Liposome

A liposome is a small artificial vesicle, spherical in shape, having at least one lipid bilayer.[2] Due
to their hydrophobicity and/or hydrophilicity, biocompatibility, particle size and many other
properties,[2] liposomes can be used as drug delivery vehicles for administration of
pharmaceutical drugs and nutrients,[3] such as lipid nanoparticles in mRNA vaccines, and DNA
vaccines. Liposomes can be prepared by disrupting biological membranes (such as by
sonication).

Scheme of a liposome formed by

phospholipids in an aqueous solution.

Liposomes are composite structures made

of phospholipids and may contain small
amounts of other molecules. Though
liposomes can vary in size from low
micrometer range to tens of micrometers,
unilamellar liposomes, as pictured here, are
typically in the lower size range with
various targeting ligands attached to their
surface allowing for their surface-
attachment and accumulation in
pathological areas for treatment of
disease.[1]

Liposomes are most often composed of phospholipids,[4] especially phosphatidylcholine, and

cholesterol,[2] but may also include other lipids, such as those found in egg and
phosphatidylethanolamine, as long as they are compatible with lipid bilayer structure.[5] A
liposome design may employ surface ligands for attaching to desired cells or tissues.[1]

Based on vesicle structure, there are seven main categories for liposomes: multilamellar large
(MLV), oligolamellar (OLV), small unilamellar (SUV), medium-sized unilamellar (MUV), large
unilamellar (LUV), giant unilamellar (GUV) and multivesicular vesicles (MVV).[6] The major types
of liposomes are the multilamellar vesicle (MLV, with several lamellar phase lipid bilayers), the
small unilamellar liposome vesicle (SUV, with one lipid bilayer), the large unilamellar vesicle
(LUV), and the cochleate vesicle. A less desirable form is multivesicular liposomes in which one
vesicle contains one or more smaller vesicles.

Seven main categories for liposomes:

multilamellar large (MLV), oligolamellar
(OLV), small unilamellar (SUV), medium-
sized unilamellar (MUV), large unilamellar
(LUV), giant unilamellar (GUV) and
multivesicular vesicles (MVV))[7].

Liposomes should not be confused with lysosomes, or with micelles and reverse micelles.[8] In
contrast to liposomes, micelles typically contain a monolayer of fatty acids or surfactants.[9]

Discovery

The word liposome derives from two Greek words: lipo ("fat") and soma ("body"); it is so named
because its composition is primarily of phospholipid.

Liposomes were first described by British hematologist Alec Douglas Bangham[10][11][12] in 1961
at the Babraham Institute, in Cambridge—findings that were published 1964. The discovery came
about when Bangham and R. W. Horne were testing the institute's new electron microscope by
adding negative stain to dry phospholipids. The resemblance to the plasmalemma was obvious,
and the microscopic pictures provided the first evidence that the cell membrane is a bilayer lipid
structure. The following year, Bangham, his colleague Malcolm Standish, and Gerald Weissmann,
an American physician, established the integrity of this closed, bilayer structure and its ability to
release its contents following detergent treatment (structure-linked latency).[13] During a
Cambridge pub discussion with Bangham, Weissmann first named the structures "liposomes"
after something which laboratory had been studying, the lysosome: a simple organelle whose
structure-linked latency could be disrupted by detergents and streptolysins.[14] Liposomes are
readily distinguishable from micelles and hexagonal lipid phases through negative staining
transmission electron microscopy.[15]

Bangham, with colleagues Jeff Watkins and Standish, wrote the 1965 paper that effectively
launched what would become the liposome "industry." Around that same time, Weissmann joined
Bangham at the Babraham. Later, Weissmann, then an emeritus professor at New York University
School of Medicine, recalled the two of them sitting in a Cambridge pub, reflecting on the role of
lipid sheets in separating the cell interior from its exterior milieu. This insight, they felt, would be
to cell function what the discovery of the double helix had been to genetics. As Bangham had
been calling his lipid structures "multilamellar smectic mesophases," or sometimes
"Banghasomes," Weissmann proposed the more user-friendly term liposome.[16][17]

Mechanism

A micrograph of phosphatidylcholine
liposomes, which were stained with
fluorochrome acridine orange. Method of
fluorescence microscopy (1250-fold
magnification).

Various types of phosphatidylcholine

liposomes in suspension. Method of
phase-contrast microscopy (1000-fold
magnification). The following types of
liposomes are visible: small monolamellar
vesicles, large monolamellar vesicles,
multilamellar vesicles, oligolamellar
vesicles.
Encapsulation in liposomes

A liposome has an aqueous solution core surrounded by a hydrophobic membrane, in the form of
a lipid bilayer; hydrophilic solutes dissolved in the core cannot readily pass through the bilayer.
Hydrophobic chemicals associate with the bilayer. This property can be utilized to load
liposomes with hydrophobic and/or hydrophilic molecules, a process known as encapsulation.[18]
Typically, liposomes are prepared in a solution containing the compound to be trapped, which
can either be an aqueous solution for encapsulating hydrophilic compounds like proteins,[19][20]
or solutions in organic solvents mixed with lipids for encapsulating hydrophobic molecules.
Encapsulation techniques can be categorized into two types: passive, which relies on the
stochastic trapping of molecules during liposome formation, and active, which relies on the
presence of charged lipids or transmembrane ion gradients.[18] A crucial parameter to consider is
the "encapsulation efficiency," which is defined as the amount of compound present in the
liposome solution divided by the total initial amount of compound used during the
preparation.[21] In more recent developments, the application of liposomes in single-molecule
experiments has introduced the concept of "single entity encapsulation efficiency." This term
refers to the probability of a specific liposome containing the required number of copies of the
compound.[22]

Delivery

To deliver the molecules to a site of action, the lipid bilayer can fuse with other bilayers such as
the cell membrane, thus delivering the liposome contents; this is a complex and non-
spontaneous event, however,[23] that does not apply to nutrients and drug delivery. By preparing
liposomes in a solution of DNA or drugs (which would normally be unable to diffuse through the
membrane) they can be (indiscriminately) delivered past the lipid bilayer.[24] Liposomes can also
be designed to deliver drugs in other ways. Liposomes that contain low (or high) pH can be
constructed such that dissolved aqueous drugs will be charged in solution (i.e., the pH is outside
the drug's pI range). As the pH naturally neutralizes within the liposome (protons can pass
through some membranes), the drug will also be neutralized, allowing it to freely pass through a
membrane. These liposomes work to deliver drug by diffusion rather than by direct cell fusion.
However, the efficacy of this pH regulated passage depends on the physiochemical nature of the
drug in question (e.g. pKa and having a basic or acid nature), which is very low for many drugs.

A similar approach can be exploited in the biodetoxification of drugs by injecting empty

liposomes with a transmembrane pH gradient. In this case the vesicles act as sinks to scavenge
the drug in the blood circulation and prevent its toxic effect.[25] Another strategy for liposome
drug delivery is to target endocytosis events. Liposomes can be made in a particular size range
that makes them viable targets for natural macrophage phagocytosis. These liposomes may be
digested while in the macrophage's phagosome, thus releasing its drug. Liposomes can also be
decorated with opsonins and ligands to activate endocytosis in other cell types.

Regarding pH-sensitive liposomes, there are three mechanisms of drug delivery intracellularly,
which occurs via endocytosis.[26] This is possible because of the acidic environment within
endosomes.[26] The first mechanism is through the destabilization of the liposome within the
endosome, triggering pore formation on the endosomal membrane and allowing diffusion of the
liposome and its contents into the cytoplasm.[26] Another is the release of the encapsulated
content within the endosome, eventually diffusing out into the cytoplasm through the endosomal
membrane.[26] Lastly, the membrane of the liposome and the endosome fuse together, releasing
the encapsulated contents onto the cytoplasm and avoiding degradation at the lysosomal level
due to minimal contact time.[26]

Certain anticancer drugs such as doxorubicin (Doxil) and daunorubicin may be administered
encapsulated in liposomes. Liposomal cisplatin has received orphan drug designation for
pancreatic cancer from EMEA.[27] A study provides a promising preclinical demonstration of the
effectiveness and ease of preparation of valrubicin-loaded immunoliposomes (Val-ILs) as a novel
nanoparticle technology. In the context of hematological cancers, Val-ILs have the potential to be
used as a precise and effective therapy based on targeted vesicle-mediated cell death. [28]

The use of liposomes for transformation or transfection of DNA into a host cell is known as
lipofection.

In addition to gene and drug delivery applications, liposomes can be used as carriers for the
delivery of dyes to textiles,[29] pesticides to plants, enzymes and nutritional supplements to
foods, and cosmetics to the skin.[30]

Liposomes are also used as outer shells of some microbubble contrast agents used in contrast-
enhanced ultrasound.

Dietary and nutritional supplements

Until recently, the clinical uses of liposomes were for targeted drug delivery, but new applications
for the oral delivery of certain dietary and nutritional supplements are in development.[31] This
new application of liposomes is in part due to the low absorption and bioavailability rates of
traditional oral dietary and nutritional tablets and capsules. The low oral bioavailability and
absorption of many nutrients is clinically well documented.[32] Therefore, the natural
encapsulation of lypophilic and hydrophilic nutrients within liposomes would be an effective
method of bypassing the destructive elements of the gastric system and small intestines
allowing the encapsulated nutrient to be efficiently delivered to the cells and tissues.[33]
The term nutraceutical combines the words nutrient and pharmaceutical, originally coined by
Stephen DeFelice, who defined nutraceuticals as "food or part of a food that provides medical or
health benefits, including the prevention and/or treatment of a disease".[34] However, currently,
there is no conclusive definition of nutraceuticals yet, to distinguish them from other food‐
derived categories, such as food (dietary) supplements, herbal products, pre‐ and probiotics,
functional foods, and fortified foods.[35] Generally, this term is used to describe any product
derived from food sources which is expected to provide health benefits additionally to the
nutritional value of daily food. A wide range of nutrients or other substances with nutritional or
physiological effects (EU Directive 2002/46/EC) might be present in these products, including
vitamins, minerals, amino acids, essential fatty acids, fibres and various plants and herbal
extracts. Liposomal nutraceuticals contain bioactive compounds with health-promoting effects.
The encapsulation of bioactive compounds in liposomes is attractive as liposomes have been
shown to be able to overcome serious hurdles bioactives would otherwise encounter in the
gastrointestinal (GI) tract upon oral intake.[36]

Certain factors have far-reaching effects on the percentage of liposome that are yielded in
manufacturing, as well as the actual amount of realized liposome entrapment and the actual
quality and long-term stability of the liposomes themselves.[37] They are the following: (1) The
actual manufacturing method and preparation of the liposomes themselves; (2) The constitution,
quality, and type of raw phospholipid used in the formulation and manufacturing of the
liposomes; (3) The ability to create homogeneous liposome particle sizes that are stable and
hold their encapsulated payload. These are the primary elements in developing effective
liposome carriers for use in dietary and nutritional supplements.

Manufacturing

The choice of liposome preparation method depends, i.a., on the following parameters:[38][39]

1. the physicochemical characteristics of the material to be entrapped and those of the

liposomal ingredients;

2. the nature of the medium in which the lipid vesicles are dispersed

3. the effective concentration of the entrapped substance and its potential toxicity;

4. additional processes involved during application/delivery of the vesicles;

5. optimum size, polydispersity and shelf-life of the vesicles for the intended application; and,

6. batch-to-batch reproducibility and possibility of large-scale production of safe and efficient

liposomal products

Useful liposomes rarely form spontaneously. They typically form after supplying enough energy
to a dispersion of (phospho)lipids in a polar solvent, such as water, to break down multilamellar
aggregates into oligo- or unilamellar bilayer vesicles.[5][24]

Liposomes can hence be created by sonicating a dispersion of amphipatic lipids, such as

phospholipids, in water.[8] Low shear rates create multilamellar liposomes. The original
aggregates, which have many layers like an onion, thereby form progressively smaller and finally
unilamellar liposomes (which are often unstable, owing to their small size and the sonication-
created defects). Sonication is generally considered a "gross" method of preparation as it can
damage the structure of the drug to be encapsulated. Newer methods such as extrusion,
micromixing[40][41][42] and Mozafari method[43] are employed to produce materials for human use.
Using lipids other than phosphatidylcholine can greatly facilitate liposome preparation.[5]

Prospect

Pictorial representation of targeted

theranostics liposomal delivery

Further advances in liposome research have been able to allow liposomes to avoid detection by
the body's immune system, specifically, the cells of reticuloendothelial system (RES). These
liposomes are known as "stealth liposomes". They were first proposed by G. Cevc and G.
Blume[44] and, independently and soon thereafter, the groups of L. Huang and Vladimir
Torchilin[45] and are constructed with PEG (Polyethylene Glycol) studding the outside of the
membrane. The PEG coating, which is inert in the body, allows for longer circulatory life for the
drug delivery mechanism. Studies have also shown that PEGylated liposomes elicit anti-IgM
antibodies, thus leading to an enhanced blood clearance of the liposomes upon re-injection,
depending on lipid dose and time interval between injections.[46][47] In addition to a PEG coating,
some stealth liposomes also have some sort of biological species attached as a ligand to the
liposome, to enable binding via a specific expression on the targeted drug delivery site. These
targeting ligands could be monoclonal antibodies (making an immunoliposome), vitamins, or
specific antigens, but must be accessible.[48] Targeted liposomes can target certain cell type in
the body and deliver drugs that would otherwise be systemically delivered. Naturally toxic drugs
can be much less systemically toxic if delivered only to diseased tissues. Polymersomes,
morphologically related to liposomes, can also be used this way. Also morphologically related to
liposomes are highly deformable vesicles, designed for non-invasive transdermal material
delivery, known as transfersomes.[49]

Liposomes are used as models for artificial cells.

Liposomes can be used on their own or in combination with traditional antibiotics as neutralizing
agents of bacterial toxins. Many bacterial toxins evolved to target specific lipids of the host cells
membrane and can be baited and neutralized by liposomes containing those specific lipid
targets.[50]

A study published in May 2018 also explored the potential use of liposomes as "nano-carriers" of
fertilizing nutrients to treat malnourished or sickly plants. Results showed that these synthetic
particles "soak into plant leaves more easily than naked nutrients", further validating the
utilization of nanotechnology to increase crop yields.[51][52]

Machine learning has started to contribute to liposome research. For example, deep learning was
used to monitor a multistep bioassay containing sucrose-loaded and nucleotides-loaded
liposomes interacting with a lipid membrane-perforating peptide.[53] Artificial neural networks
were also used to optimize formulation parameters of leuprolide acetate loaded liposomes[54]
and to predict the particle size and the polydispersity index of liposomes.[55]

See also

Azotosome

Lamella (cell biology)

Langmuir–Blodgett film

Lipid bilayer

Targeted drug delivery

References

1. Torchilin, V (2006). "Multifunctional nanocarriers". Advanced Drug Delivery Reviews. 58 (14):

1532–55. doi:10.1016/j.addr.2006.09.009 (https://doi.org/10.1016%2Fj.addr.2006.09.00
9) . PMID 17092599 (https://pubmed.ncbi.nlm.nih.gov/17092599) . S2CID 9464592 (http
s://api.semanticscholar.org/CorpusID:9464592) .
 2. Akbarzadeh, A.; Rezaei-Sadabady, R.; Davaran, S.; Joo, S. W.; Zarghami, N.; Hanifehpour, Y.;
Samiei, M.; Kouhi, M.; Nejati-Koshki, K. (22 February 2013). "Liposome: classification,
preparation, and applications" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC359957
3) . Nanoscale Research Letters. 8 (1): 102. Bibcode:2013NRL.....8..102A (https://ui.adsab
s.harvard.edu/abs/2013NRL.....8..102A) . doi:10.1186/1556-276X-8-102 (https://doi.org/1
0.1186%2F1556-276X-8-102) . ISSN 1931-7573 (https://search.worldcat.org/issn/1931-75
73) . PMC 3599573 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3599573) .
PMID 23432972 (https://pubmed.ncbi.nlm.nih.gov/23432972) .

3. "Cell Membranes - Kimball's Biology Pages" (https://web.archive.org/web/2009012522425

5/http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/C/CellMembranes.html#:~:text=
The%20lipids,hydrophilic) . 16 August 2002. Archived from the original (http://users.rcn.co
m/jkimball.ma.ultranet/BiologyPages/C/CellMembranes.html) on 25 January 2009.

4. Mashaghi S., et al. Lipid Nanotechnology. Int J Mol Sci. 2013 Feb; 14(2): 4242–4282.

5. Cevc, G (1993). "Rational design of new product candidates: the next generation of highly
deformable bilayer vesicles for noninvasive, targeted therapy". Journal of Controlled Release.
160 (2): 135–146. doi:10.1016/j.jconrel.2012.01.005 (https://doi.org/10.1016%2Fj.jconrel.2
012.01.005) . PMID 22266051 (https://pubmed.ncbi.nlm.nih.gov/22266051) .

6. Moghassemi, Saeid; Dadashzadeh, Arezoo; Azevedo, Ricardo Bentes; Feron, Olivier; Amorim,
Christiani A. (November 2021). "Photodynamic cancer therapy using liposomes as an
advanced vesicular photosensitizer delivery system". Journal of Controlled Release. 339:
75–90. doi:10.1016/j.jconrel.2021.09.024 (https://doi.org/10.1016%2Fj.jconrel.2021.09.02
4) . PMID 34562540 (https://pubmed.ncbi.nlm.nih.gov/34562540) . S2CID 237636495 (ht
tps://api.semanticscholar.org/CorpusID:237636495) .

7. Moghassemi, Saeid; Dadashzadeh, Arezoo; Azevedo, Ricardo Bentes; Feron, Olivier; Amorim,
Christiani A. (November 2021). "Photodynamic cancer therapy using liposomes as an
advanced vesicular photosensitizer delivery system". Journal of Controlled Release. 339:
75–90. doi:10.1016/j.jconrel.2021.09.024 (https://doi.org/10.1016%2Fj.jconrel.2021.09.02
4) . PMID 34562540 (https://pubmed.ncbi.nlm.nih.gov/34562540) . S2CID 237636495 (ht
tps://api.semanticscholar.org/CorpusID:237636495) .

8. Stryer S. (1981) Biochemistry, 213

9. Mashaghi S., et al. Lipid Nanotechnology. Int J Mol Sci. 2013 Feb; 14(2): 4242–4282.

10. Bangham, A. D.; Horne, R. W. (1964). "Negative Staining of Phospholipids and Their
Structural Modification by Surface-Active Agents As Observed in the Electron Microscope".
Journal of Molecular Biology. 8 (5): 660–668. doi:10.1016/S0022-2836(64)80115-7 (https://
doi.org/10.1016%2FS0022-2836%2864%2980115-7) . PMID 14187392 (https://pubmed.nc
bi.nlm.nih.gov/14187392) .
11. Horne, R. W.; Bangham, A. D.; Whittaker, V. P. (1963). "Negatively Stained Lipoprotein
Membranes" (https://doi.org/10.1038%2F2001340a0) . Nature. 200 (4913): 1340.
Bibcode:1963Natur.200.1340H (https://ui.adsabs.harvard.edu/abs/1963Natur.200.1340
H) . doi:10.1038/2001340a0 (https://doi.org/10.1038%2F2001340a0) . PMID 14098499
(https://pubmed.ncbi.nlm.nih.gov/14098499) . S2CID 4153775 (https://api.semanticschol
ar.org/CorpusID:4153775) .

12. Bangham, A. D.; Horne, R. W.; Glauert, A. M.; Dingle, J. T.; Lucy, J. A. (1962). "Action of
saponin on biological cell membranes". Nature. 196 (4858): 952–955.
Bibcode:1962Natur.196..952B (https://ui.adsabs.harvard.edu/abs/1962Natur.196..952B) .
doi:10.1038/196952a0 (https://doi.org/10.1038%2F196952a0) . PMID 13966357 (https://
pubmed.ncbi.nlm.nih.gov/13966357) . S2CID 4181517 (https://api.semanticscholar.org/C
orpusID:4181517) .

13. Bangham A.D.; Standish M.M.; Weissmann G. (1965). "The action of steroids and
streptolysin S on the permeability of phospholipid structures to cations". J. Molecular Biol.
13 (1): 253–259. doi:10.1016/s0022-2836(65)80094-8 (https://doi.org/10.1016%2Fs0022-2
836%2865%2980094-8) . PMID 5859040 (https://pubmed.ncbi.nlm.nih.gov/5859040) .

14. Sessa G.; Weissmann G. (1970). "Incorporation of lysozyme into liposomes: A model for
structure-linked latency" (https://doi.org/10.1016%2FS0021-9258%2818%2962994-1) . J.
Biol. Chem. 245 (13): 3295–3301. doi:10.1016/S0021-9258(18)62994-1 (https://doi.org/10.
1016%2FS0021-9258%2818%2962994-1) . PMID 5459633 (https://pubmed.ncbi.nlm.nih.g
ov/5459633) .

15. YashRoy R.C. (1990). "Lamellar dispersion and phase separation of chloroplast membrane
lipids by negative staining electron microscopy" (http://www.ias.ac.in/jarch/jbiosci/15/93-9
8.pdf) (PDF). Journal of Biosciences. 15 (2): 93–98. doi:10.1007/bf02703373 (https://doi.
org/10.1007%2Fbf02703373) . S2CID 39712301 (https://api.semanticscholar.org/CorpusI
D:39712301) .

16. Weissmann G.; Sessa G.; Standish M.; Bangham A. D. (1965). "ABSTRACTS" (https://www.nc
bi.nlm.nih.gov/pmc/articles/PMC539946) . J. Clin. Invest. 44 (6): 1109–1116.
doi:10.1172/jci105203 (https://doi.org/10.1172%2Fjci105203) . PMC 539946 (https://ww
w.ncbi.nlm.nih.gov/pmc/articles/PMC539946) .

17. Geoff Watts (2010-06-12). "Alec Douglas Bangham" (http://www.thelancet.com/journals/lan

cet/article/PIIS0140-6736%2810%2960950-6/fulltext) . The Lancet. 375 (9731): 2070.
doi:10.1016/S0140-6736(10)60950-6 (https://doi.org/10.1016%2FS0140-6736%2810%2960
950-6) . S2CID 54382511 (https://api.semanticscholar.org/CorpusID:54382511) .
Retrieved 2014-10-01.
18. Mayer, Lawrence D.; Bally, Marcel B.; Hope, Michael J.; Cullis, Pieter R. (1 June 1986).
"Techniques for encapsulating bioactive agents into liposomes" (https://www.sciencedirect.
com/science/article/abs/pii/0009308486900770) . Chemistry and Physics of Lipids. 40
(2): 333–345. doi:10.1016/0009-3084(86)90077-0 (https://doi.org/10.1016%2F0009-3084%
2886%2990077-0) . ISSN 0009-3084 (https://search.worldcat.org/issn/0009-3084) .
PMID 3742676 (https://pubmed.ncbi.nlm.nih.gov/3742676) .

19. Chaize, Barnabé; Colletier, Jacques-Philippe; Winterhalter, Mathias; Fournier, Didier (January
2004). "Encapsulation of Enzymes in Liposomes: High Encapsulation Efficiency and Control
of Substrate Permeability" (https://doi.org/10.1081%2FBIO-120028669) . Artificial Cells,
Blood Substitutes, and Biotechnology. 32 (1): 67–75. doi:10.1081/BIO-120028669 (https://d
oi.org/10.1081%2FBIO-120028669) . ISSN 1073-1199 (https://search.worldcat.org/issn/10
73-1199) . PMID 15027802 (https://pubmed.ncbi.nlm.nih.gov/15027802) .
S2CID 21897676 (https://api.semanticscholar.org/CorpusID:21897676) .

20. Colletier, Jacques-Philippe; Chaize, Barnabé; Winterhalter, Mathias; Fournier, Didier (10 May
2002). "Protein encapsulation in liposomes: efficiency depends on interactions between
protein and phospholipid bilayer" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11374
1) . BMC Biotechnology. 2 (1): 9. doi:10.1186/1472-6750-2-9 (https://doi.org/10.1186%2F1
472-6750-2-9) . ISSN 1472-6750 (https://search.worldcat.org/issn/1472-6750) .
PMC 113741 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC113741) . PMID 12003642
(https://pubmed.ncbi.nlm.nih.gov/12003642) .

21. Edwards, Katie A.; Baeumner, Antje J. (28 February 2006). "Analysis of liposomes" (https://w
ww.sciencedirect.com/science/article/abs/pii/S0039914005005436) . Talanta. 68 (5):
1432–1441. doi:10.1016/j.talanta.2005.08.031 (https://doi.org/10.1016%2Fj.talanta.2005.0
8.031) . ISSN 0039-9140 (https://search.worldcat.org/issn/0039-9140) . PMID 18970482
(https://pubmed.ncbi.nlm.nih.gov/18970482) .

22. Longatte, Guillaume; Lisi, Fabio; Chen, Xueqian; Walsh, James; Wang, Wenqian; Ariotti,
Nicholas; Boecking, Till; Gaus, Katharina; Gooding, J. Justin (23 November 2022).
"Statistical predictions on the encapsulation of single molecule binding pairs into sized-
dispersed nanocontainers" (https://pubs.rsc.org/en/content/articlelanding/2022/cp/d2cp0
3627d) . Physical Chemistry Chemical Physics. 24 (45): 28029–28039.
Bibcode:2022PCCP...2428029L (https://ui.adsabs.harvard.edu/abs/2022PCCP...2428029
L) . doi:10.1039/D2CP03627D (https://doi.org/10.1039%2FD2CP03627D) .
hdl:1959.4/unsworks_83972 (https://hdl.handle.net/1959.4%2Funsworks_83972) .
ISSN 1463-9084 (https://search.worldcat.org/issn/1463-9084) . PMID 36373851 (https://p
ubmed.ncbi.nlm.nih.gov/36373851) .
23. Cevc, G; Richardsen, H (1993). "Lipid vesicles and membrane fusion". Advanced Drug
Delivery Reviews. 38 (3): 207–232. doi:10.1016/s0169-409x(99)00030-7 (https://doi.org/10.
1016%2Fs0169-409x%2899%2900030-7) . PMID 10837758 (https://pubmed.ncbi.nlm.nih.g
ov/10837758) .

24. Barenholz, Y; G, Cevc (2000). Physical chemistry of biological surfaces, Chapter 7: Structure
and properties of membranes. New York: Marcel Dekker. pp. 171–241.

25. Bertrand, Nicolas; Bouvet, CéLine; Moreau, Pierre; Leroux, Jean-Christophe (2010).
"Transmembrane pH-Gradient Liposomes to Treat Cardiovascular Drug Intoxication" (http
s://figshare.com/articles/Transmembrane_pH_Gradient_Liposomes_To_Treat_Cardiovascul
ar_Drug_Intoxication/2702173) . ACS Nano. 4 (12): 7552–8. doi:10.1021/nn101924a (http
s://doi.org/10.1021%2Fnn101924a) . PMID 21067150 (https://pubmed.ncbi.nlm.nih.gov/2
1067150) .

26. Paliwal, Shivani Rai; Paliwal, Rishi; Vyas, Suresh P. (2015-04-03). "A review of mechanistic
insight and application of pH-sensitive liposomes in drug delivery" (http://www.tandfonline.
com/doi/full/10.3109/10717544.2014.882469) . Drug Delivery. 22 (3): 231–242.
doi:10.3109/10717544.2014.882469 (https://doi.org/10.3109%2F10717544.2014.88246
9) . ISSN 1071-7544 (https://search.worldcat.org/issn/1071-7544) . PMID 24524308 (htt
ps://pubmed.ncbi.nlm.nih.gov/24524308) .

27. Anonymous (2018-09-17). "EU/3/07/451" (https://www.ema.europa.eu/en/medicines/huma

n/orphan-designations/eu307451) . European Medicines Agency. Retrieved 2020-01-10.

28. Georgievski A, Bellaye PS, Tournier B, Choubley H, Pais de Barros JP, Herbst M, Béduneau A,
Callier P, Collin B, Végran F, Ballerini P, Garrido C, Quéré R (May 2024). "Valrubicin-loaded
immunoliposomes for specific vesicle-mediated cell death in the treatment of
hematological cancers" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11088660) . Cell
Death Dis. 15 (15(5):328): 328. doi:10.1038/s41419-024-06715-5 (https://doi.org/10.1038%
2Fs41419-024-06715-5) . PMC 11088660 (https://www.ncbi.nlm.nih.gov/pmc/articles/PM
C11088660) . PMID 38734740 (https://pubmed.ncbi.nlm.nih.gov/38734740) .

29. Barani, H; Montazer, M (2008). "A review on applications of liposomes in textile processing".
Journal of Liposome Research. 18 (3): 249–62. doi:10.1080/08982100802354665 (https://d
oi.org/10.1080%2F08982100802354665) . PMID 18770074 (https://pubmed.ncbi.nlm.nih.
gov/18770074) . S2CID 137500401 (https://api.semanticscholar.org/CorpusID:13750040
1) .

30. Meure, LA; Knott, R; Foster, NR; Dehghani, F (2009). "The depressurization of an expanded
solution into aqueous media for the bulk production of liposomes". Langmuir: The ACS
Journal of Surfaces and Colloids. 25 (1): 326–37. doi:10.1021/la802511a (https://doi.org/1
0.1021%2Fla802511a) . PMID 19072018 (https://pubmed.ncbi.nlm.nih.gov/19072018) .
31. Yoko Shojia; Hideki Nakashima (2004). "Nutraceutics and Delivery Systems". Journal of
Drug Targeting.

32. Williamson, G; Manach, C (2005). "Bioavailability and bioefficacy of polyphenols in humans.

II. Review of 93 intervention studies" (https://doi.org/10.1093%2Fajcn%2F81.1.243S) . The
American Journal of Clinical Nutrition. 81 (1 Suppl): 243S – 255S.
doi:10.1093/ajcn/81.1.243S (https://doi.org/10.1093%2Fajcn%2F81.1.243S) .
PMID 15640487 (https://pubmed.ncbi.nlm.nih.gov/15640487) .

33. Bender, David A. (2003). Nutritional Biochemistry of Vitamins. Cambridge, U.K.: Cambridge
University Press. OCLC 57204737 (https://search.worldcat.org/oclc/57204737) .

34. DeFelice, Stephen L. (February 1995). "The nutraceutical revolution: its impact on food
industry R&D" (https://dx.doi.org/10.1016/s0924-2244(00)88944-x) . Trends in Food
Science & Technology. 6 (2): 59–61. doi:10.1016/s0924-2244(00)88944-x (https://doi.org/1
0.1016%2Fs0924-2244%2800%2988944-x) . ISSN 0924-2244 (https://search.worldcat.org/
issn/0924-2244) .

35. Santini, Antonello; Cammarata, Silvia Miriam; Capone, Giacomo; Ianaro, Angela; Tenore, Gian
Carlo; Pani, Luca; Novellino, Ettore (2018-02-14). "Nutraceuticals: opening the debate for a
regulatory framework" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5867125) . British
Journal of Clinical Pharmacology. 84 (4): 659–672. doi:10.1111/bcp.13496 (https://doi.org/
10.1111%2Fbcp.13496) . ISSN 0306-5251 (https://search.worldcat.org/issn/0306-5251) .
PMC 5867125 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5867125) .
PMID 29433155 (https://pubmed.ncbi.nlm.nih.gov/29433155) .

36. Porter, Christopher J. H.; Trevaskis, Natalie L.; Charman, William N. (March 2007). "Lipids
and lipid-based formulations: optimizing the oral delivery of lipophilic drugs" (https://dx.doi.
org/10.1038/nrd2197) . Nature Reviews Drug Discovery. 6 (3): 231–248.
doi:10.1038/nrd2197 (https://doi.org/10.1038%2Fnrd2197) . ISSN 1474-1776 (https://sear
ch.worldcat.org/issn/1474-1776) . PMID 17330072 (https://pubmed.ncbi.nlm.nih.gov/173
30072) . S2CID 29805601 (https://api.semanticscholar.org/CorpusID:29805601) .

37. Szoka Jr, F; Papahadjopoulos, D (1980). "Comparative properties and methods of

preparation of lipid vesicles (liposomes)". Annual Review of Biophysics and Bioengineering.
9: 467–508. doi:10.1146/annurev.bb.09.060180.002343 (https://doi.org/10.1146%2Fannure
v.bb.09.060180.002343) . PMID 6994593 (https://pubmed.ncbi.nlm.nih.gov/6994593) .

38. Gomezhens, A; Fernandezromero, J (2006). "Analytical methods for the control of liposomal
delivery systems". TrAC Trends in Analytical Chemistry. 25 (2): 167–178.
doi:10.1016/j.trac.2005.07.006 (https://doi.org/10.1016%2Fj.trac.2005.07.006) .
39. Mozafari, MR; Johnson, C; Hatziantoniou, S; Demetzos, C (2008). "Nanoliposomes and their
applications in food nanotechnology". Journal of Liposome Research. 18 (4): 309–27.
doi:10.1080/08982100802465941 (https://doi.org/10.1080%2F08982100802465941) .
PMID 18951288 (https://pubmed.ncbi.nlm.nih.gov/18951288) . S2CID 98836972 (https://a
pi.semanticscholar.org/CorpusID:98836972) .

40. Jahn, Andreas; Stavis, Samuel M.; Hong, Jennifer S.; Vreeland, Wyatt N.; DeVoe, Don L.;
Gaitan, Michael (2010-04-27). "Microfluidic Mixing and the Formation of Nanoscale Lipid
Vesicles". ACS Nano. 4 (4): 2077–2087. doi:10.1021/nn901676x (https://doi.org/10.1021%2
Fnn901676x) . ISSN 1936-0851 (https://search.worldcat.org/issn/1936-0851) .
PMID 20356060 (https://pubmed.ncbi.nlm.nih.gov/20356060) .

41. Zhigaltsev, Igor V.; Belliveau, Nathan; Hafez, Ismail; Leung, Alex K. K.; Huft, Jens; Hansen,
Carl; Cullis, Pieter R. (2012-02-21). "Bottom-Up Design and Synthesis of Limit Size Lipid
Nanoparticle Systems with Aqueous and Triglyceride Cores Using Millisecond Microfluidic
Mixing". Langmuir. 28 (7): 3633–3640. doi:10.1021/la204833h (https://doi.org/10.1021%2Fl
a204833h) . ISSN 0743-7463 (https://search.worldcat.org/issn/0743-7463) .
PMID 22268499 (https://pubmed.ncbi.nlm.nih.gov/22268499) .

42. López, Rubén R.; Ocampo, Ixchel; Sánchez, Luz-María; Alazzam, Anas; Bergeron, Karl-F.;
Camacho-León, Sergio; Mounier, Catherine; Stiharu, Ion; Nerguizian, Vahé (2020-02-25).
"Surface Response Based Modeling of Liposome Characteristics in a Periodic Disturbance
Mixer" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7143066) . Micromachines. 11
(3): 235. doi:10.3390/mi11030235 (https://doi.org/10.3390%2Fmi11030235) . ISSN 2072-
666X (https://search.worldcat.org/issn/2072-666X) . PMC 7143066 (https://www.ncbi.nl
m.nih.gov/pmc/articles/PMC7143066) . PMID 32106424 (https://pubmed.ncbi.nlm.nih.go
v/32106424) .

43. Colas, JC; Shi, W; Rao, VS; Omri, A; Mozafari, MR; Singh, H (2007). "Microscopical
investigations of nisin-loaded nanoliposomes prepared by Mozafari method and their
bacterial targeting". Micron. 38 (8): 841–7. doi:10.1016/j.micron.2007.06.013 (https://doi.or
g/10.1016%2Fj.micron.2007.06.013) . PMID 17689087 (https://pubmed.ncbi.nlm.nih.gov/
17689087) .

44. Blume, G; Cevc, G (1990). "Liposomes for the sustained drug release in vivo". Biochimica et
Biophysica Acta (BBA) - Biomembranes. 1029 (1): 92–97. doi:10.1016/0005-2736(90)90440-
y (https://doi.org/10.1016%2F0005-2736%2890%2990440-y) . PMID 2223816 (https://pub
med.ncbi.nlm.nih.gov/2223816) .
45. Klibanov, AL; Maruyama, K; Torchilin, VP; Huang, L (1990). "Amphipathic polyethyleneglycols
effectively prolong the circulation time of liposomes" (https://doi.org/10.1016%2F0014-579
3%2890%2981016-h) . FEBS Letters. 268 (1): 235–237. Bibcode:1990FEBSL.268..235K (htt
ps://ui.adsabs.harvard.edu/abs/1990FEBSL.268..235K) . doi:10.1016/0014-
5793(90)81016-h (https://doi.org/10.1016%2F0014-5793%2890%2981016-h) .
PMID 2384160 (https://pubmed.ncbi.nlm.nih.gov/2384160) . S2CID 11437990 (https://api.
semanticscholar.org/CorpusID:11437990) .

46. Wang, XinYu; Ishida, Tatsuhiro; Kiwada, Hiroshi (2007-06-01). "Anti-PEG IgM elicited by
injection of liposomes is involved in the enhanced blood clearance of a subsequent dose of
PEGylated liposomes". Journal of Controlled Release. 119 (2): 236–244.
doi:10.1016/j.jconrel.2007.02.010 (https://doi.org/10.1016%2Fj.jconrel.2007.02.010) .
ISSN 0168-3659 (https://search.worldcat.org/issn/0168-3659) . PMID 17399838 (https://p
ubmed.ncbi.nlm.nih.gov/17399838) .

47. Dams, E.T.M.; Laverman, P.; Oyen, W.J.G.; Storm, G.; Scherphof, G.L.; Meer, J.W.M.; van der
Corstens, F.H.M.; Boerman, O.C. (March 2000). "Accelerated blood clearance and altered
biodistribution of repeated injections of sterically stabilized liposomes". The Journal of
Pharmacology and Experimental Therapeutics. 292 (3). Amer soc pharmacology
experimental therapeutics: 1071–9. PMID 10688625 (https://pubmed.ncbi.nlm.nih.gov/106
88625) .

48. Blume, G; Cevc, G; Crommelin, M D A J; Bakker-Woudenberg, I A J M; Kluft, C; Storm, G

(1993). "Specific targeting with poly (ethylene glycol)-modified liposomes: coupling of
homing devices to the ends of the polymeric chains combines effective target binding with
long circulation times". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1149 (1): 180–
184. doi:10.1016/0005-2736(93)90039-3 (https://doi.org/10.1016%2F0005-2736%2893%29
90039-3) . PMID 8318529 (https://pubmed.ncbi.nlm.nih.gov/8318529) .

49. Cevc, G (2004). "Lipid vesicles and other colloids as drug carriers on the skin". Advanced
Drug Delivery Reviews. 56 (5): 675–711. doi:10.1016/j.addr.2003.10.028 (https://doi.org/10.
1016%2Fj.addr.2003.10.028) . PMID 15019752 (https://pubmed.ncbi.nlm.nih.gov/1501975
2) .

50. Besançon, Hervé; Babiychuk, Viktoriia; Larpin, Yu; Köffel, René; Schittny, Dominik; Brockhus,
Lara; Hathaway, Lucy J.; Sendi, Parham; Draeger, Annette; Babiychuk, Eduard (14 February
2021). "Tailored liposomal nanotraps for the treatment of Streptococcal infections" (https://
www.ncbi.nlm.nih.gov/pmc/articles/PMC7885208) . Journal of Nanobiotechnology. 19 (1):
46. doi:10.1186/s12951-021-00775-x (https://doi.org/10.1186%2Fs12951-021-00775-x) .
PMC 7885208 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885208) .
PMID 33588835 (https://pubmed.ncbi.nlm.nih.gov/33588835) ..
51. Karny, Avishai; Zinger, Assaf; Kajal, Ashima; Shainsky-Roitman, Janna; Schroeder, Avi (2018-
05-17). "Therapeutic nanoparticles penetrate leaves and deliver nutrients to agricultural
crops" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5958142) . Scientific Reports. 8
(1): 7589. Bibcode:2018NatSR...8.7589K (https://ui.adsabs.harvard.edu/abs/2018NatSR...8.
7589K) . doi:10.1038/s41598-018-25197-y (https://doi.org/10.1038%2Fs41598-018-25197
-y) . ISSN 2045-2322 (https://search.worldcat.org/issn/2045-2322) . PMC 5958142 (http
s://www.ncbi.nlm.nih.gov/pmc/articles/PMC5958142) . PMID 29773873 (https://pubmed.
ncbi.nlm.nih.gov/29773873) .

52. Temming, Maria (2018-05-17). "Nanoparticles could help rescue malnourished crops" (http
s://www.sciencenews.org/article/nanoparticles-could-help-rescue-malnourished-crops?tgt=
nr) . Science News. Retrieved 2018-05-18.

53. John-Herpin, Aurelian; Kavungal, Deepthy; von Mücke, Lea; Altug, Hatice (2020). "Infrared
Metasurface Augmented by Deep Learning for Monitoring Dynamics between All Major
Classes of Biomolecules" (https://doi.org/10.1002%2Fadma.202006054) . Advanced
Materials. 33 (14): e2006054. doi:10.1002/adma.202006054 (https://doi.org/10.1002%2Fad
ma.202006054) . PMID 33615570 (https://pubmed.ncbi.nlm.nih.gov/33615570) .

54. Arulsudar, N.; Subramanian, N.; Murthy, R. S. R. (2005). "Comparison of artificial neural
network and multiple linear regression in the optimization of formulation parameters of
leuprolide acetate loaded liposomes". J Pharm Pharm Sci. 8 (2): 243–258. PMID 16124936
(https://pubmed.ncbi.nlm.nih.gov/16124936) .

55. Sansare, Sameera; Duran, Tibo; Mohammadiarani, Hossein; Goyal, Manish; Yenduri,
Gowtham; Costa, Antonio; Xu, Xiaoming; O'Connor, Thomas; Burgess, Diane; Chaudhuri,
Bodhisattwa (2021). "Artificial neural networks in tandem with molecular descriptors as
predictive tools for continuous liposome manufacturing". International Journal of
Pharmaceutics. 603 (120713): 120713. doi:10.1016/j.ijpharm.2021.120713 (https://doi.org/
10.1016%2Fj.ijpharm.2021.120713) . PMID 34019974 (https://pubmed.ncbi.nlm.nih.gov/3
4019974) . S2CID 235093636 (https://api.semanticscholar.org/CorpusID:235093636) .

External links

Journal of Liposome Research (http://informahealthcare.com/loi/lpr)