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Technical
Specification
ISO/TS 4958
First edition
Nanotechnologies — Vocabulary —
2024-03
Liposomes
Nanotechnologies — Vocabulaire — Liposomes
Reference number
© ISO 2024
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ii
Contents Page
Foreword .iv
Introduction .v
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 1
3.1 Core terms related to liposomes .1
3.2 Terms related to lipid-bilayer vesicles .2
3.3 Terms related to the components and regions of liposomes .3
3.4 Terms related to the characteristics and formation of liposomes .4
Bibliography . 7
Index . 8
iii
Foreword
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This document was prepared by Technical Committee TC 229, Nanotechnologies.
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iv
Introduction
Lipid-based nanomaterials represent an important class of carriers for the in vivo transport and delivery of
active pharmaceutical ingredients (APIs). By encapsulating the API inside a lipid-based structure, payloads
can be protected from degradation while potent APIs can be delivered with reduced adverse physiological
effects. These lipid-based carriers are carefully formulated to achieve specific properties and are generally
well tolerated and biocompatible.
Lipid particles include different structural forms or subclasses that can be differentiated by structure,
composition and chemistry (e.g. liposomes, solid lipid nanoparticles). The first lipid-based nanomaterial
product to obtain regulatory approval in the US and EU was liposomal doxorubicin, approved in 1995 in
the US for the treatment of ovarian cancer and AIDS-related Kaposi sarcoma. More recently, cationic lipid-
containing nanoparticles complexed with mRNA were formulated as highly effective vaccines against the
coronavirus SARS-CoV-2. This document aims to standardize the terminology associated with the most
studied and mature form of lipid-based carriers, namely liposomes.
Liposomes are synthetic vesicles composed of a single bilayer (most common form for drug delivery) or of
multiple concentric or non-concentric bilayers separated by aqueous compartments. Figure 1 schematically
illustrates these basic structural forms of liposome as used within a biomedical context. An example of
pharmaceutical relevance (e.g. a drug product) is provided for each vesicle form defined in 3.2.
a) Small unilamellar b) Large unilamellar c) Multilamellar d) Multivesicular
vesicle ≤100 nm vesicle >100 nm vesicle ≥500 nm liposome >1 000 nm
NOTE Images are not drawn to scale.
SOURCE Scientific Publications, Graphics and Media, Frederick National Laboratory for Cancer Research.
Figure 1 — Schematic illustration showing lamellar structure of different vesicle types
The bilayers are formed by amphipathic molecules, primarily phospholipids, but can include other
molecular components necessary for membrane integrity (e.g. cholesterol) or avoidance of opsonization and
reticuloendothelial clearance [e.g. polyethylene glycol (PEG)].
The size of liposomes can range from approximately 20 nm to over 1 000 nm, though therapeutic delivery
most commonly involves particles in the 50 nm to 200 nm diameter range. Therefore, while not all liposomes
are nano-objects as defined in this document, all liposomes consist of bilayers of nanoscale thickness and
are therefore generally considered both nanomaterials and nanostructured materials.
Figure 2 depicts a 3D cross-sectional perspective of an idealized unilamellar liposome, a lipid bilayer and a
liposomal drug formulation showing the location of compartments and APIs.
Figure 3 illustrates the three principal structural phases associated with lipid bilayers. These phases are
principally dependent on composition and temperature, but other factors such as pH can also play a role.
v
a) 3D hemispherical view b) Cross-section of bilayer c) Liposome cross-section show-
segment ing bilayer with details
Key
1 hydrophobic compartment (lipid bilayer)
2 hydrophilic compartment (aqueous phase core)
3 hydrophilic active pharmaceutical ingredient (API)
4 hydrophobic API
5 amphiphilic API
6 polyethylene glycol (PEG)
NOTE 1 Images are not drawn to scale.
NOTE 2 Polar headgroups are shown in green and hydrophobic tails are shown in black.
SOURCE Scientific Publications, Graphics and Media, Frederick National Laboratory for Cancer Research.
Figure 2 — Idealized unilamellar liposome showing phospholipid bilayer structure, internal
compartments and representative details
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Key
1 liquid disordered phase (above phase transition temperature)
2 liquid ordered phase (induced by cholesterol)
3 gel phase (below phase transition temperature)
4 phospholipid fatty acid tails
5 phospholipid polar headgroup
6 cholesterol
a
Increasing membrane fluidity.
NOTE Images are not drawn to scale.
SOURCE Scientific Publications, Graphics and Media, Frederick National Laboratory for Cancer Research.
Figure 3 — Idealized illustration of phospholipid bilayer structural phases
Due to their versatile nature, liposomes are promising materials in many industrial fields. In addition to
therapeutics, liposome technologies have also been applied in products such as cosmetics and dietary
supplements.
Additional terms that relate to the nano/bio interface and nanotechnologies related to diagnostics and
therapeutics for healthcare are defined in ISO/TS 80004-5 and ISO/TS 80004-7, respectively.
vii
Technical Specification ISO/TS 4958:2024(en)
Nanotechnologies — Vocabulary — Liposomes
1 Scope
This document defines terms related to liposomes in nanotechnologies, within the context of biological
systems and biomedical applications. In this context, liposomes are one form of lipid-based nanomaterials.
This document does not address terms that can be relevant to other types of lipid-based particles (e.g. solid
lipid nanoparticles).
2 Normative references
There are no normative references in this document.
3 Terms and definitions
ISO and IEC maintain terminology databases for use in standardization at the following addresses:
— ISO Online browsing platform: available at https:// www .iso .org/ obp
— IEC Electropedia: available at https:// www .electropedia .org/
3.1 Core terms related to liposomes
3.1.1
nanoscale
length range approximately from 1 nm to 100 nm
Note 1 to entry: Properties that are not extrapolations from a larger size are predominantly exhibited in this length range.
[SOURCE: ISO 80004-1:2023, 3.1.1, modified— Note 1 to entry has been added.]
3.1.2
nanomaterial
material with any external dimension in the nanoscale (3.1.1) or having an internal structure or surface
structure in the nanoscale
Note 1 to entry: This term is inclusive of nano‐objects (3.1.3) and nanostructured materials (3.1.4).
[SOURCE: ISO 80004-1:2023, 3.1.4, modified— Note 1 to entry has been replaced and Note 2 to entry has
been deleted.]
3.1.3
nano-object
discrete piece of material with one, two or three external dimensions in the nanoscale (3.1.1)
[SOURCE: ISO 80004-1:2023, 3.1.5]
3.1.4
nanostructured material
material having internal nanostructure (3.1.5) or surface nanostructure
Note 1 to entry: This definition does not exclude the possibility for a nano‐object (3.1.3) to have internal structure or
surface structure. If external dimension(s) are in the nanoscale (3.1.1), the term nano-object is recommended.
[SOURCE: ISO 80004-1:2023, 3.1.7]
3.1.5
nanostructure
surface or internal feature with one or more dimensions in the nanoscale (3.1.1)
Note 1 to entry: A feature includes but is not limited to nano‐objects (3.1.3), structures, morphologies or other identifiable
areas of nanoscale dimensions. For example, the nanostructure can be a nanopore or a solid feature on an object.
[SOURCE: ISO 80004-1:2023, 3.1.6]
3.1.6
nanoparticle
nano‐object (3.1.3) with all external dimensions in the nanoscale (3.1.1)
Note 1 to entry: If the dimensions differ significantly (typically by more than three times), terms such as nanofibre or
nanoplate are preferred to the term nanoparticle.
[SOURCE: ISO 80004-1:2023, 3.3.4]
3.2 Terms related to lipid-bilayer vesicles
3.2.1
liposome
synthetic vesicle (3.2.2) consisting of one or more lipid bilayers (3.3.3) that form both hydrophobic and
hydrophilic compartments (3.3.4)
Note 1 to entry: Liposomes are principally composed of phospholipids (3.3.11) and cholesterol (3.3.10), and can contain
both naturally-derived and synthetic lipids (3.3.1).
Note 2 to entry: The external dimensions of liposomes can range from tens of nanometres to micrometres, while the
thickness of a typical lipid bilayer (3.3.3) is in the order of 5 nm.
3.2.2
vesicle
structure in which a fluid phase is enclosed by a lipid bilayer (3.3.3)
Note 1 to entry: Vesicles are typically spheroidal when referring to liposomes (3.2.1).
3.2.3
small unilamellar vesicle
SUV
vesicle (3.2.2) consisting of a single lipid bilayer (3.3.3) having external dimensions predominantly in the
range 20 nm to 100 nm
EXAMPLE Liposomal doxorubicin hydrochloride is a chemotherapy drug product.
3.2.4
large unilamellar vesicle
LUV
vesicle (3.2.2) consisting of a single lipid bilayer (3.3.3) having external dimensions predominantly greater
than 100 nm
Note 1 to entry: LUVs are typically between 100 nm and 1 000 nm.
EXAMPLE Liposomal amikacin is a dru
...