Diabetes mellitus type1 / SARS-CoV-2 pneumonia / Dry eye / Macular
holes / Cerebrovascular disorder / Periodontitis / Alzheimer’s disease / Acute
respiratory distress syndrome / Dystrophic epidermolysis bullosa / Ulcer / Head
and neck cancer / Oral mucositis / Metastatic pancreatic adenocarcinoma /
Pancreatic ductal adenocarcinoma / Colon cancer / Non-small-cell lung cancer
//Additional note//---
(Autogeneous)
stem cell derived and blood-cell-derived EVs may be promising. Therefore,
efficient EV-secreting environment needs to be prepared. EVs derived frommesenchymal
stem cell are already under clinical assessment(12).
It
is not always necessary to make a choice for EVs from “a healthy cell”. For
example, mammalian tumor EVs has some affinity of the integrin expression
tissue, such as epithelial cells and lung fibroblasts(22), however cancer EVs
are not suitable as a drug carrier because of promoting cancer progression(23).
Therefore, in the case where this disease-trait EV is used, we need to modify
the function and have careful risk assessment.
//The perspective of the cell-specific
delivery system//---
The
size of EVs is substantial small compared to cells. Therefore, the design and
the production of arbitrary surface protein on EVs may be difficult. In vivo,
whether large number of arbitrary EVs including surface protein is efficiently
creating is open matter. EVs is one of the choices as a delivery vesicle in the
cell-specific delivery system.
//Peer review information(1)//---
Nature Nanotechnology thanks Mansoor Amiji
and the other, anonymous, reviewer(s) for their contribution to the peer review
of this work.
(Reference)
(1)
Inge Katrin Herrmann, Matthew John Andrew
Wood & Gregor Fuhrmann
Extracellular vesicles as a next-generation
drug delivery platform
Nature Nanotechnology (2021)
---
Author information
Author notes
Gregor Fuhrmann
Present address: Chair for Pharmaceutical
Biology, Department of Biology, Friedrich-Alexander-University Erlangen
Nuremberg, Erlangen, Germany
Affiliations
Nanoparticle Systems Engineering
Laboratory, Institute of Energy and Process Engineering, Department of
Mechanical and Process Engineering, ETH Zurich, Zurich, Switzerland
Inge Katrin Herrmann
Particles–Biology Interactions, Department
of Materials Meet Life, Swiss Federal Laboratories for Materials Science and
Technology (Empa), St. Gallen, Switzerland
Inge Katrin Herrmann
Department of Paediatrics and Oxford
Harrington Rare Disease Centre, University of Oxford, Oxford, UK
Matthew John Andrew Wood
Helmholtz Centre for Infection Research
(HZI), Biogenic Nanotherapeutics Group (BION), Helmholtz Institute for
Pharmaceutical Research Saarland (HIPS), Saarbrücken, Germany
Gregor Fuhrmann
Department of Pharmacy, Saarland
University, Saarbrücken, Germany
Gregor Fuhrmann
---
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