siRNA Functionalized Lipid Nanoparticles (LNPs) in Management of Diseases
Abstract
:1. Introduction
2. Overview of LNPs
2.1. Liposomes
2.2. Solid Lipid NPs (SLNs)
2.3. Nanostructured Lipid Carriers (NLCs)
2.4. Nanoemulsions (NEs)
Solid Lipids | Liquid Lipids | Common Lipids | Surfactants |
---|---|---|---|
Paraffin Tricaprin Trilaurin Trimyristin Tripalmitin Tristearin Acyl glycerols Glyceryl behenate Glyceryl distearate Glyceryl monostearate Glyceryl monooleate Glyceryl palmitostearate Cetyl palmitate Beeswaxes Palmitic acid Stearic acid Behenic acid Decanoic acid | Lutrol® F68 Miglyol® 812 Castor oil Oleic acid | Phospholipids PA; PCPE; PG; PS Ionizable cationic lipid DODAP; DLin-K-DMA; DLinDMA; DlinMC3-DMA; DLin-KC2-DMA Additional lipids Cholesterol; DMG-PEG2000; DSPE-PEG2000PE | Lecithin Polysorbate 80 Polysorbate 60 Polysorbate 20 Poloxamer 407 Poloxamer 188 Sodium oleate Sodium dodecyl sulphate Polyvinyl alcohol Butanol Butyric acid |
Procedure | Advantages | Disadvantages |
---|---|---|
Hot Homogenization | ||
It is carried out at temperatures greater than the melting point of solid lipids. The drug and lipids are melted together and added in a hot aqueous phase having the surfactants, using a high-shear mixing device. The system is then cooled leading to the solidification of lipids and the formation of NPs [56] |
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Cold Homogenization | ||
Drug is dissolved in the melted lipid mixture and the mixture is quickly cooled down using dry ice or liquid nitrogen and solidified. It is then grinded into a very fine powder using high-pressure milling. The resulting microparticles are dispersed in a cold aqueous phase having the surfactant [57] |
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Solvent Emulsification Evaporation | ||
The lipid is first dissolved in a non-polar organic solvent and then emulsified by high-speed homogenization in an aqueous phase. The solvent is evaporated using mechanical stirring under reduced pressure and room temperature, resulting in the formation of LNPs [58] |
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Ultrasonication | ||
Applies the temperatures that are greater than the melting point of the solid lipid. The melted lipid is then dispersed into the warm aqueous phase containing the surfactant. The pre-emulsion is then placed into the ice-water bath and subjected to ultrasonication using a probe sonicator [59] |
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Supercritical Fluid extraction of Emulsion | ||
An aqueous solution containing lipid, drug, and surfactant is placed in a high-pressure homogenizer to form an oil/water emulsion. A supercritical fluid such as CO2 is used for the removal of the solvent from o/w emulsions after which lipid NPs are obtained [60] |
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Solvent Emulsification–Diffusion | ||
Solid lipid is dissolved in non-polar organic solvent and dispersed into the aqueous phase containing a surfactant forming an emulsion. The organic solvent is evaporated from the emulsion, under reduced pressure. As a result, the SLNPs are prepared in the aqueous phase [61] |
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Double Emulsion | ||
The dissolved drug in the aqueous phase is added to the melted lipid and surfactant at a higher temperature. The microemulsion is then further added to a mixture of containing the water and surfactant in order to obtain a water/oil/water emulsion [62] |
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Spray-drying | ||
In a one-step process, using an organic solvent, the lipid particles are dissolved, and the solution is then evaporated resulting in a dried particulate formation [41] |
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Coacervation | ||
A mixture containing fatty acids salts and polymeric stabilizing agents is added in the aqueous phase which is then heated to a temperature to obtain a transparent alkaline micellar lipid salt solution. A suspension is obtained by gradually adding the coacervating solution into the mixture. The suspension is then cooled in a water bath under agitation resulting in the formation of LNPs. The drug is mainly dissolved in alcohol which is then added in the lipid phase or incorporated into the blank LNPs [63] |
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3. Properties of Lipid NPs Impacting Performances
3.1. Particle Size
3.2. Particle Surface Charge
3.3. PEGylation
3.4. Surface Modification with Targeting Ligands
4. Biological Barriers to Lipid Nanoparticle Delivery
4.1. Liver Accumulation
4.2. Spleen Accumulation
4.3. Maintaining Prolonged Protein Expression
4.4. Immunological Responses
4.5. Endosomal Escape
- (i)
- Headgroups containing tertiary amines which are uncharged (zwitterionic) under physiological pH and become protonated at acidic pH [92],
- (ii)
- Lipid tails that promote self-assembly into a nanoparticle due to hydrophobic association. The tail properties can further affect the endosomal escape capability of LNPs. For instance, due to the stronger protonation at endosomal pH, branched-tail lipids demonstrate improved endosomal escape in comparison with their linear counterparts [88]. Lipid type and ratio can also enhance endosomal escape [141,142,143,144,145,146].
- (iii)
- Protonated lipids which contribute to an elevated propensity for membrane fusion in acidified endosomes in target cells [92]. Optimizing the pKa values of the ILs can positively affect the endosomal escape. Alabi et al. showed that among the three key variables, LNP size, LNP pKa, and siRNA entrapment, the strongest correlation with overcoming the biological barriers and consequently gene silencing capability was related to the pKa. They demonstrated that LNPs with pKa lower than 5.5 were not successful in gene knockout in vitro and in vivo systems [147].
4.6. Cytotoxicity
4.7. Post-Administration Reactions
5. Therapeutic Applications of LNP Formulations of siRNA
5.1. Acute Myeloid Leukaemia (AML)
5.2. Breast Cancer
5.3. Liver Disease
5.4. Hepatitis B
5.5. COVID-19
6. Summary and Future Perspective
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Target | Predicted Duplex siRNA Candidate at 37 °C | GC% | Free Energy of Binding (kcal/mol) | Score |
---|---|---|---|---|
Sequence 1 | AGUAGAAAUACCAUCUUGGAC CCAAGAUGGUAUUUCUACUAC | 38 | −31.50 | 0.946 |
Sequence 2 | UUUCUUAGUGACAGUUUGGCC CCAAACUGUCACUAAGAAAUC | 40 | −34.54 | 0.861 |
Sequence 3 | ACAUUGUAUGCUUUAGUGGCA CCACUAAAGCAUACAAUGUAA | 36 | −30.74 | 0.986 |
Sequence 4 | AAUUUGCGGCCAAUGUUUGUA CAAACAUUGGCCGCAAAUUGC | 43 | −31.61 | 0.793 |
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Kalita, T.; Dezfouli, S.A.; Pandey, L.M.; Uludag, H. siRNA Functionalized Lipid Nanoparticles (LNPs) in Management of Diseases. Pharmaceutics 2022, 14, 2520. https://doi.org/10.3390/pharmaceutics14112520
Kalita T, Dezfouli SA, Pandey LM, Uludag H. siRNA Functionalized Lipid Nanoparticles (LNPs) in Management of Diseases. Pharmaceutics. 2022; 14(11):2520. https://doi.org/10.3390/pharmaceutics14112520
Chicago/Turabian StyleKalita, Tutu, Saba Abbasi Dezfouli, Lalit M. Pandey, and Hasan Uludag. 2022. "siRNA Functionalized Lipid Nanoparticles (LNPs) in Management of Diseases" Pharmaceutics 14, no. 11: 2520. https://doi.org/10.3390/pharmaceutics14112520
APA StyleKalita, T., Dezfouli, S. A., Pandey, L. M., & Uludag, H. (2022). siRNA Functionalized Lipid Nanoparticles (LNPs) in Management of Diseases. Pharmaceutics, 14(11), 2520. https://doi.org/10.3390/pharmaceutics14112520