Solid lipid nanoparticle

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Solid lipid nanoparticles (SLNs). There is only one phospholipid layer because the bulk of the interior of the particle is composed of lipophilic substance. Payloads such as modRNA, RNA vaccine or others can be embedded in the interior, as desired. Optionally, targeting-molecules such as antibodies, cell-targeting peptides, and/or other drug molecules can be bound to the exterior surface of the SLN. SolidLipidNanoparticle.jpg
Solid lipid nanoparticles (SLNs). There is only one phospholipid layer because the bulk of the interior of the particle is composed of lipophilic substance. Payloads such as modRNA, RNA vaccine or others can be embedded in the interior, as desired. Optionally, targeting-molecules such as antibodies, cell-targeting peptides, and/or other drug molecules can be bound to the exterior surface of the SLN.
Liposomes are ("hollow") lipid nanoparticles which have a phospholipid bilayer as coat, because the bulk of the interior of the particle is composed of aqueous substance. In various popular uses, the optional payload is e.g. DNA vaccines, Gene therapy, vitamins, antibiotics, cosmetics and many others. Liposome.jpg
Liposomes are ("hollow") lipid nanoparticles which have a phospholipid bilayer as coat, because the bulk of the interior of the particle is composed of aqueous substance. In various popular uses, the optional payload is e.g. DNA vaccines, Gene therapy, vitamins, antibiotics, cosmetics and many others.

Lipid nanoparticles (LNPs) are nanoparticles composed of lipids. They are a novel pharmaceutical drug delivery system (and part of nanoparticle drug delivery), and a novel pharmaceutical formulation. [1] [2] LNPs as a drug delivery vehicle were first approved in 2018 for the siRNA drug Onpattro. [3] LNPs became more widely known in late 2020, as some COVID-19 vaccines that use RNA vaccine technology coat the fragile mRNA strands with PEGylated lipid nanoparticles as their delivery vehicle (including both the Moderna and the Pfizer–BioNTech COVID-19 vaccines). [4]

Contents

Characteristics

A lipid nanoparticle is typically spherical with an average diameter between 10 and 1000 nanometers. Solid lipid nanoparticles possess a solid lipid core matrix that can solubilize lipophilic molecules. The lipid core is stabilized by surfactants (emulsifiers). The emulsifier used depends on administration routes and is more limited for parenteral administrations. [5] The term lipid is used here in a broader sense and includes triglycerides (e.g. tristearin), diglycerides (e.g. glycerol bahenate), monoglycerides (e.g. glycerol monostearate), fatty acids (e.g. stearic acid), steroids (e.g. cholesterol), and waxes (e.g. cetyl palmitate). All classes of 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 phospholipids, sphingomyelins, bile salts (sodium taurocholate), and 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 mRNA vaccines for SARS-CoV-2 (the virus that causes 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 nanoparticles is one of the emerging fields of lipid nanotechnology (for a review on lipid nanotechnology, see [12] ) with several potential applications in drug delivery, 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 drug delivery systems. SLNs combine the advantages of lipid emulsion and polymeric nanoparticle systems while overcoming the temporal and in vivo stability issues that troubles the conventional as well as polymeric nanoparticles drug delivery approaches. [5] It has been proposed that SLNs combine numerous advantages over the other colloidal carriers i.e. incorporation of lipophilic and hydrophilic drugs feasible, no biotoxicity of the carrier, avoidance of organic solvents, possibility of controlled drug release and drug targeting, increased drug stability and no problems with respect to large scale production. [5] Furthermore, various functions such as molecules for targeting, PEG chains for stealth properties [14] or thiol groups for adhesion via disulfide bond formation [15] can be immobilized on their surface. A recent study has demonstrated the use of solid lipid nanoparticles as a platform for oral delivery of the nutrient mineral iron, by incorporating the hydrophilic molecule ferrous sulfate (FeSO4) in a lipid matrix composed of stearic acid. [16] Carvedilol-loaded solid lipid nanoparticles were prepared using hot-homogenization technique for oral delivery using compritol and poloxamer 188 as a lipid and surfactant, respectively. [17] Another example of drug delivery using SLN would be oral solid SLN suspended in distilled water, which was synthesized to trap drugs within the SLN structure. Upon indigestion, the SLNs are exposed to gastric and intestinal acids that dissolve the SLNs and release the drugs into the system. [18]

Many nano-structured systems have been employed for ocular drug delivery and yielded some promising results. SLNs have been looked at as a potential drug carrier system since the 1990s. SLNs do not show biotoxicity as they are prepared from physiological lipids. SLNs are especially useful in ocular drug delivery as they can enhance the corneal absorption of drugs and improve the ocular bioavailability of both 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 (dermal, per os, 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

Related Research Articles

<span class="mw-page-title-main">Emulsion</span> Mixture of two or more immiscible liquids

An emulsion is a mixture of two or more liquids that are normally immiscible owing to liquid-liquid phase separation. Emulsions are part of a more general class of two-phase systems of matter called colloids. Although the terms colloid and emulsion are sometimes used interchangeably, emulsion should be used when both phases, dispersed and continuous, are liquids. In an emulsion, one liquid is dispersed in the other. Examples of emulsions include vinaigrettes, homogenized milk, liquid biomolecular condensates, and some cutting fluids for metal working.

<span class="mw-page-title-main">Polysorbate 80</span> Nonionic surfactant and emulsifier used in food and cosmetics

Polysorbate 80 is a nonionic surfactant and emulsifier often used in pharmaceuticals, foods, and cosmetics. This synthetic compound is a viscous, water-soluble yellow liquid.

<span class="mw-page-title-main">Cationic liposome</span>

Cationic liposomes are spherical structures that contain positively charged lipids. Cationic liposomes can vary in size between 40 nm and 500 nm, and they can either have one lipid bilayer (monolamellar) or multiple lipid bilayers (multilamellar). The positive charge of the phospholipids allows cationic liposomes to form complexes with negatively charged nucleic acids through ionic interactions. Upon interacting with nucleic acids, cationic liposomes form clusters of aggregated vesicles. These interactions allow cationic liposomes to condense and encapsulate various therapeutic and diagnostic agents in their aqueous compartment or in their lipid bilayer. These cationic liposome-nucleic acid complexes are also referred to as lipoplexes. Due to the overall positive charge of cationic liposomes, they interact with negatively charged cell membranes more readily than classic liposomes. This positive charge can also create some issues in vivo, such as binding to plasma proteins in the bloodstream, which leads to opsonization. These issues can be reduced by optimizing the physical and chemical properties of cationic liposomes through their lipid composition. Cationic liposomes are increasingly being researched for use as delivery vectors in gene therapy due to their capability to efficiently transfect cells. A common application for cationic liposomes is cancer drug delivery.

<span class="mw-page-title-main">Drug delivery</span> Methods for delivering drugs to target sites

Drug delivery refers to approaches, formulations, manufacturing techniques, storage systems, and technologies involved in transporting a pharmaceutical compound to its target site to achieve a desired therapeutic effect. Principles related to drug preparation, route of administration, site-specific targeting, metabolism, and toxicity are used to optimize efficacy and safety, and to improve patient convenience and compliance. Drug delivery is aimed at altering a drug's pharmacokinetics and specificity by formulating it with different excipients, drug carriers, and medical devices. There is additional emphasis on increasing the bioavailability and duration of action of a drug to improve therapeutic outcomes. Some research has also been focused on improving safety for the person administering the medication. For example, several types of microneedle patches have been developed for administering vaccines and other medications to reduce the risk of needlestick injury.

<span class="mw-page-title-main">PEGylation</span> Chemical reaction

PEGylation is the process of both covalent and non-covalent attachment or amalgamation of polyethylene glycol polymer chains to molecules and macrostructures, such as a drug, therapeutic protein or vesicle, which is then described as PEGylated. PEGylation affects the resulting derivatives or aggregates interactions, which typically slows down their coalescence and degradation as well as elimination in vivo.

A self-microemulsifying drug delivery system (SMEDDS) is a drug delivery system that uses a microemulsion achieved by chemical rather than mechanical means. That is, by an intrinsic property of the drug formulation, rather than by special mixing and handling. It employs the familiar ouzo effect displayed by anethole in many anise-flavored liquors. Microemulsions have significant potential for use in drug delivery, and SMEDDS are the best of these systems identified to date. SMEDDS are of particular value in increasing the absorption of lipophilic drugs taken by mouth.

Biomagnetics is a field of biotechnology. It has actively been researched since at least 2004. Although the majority of structures found in living organisms are diamagnetic, the magnetic field itself, as well as magnetic nanoparticles, microstructures and paramagnetic molecules can influence specific physiological functions of organisms under certain conditions. The effect of magnetic fields on biosystems is a topic of research that falls under the biomagnetic umbrella, as well as the construction of magnetic structures or systems that are either biocompatible, biodegradable or biomimetic. Magnetic nanoparticles and magnetic microparticles are known to interact with certain prokaryotes and certain eukaryotes.

Nanoparticles for drug delivery to the brain is a method for transporting drug molecules across the blood–brain barrier (BBB) using nanoparticles. These drugs cross the BBB and deliver pharmaceuticals to the brain for therapeutic treatment of neurological disorders. These disorders include Parkinson's disease, Alzheimer's disease, schizophrenia, depression, and brain tumors. Part of the difficulty in finding cures for these central nervous system (CNS) disorders is that there is yet no truly efficient delivery method for drugs to cross the BBB. Antibiotics, antineoplastic agents, and a variety of CNS-active drugs, especially neuropeptides, are a few examples of molecules that cannot pass the BBB alone. With the aid of nanoparticle delivery systems, however, studies have shown that some drugs can now cross the BBB, and even exhibit lower toxicity and decrease adverse effects throughout the body. Toxicity is an important concept for pharmacology because high toxicity levels in the body could be detrimental to the patient by affecting other organs and disrupting their function. Further, the BBB is not the only physiological barrier for drug delivery to the brain. Other biological factors influence how drugs are transported throughout the body and how they target specific locations for action. Some of these pathophysiological factors include blood flow alterations, edema and increased intracranial pressure, metabolic perturbations, and altered gene expression and protein synthesis. Though there exist many obstacles that make developing a robust delivery system difficult, nanoparticles provide a promising mechanism for drug transport to the CNS.

Cancer treatments may vary depending on what type of cancer is being targeted, but one challenge remains in all of them: it is incredibly difficult to target without killing good cells. Cancer drugs and therapies all have very low selective toxicity. However, with the help of nanotechnology and RNA silencing, new and better treatments may be on the horizon for certain forms of cancer.

mRNA vaccine Type of vaccine

An mRNAvaccine is a type of vaccine that uses a copy of a molecule called messenger RNA (mRNA) to produce an immune response. The vaccine delivers molecules of antigen-encoding mRNA into immune cells, which use the designed mRNA as a blueprint to build foreign protein that would normally be produced by a pathogen or by a cancer cell. These protein molecules stimulate an adaptive immune response that teaches the body to identify and destroy the corresponding pathogen or cancer cells. The mRNA is delivered by a co-formulation of the RNA encapsulated in lipid nanoparticles that protect the RNA strands and help their absorption into the cells.

<span class="mw-page-title-main">ALC-0315</span> Chemical compound

ALC-0315 is a synthetic lipid. A colorless oily material, it has attracted attention as a component of the SARS-CoV-2 vaccine, BNT162b2, from BioNTech and Pfizer. Specifically, it is one of four components that form lipid nanoparticles (LNPs), which encapsulate and protect the otherwise fragile mRNA that is the active ingredient in these drugs. These nanoparticles promote the uptake of therapeutically effective nucleic acids such as oligonucleotides or mRNA both in vitro and in vivo.

Distearoylphosphatidylcholine is a phosphatidylcholine, a kind of phospholipid. It is a natural constituent of cell membranes, eg. soybean phosphatidylcholines are mostly different 18-carbon phosphatidylcholines, and their hydrogenation results in 85% DSPC. It can be used to prepare lipid nanoparticles which are used in mRNA vaccines, In particular, it forms part of the drug delivery system for the Moderna and Pfizer COVID-19 vaccines.

SM-102 is a synthetic amino lipid which is used in combination with other lipids to form lipid nanoparticles. These are used for the delivery of mRNA-based vaccines, and in particular SM-102 forms part of the drug delivery system for the Moderna COVID-19 vaccine.

Pieter Rutter Cullis is a Canadian physicist and biochemist known for his contributions to the field of lipid nanoparticles (LNP). Lipid nanoparticles are essential to current mRNA vaccines as a delivery system. Prof. Cullis is best known for the development of ionizable cationic lipids. These lipids are able to complex with negatively charged nucleic acids at low pH (≈4.0) where they are positively charged because they have a pKa if approximately 6.4. They reduce or eliminate toxicity associated with cationic lipids at physiological pH of 7.4 because they adopt a net neutral charge. Finally, they enable endosomal escape because they again become positively charged in acidified endosomes and promote formation of non-bilayer structures by interaction with negatively charged lipids. These properties are critical to the function of the mRNA vaccines and are rapidly enabling gene therapy in clinical settings.

Chitosan-poly is a composite that has been increasingly used to create chitosan-poly(acrylic acid) nanoparticles. More recently, various composite forms have come out with poly(acrylic acid) being synthesized with chitosan which is often used in a variety of drug delivery processes. Chitosan which already features strong biodegradability and biocompatibility nature can be merged with polyacrylic acid to create hybrid nanoparticles that allow for greater adhesion qualities as well as promote the biocompatibility and homeostasis nature of chitosan poly(acrylic acid) complex. The synthesis of this material is essential in various applications and can allow for the creation of nanoparticles to facilitate a variety of dispersal and release behaviors and its ability to encapsulate a multitude of various drugs and particles.

<span class="mw-page-title-main">Intracellular delivery</span> Scientific research area

Intracellular delivery is the process of introducing external materials into living cells. Materials that are delivered into cells include nucleic acids, proteins, peptides, impermeable small molecules, synthetic nanomaterials, organelles, and micron-scale tracers, devices and objects. Such molecules and materials can be used to investigate cellular behavior, engineer cell operations or correct a pathological function.

<span class="mw-page-title-main">Acuitas Therapeutics</span> Canadian biotechnology company

Acuitas Therapeutics Inc. is a Canadian biotechnology company based in Vancouver, British Columbia. The company was established in February 2009 to specialize in the development of delivery systems for nucleic acid therapeutics based on lipid nanoparticle (LNP) technology, a key component of the mRNA vaccines deployed for COVID-19.

Penetration enhancers are chemical compounds that can facilitate the penetration of active pharmaceutical ingredients (API) into or through the poorly permeable biological membranes. These compounds are used in some pharmaceutical formulations to enhance the penetration of APIs in transdermal drug delivery and transmucosal drug delivery. They typically penetrate into the biological membranes and reversibly decrease their barrier properties.

Intranasal drug delivery occurs when particles are inhaled into the nasal cavity and transported directly into the nervous system. Though pharmaceuticals can be injected into the nose, some concerns include injuries, infection, and safe disposal. Studies demonstrate improved patient compliance with inhalation. Treating brain diseases has been a challenge due to the blood brain barrier. Previous studies evaluated the efficacy of delivery therapeutics through intranasal route for brain diseases and mental health conditions. Intranasal administration is a potential route associated with high drug transfer from nose to brain and drug bioavailability.

Selective organ targeting (SORT) is a novel approach in the field of targeted drug delivery that systematically engineers multiple classes of lipid nanoparticles (LNPs) to enable targeted delivery of therapeutics to specific organs in the body. The SORT molecule alters tissue tropism by adjusting the composition and physical characteristics of the nanoparticle. Adding a permanently cationic lipid, a permanently anionic lipid, or ionizable amino lipid increases delivery to the lung, spleen, and liver, respectively. SORT LNPs utilize SORT molecules to accurately tune and mediate gene delivery and editing, resulting in predictable and manageable protein synthesis from mRNA in particular organ(s), which can potentially improve the efficacy of drugs while reducing side effects.

References

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  17. 1 2 Shah, Mansi K.; Madan, Parshotam; Lin, Senshang (23 May 2013). "Preparation, evaluation and statistical optimization of carvedilol-loaded solid lipid nanoparticle for lymphatic absorption via oral administration". Pharmaceutical Development and Technology. 19 (4): 475–485. doi:10.3109/10837450.2013.795169. PMID   23697916. S2CID   42174732.
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