Solid lipid nanoparticle

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Lipid nanoparticles
)
See also:
RNA vaccine and DNA vaccine
antibodies
, cell-targeting peptides, and/or other drug molecules can be bound to the exterior surface of the SLN.
antibiotics, cosmetics
and many others.
Part of a series of articles on
Nanomaterials
Carbon nanotubes
Fullerenes
Other nanoparticles
Nanostructured materials

Lipid nanoparticles (LNPs) are

mRNA strands with PEGylated lipid nanoparticles as their delivery vehicle (including both the Moderna and the Pfizer–BioNTech COVID-19 vaccines).[4]

Characteristics

A lipid nanoparticle is typically

emulsifiers (with respect to charge and molecular weight) have been used to stabilize the lipid dispersion. It has been found that the combination of emulsifiers might prevent particle agglomeration more efficiently.[5][6]

An SLN is generally spherical in shape and consists of a solid lipid core stabilized by a surfactant. The core lipids can be fatty acids, acylglycerols, waxes, and mixtures of these surfactants. Biological membrane lipids such as

sterols (cholesterol) are utilized as stabilizers. Biological lipids having minimum carrier cytotoxicity and the solid state of the lipid permit better controlled drug release due to increased mass transfer resistance.[7] Shah et al. in their book Lipid Nanoparticles: Production, Characterization and Stability discuss these in detail.[citation needed
]

LNPs used in

COVID-19) are made of four types of lipids: an ionizable cationic lipid (whose positive charge binds to negatively charged mRNA), a PEGylated lipid (for stability), a phospholipid (for structure), and cholesterol (for structure).[8] Because of rapid clearance by the immune system of the positively charged lipid, neutral ionizable amino lipids were developed. A novel squaramide lipid (that is, partially aromatic four-membered rings, which can participate in pi–pi interactions) has been a favored part of the delivery system used, for example, by Moderna.[9]

Synthesis

Different formulation procedures include high shear homogenization and ultrasound, solvent emulsification/evaporation, or microemulsion. Obtaining size distributions in the range of 30-180 nm is possible using ultrasonification at the cost of long sonication time. Solvent-emulsification is suitable in preparing small, homogeneously sized lipid nanoparticles dispersions with the advantage of avoiding heat.[10]

The obtained LNP formulation can subsequently be filled into sterile containers and subjected to final quality control. However, various measures to monitor and evaluate product quality are integrated in every step of LNP manufacturing and include testing of polydispersity, particle size, drug loading efficiency and endotoxin levels.[11]

Applications

Development of solid lipid

clinical medicine and research, as well as in other disciplines. Due to their unique size-dependent properties, lipid nanoparticles offer the possibility to develop new therapeutics. The ability to incorporate drugs into nanocarriers offers a new prototype in drug delivery that could hold great promise for attaining the bioavailability enhancement along with controlled and site-specific drug delivery. SLN's are also considered to well tolerated in general, due to their composition from physiologically similar lipids.[citation needed
]

The conventional approaches such as use of permeation enhancers, surface modification, prodrug synthesis, complex formation and colloidal lipid carrier-based strategies have been developed for the delivery of drugs to intestinal lymphatics. In addition, polymeric nanoparticles, self-emulsifying delivery systems, liposomes, microemulsions, micellar solutions and recently solid lipid nanoparticles (SLN) have been exploited as probable possibilities as carriers for oral intestinal lymphatic delivery.[13]

Drug delivery

Solid lipid nanoparticles can function as the basis for oral and parenteral

gastric and intestinal acids that dissolve the SLNs and release the drugs into the system.[18]

Many nano-structured systems have been employed for

hydrophilic and lipophilic drugs.[19] Solid lipid nanoparticles have another advantage of allowing autoclave sterilization, a necessary step towards formulation of ocular preparations.[20]

Advantages of SLNs include the use of physiological lipids (which decreases the danger of acute and chronic toxicity), the avoidance of organic solvents, a potential wide application spectrum (

intravenous) and the high pressure homogenization as an established production method. Additionally, improved bioavailability, protection of sensitive drug molecules from the outer environment water, light) and even controlled release characteristics were claimed by the incorporation of poorly water-soluble drugs in the solid lipid matrix. Moreover, SLN can carry both lipophilic and hydrophilic drugs and are more affordable compared to polymeric/surfactant-based carriers.[21]

Nucleic acids

A significant obstacle to using LNPs as a delivery vehicle for nucleic acids is that in nature, lipids and nucleic acids both carry a negative electric charge—meaning they do not easily mix with each other.[22] While working at Syntex in the mid-1980s,[23] Philip Felgner pioneered the use of artificially-created cationic lipids (positively-charged lipids) to bind lipids to nucleic acids in order to transfect the latter into cells.[24] However, by the late 1990s, it was known from in vitro experiments that this use of cationic lipids had undesired side effects on cell membranes.[25]

During the late 1990s and 2000s, Pieter Cullis of the University of British Columbia developed ionizable cationic lipids which are "positively charged at an acidic pH but neutral in the blood."[8] Cullis also led the development of a technique involving careful adjustments to pH during the process of mixing ingredients in order to create LNPs which could safely pass through the cell membranes of living organisms.[22][26] As of 2021, the current understanding of LNPs formulated with such ionizable cationic lipids is that they enter cells through receptor-mediated endocytosis and end up inside endosomes.[8] The acidity inside the endosomes causes LNPs' ionizable cationic lipids to acquire a positive charge, and this is thought to allow LNPs to escape from endosomes and release their RNA payloads.[8]

From 2005 into the early 2010s, LNPs were investigated as a drug delivery system for small interfering RNA (siRNA) drugs.[8] In 2009, Cullis co-founded a company called Acuitas Therapeutics to commercialize his LNP research; Acuitas worked on developing LNPs for Alnylam Pharmaceuticals's siRNA drugs.[27] In 2018, the FDA approved Alnylam's siRNA drug Onpattro (patisiran), the first drug to use LNPs as the drug delivery system.[3][8]

By that point in time, siRNA drug developers like Alnylam were already looking at other options for future drugs like chemical conjugate systems, but during the 2010s, the earlier research into using LNPs for siRNA became a foundation for new research into using LNPs for mRNA.[8] Lipids intended for short siRNA strands did not work well for much longer mRNA strands, which led to extensive research during the mid-2010s into the creation of novel ionizable cationic lipids appropriate for mRNA.[8] As of late 2020, several mRNA vaccines for SARS-CoV-2 use LNPs as their drug delivery system, including both the Moderna COVID-19 vaccine and the Pfizer–BioNTech COVID-19 vaccines.[3] Moderna uses its own proprietary ionizable cationic lipid called SM-102, while Pfizer and BioNTech licensed an ionizable cationic lipid called ALC-0315 from Acuitas.[8]

Lymphatic absorption mechanism

Elucidation of intestinal lymphatic absorption mechanism from solid lipid nanoparticles using Caco-2 cell line as in vitro model was developed.[28] Several researchers have shown the enhancement of oral bioavailibility of poorly water-soluble drugs when encapsulated in solid lipid nanoparticle. This enhanced bioavailibility is achieved via lymphatic delivery. To elucidate the absorption mechanism, from solid lipid nanoparticle, human excised Caco-2 cell monolayer could be alternative tissue for development of an in-vitro model to be used as a screening tool before animal studies are undertaken. The results obtained in this model suggested that the main absorption mechanism of carvedilol loaded solid lipid nanoparticle could be endocytosis and, more specifically, clathrin-mediated endocytosis. [17]

See also

References

  1. ISBN 978-1-4020-5040-4
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  2. PMID 10802410
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  3. ^ a b c Cooney, Elizabeth (1 December 2020). "How nanotechnology helps mRNA Covid-19 vaccines work". Stat. Retrieved 3 December 2020.
  4. PMID 29326426
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  5. ^ a b c d Mehnert et al., 2001
  6. ^ Small, 1986
  7. ^ Manzunath et al., 2005
  8. ^ a b c d e f g h i Cross, Ryan (March 6, 2021). "Without these lipid shells, there would be no mRNA vaccines for COVID-19". Chemical & Engineering News. American Chemical Society. Retrieved March 6, 2021.
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  10. ^ Wolfgang Mehnert, Karsten Mäder, Solid lipid nanoparticles: Production, characterization and applications, Advanced Drug Delivery Reviews, Volume 64, 2012, Pages 83-101, ISSN 0169-409X, https://doi.org/10.1016/j.addr.2012.09.021
  11. ^ Marciniak, Mike (June 21, 2023). "Lipid nanoparticle (LNP) manufacturing: Challenges & Solutions". Retrieved July 5, 2023.
  12. ^ Mashaghi, S.; Jadidi, T.; Koenderink, G.; Mashaghi, A. Lipid Nanotechnology. Int. J. Mol. Sci. 2013, 14, 4242-4282.[1]
  13. ^ Studies on binary lipid matrix-based solid lipid nanoparticles of repaglinide: in vitro and in vivo evaluation. Rawat MK, Jain A and Singh S, Journal of Pharmaceutical Sciences, 2011, volume 100, issue 6, pages 2366-2378
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  21. ^ Mukherjee, S et al. “Solid lipid nanoparticles: a modern formulation approach in drug delivery system.” Indian journal of pharmaceutical sciences vol. 71,4 (2009): 349-58. doi:10.4103/0250-474X.57282
  22. ^ a b Foley, Katherine Ellen (22 December 2020). "The first Covid-19 vaccines have changed biotech forever". Quartz. Quartz Media. Retrieved 11 January 2021.
  23. ^ Jones, Mark (22 July 1997). "Phil Felgner Interview – July 22, 1997". UC San Diego Library: San Diego Technology Archive. Regents of the University of California.
  24. ISBN 9780203300961
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  25. ISBN 9780849331091
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  27. ^ Shore, Randy (November 17, 2020). "COVID-19: Vancouver's Acuitas Therapeutics a key contributor to coronavirus solution". Vancouver Sun.
  28. S2CID 40506806
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Further reading

External links

Scholia has a profile for solid lipid nanoparticle (Q7557912).
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