Release date:2022/7/22 15:57:24

Lipid nanoparticles (LNPs) have emerged across the pharmaceutical industry as promising vehicles for deliverying various therapeutic drugs. And the application of LNPs has also expanded to other fields, such as medical imaging, cosmetics, nutrition, agriculture, and other innovative fields such as nanoreactors. LNPs are currently attracting attention as an important part of the COVID-19 mRNA vaccine, which plays a key role in effectively protecting mRNA and transporting it to cells. Liposomes, an early version of LNPs, are an extremely versatile nanocarrier platform. Here, we mainly discuss the application of LNPs in vaccine and drug delivery.

Approved Products Based On Lipid Nanoparticles (LNPs)

For more than 50 years, liposomes have been recognized as a powerful medical tool. It can encapsulate drugs and controllably deliver drugs to specific locations in the body, which makes it useful for the treatment of various diseases. At present, many lipid nanoparticle drug preparations have been approved and used in the clinic.

Approved marketed drug-loaded lipid-based nanoparticle

Table 1 Approved marketed drug-loaded lipid-based nanoparticle

The largest application of lipid nanoparticles in drug delivery is cancer therapy because the bioavailability and selectivity of lipid nanoparticles-encapsulated antitumor drugs are superior to free drugs. Lipid-based nanocarriers can reduce the toxicity of anticancer drugs to normal tissues, increase the water solubility of hydrophobic drugs, prolong drug residence time, and improve the control efficiency of drug release. 

Lipid nanoparticles also improve the efficiency of cancer therapy through enhanced permeability and retention (EPR) effects. Rapid but defective angiogenesis in tumors results in large vascular spaces (particle size >100 nm) through which lipid nanoparticles can easily enter tumors. Thus, tumor blood vessels are much more permeable to lipid nanoparticles, allowing their selective accumulation in tumors when administered intravenously. In addition, dysfunctional lymphatic drainage in tumors reduces the rate at which lipid nanoparticles are excreted from the inside and outside of the tumor, thereby prolonging their retention in the tumor.

Schematic diagram of EPR effect

FIG. 1 Schematic diagram of EPR effect

Due to the EPR effect, the accumulation of lipid nanoparticles in tumors enables nanoparticles to selectively release antitumor drugs near tumor cells. Doxil is the first approved antitumor nanoagent and the first approved liposome drug. The product improves the pharmacokinetics and biodistribution of anthracycline doxorubicin, a potent anticancer agent but cardiotoxic. Doxil utilizes EPR, using sterically stable nanoparticles (~100 nm) to prolong the circulation time of the drug in plasma while reducing the cardiotoxicity of doxorubicin. Doxil was developed as an intravenous formulation consisting of soy phosphatidylcholine, cholesterol and DSPE-PEG2000 for the treatment of advanced ovarian cancer, multiple myeloma and HIV-related Kaposi's sarcoma.

The second largest use of liposomes is as an antibacterial agent. The broad-spectrum polyene antibiotic amphotericin B has been used in medicine for decades as the gold standard for the treatment of invasive fungal infections. Amphotericin B targets the cell membrane with a higher affinity for ergosterol-containing fungal cell membranes than for cholesterol-containing mammalian cell membranes. However, although amphotericin B has high antifungal activity, it has serious side effects, especially nephrotoxicity. Amphotericin B is an amphiphilic molecule with complex self-association behavior. Different types of aggregates show different solubility and toxicity. Aggregation status is also associated with drug efficacy. Therefore, controlling drug aggregation can enhance its therapeutic effect and reduce toxicity. Lipid nanoparticles can control this aggregation state, and several lipid-based amphotericin B nanoparticles have been developed that exhibit favorable pharmacokinetic characteristics and significantly reduce the side effects of this drug.

Nucleic acid therapy agents are an emerging class of drugs with great potential for the treatment of various diseases. However, since nucleic acids are polyvalent anions and highly hydrophilic molecules, they are hardly taken up by cells and are easily degraded by nucleases in blood. Therefore, nucleic acid drugs need to rely on delivery carrier to enter the cell to play a role. Lipid nanoparticles as a carrier is one of the efficient ways to deliver nucleic acid drugs. The nucleic acid drug Patisiran (Onpattro), a lipid nanoparticle encapsulated siRNA product that reduces liver transthyroxine protein formation, has been approved by the FDA for the treatment of hereditary transthyroxine-mediated amyloidosis. As the first approved siRNA drug and nucleic acid drug delivered by lipid nanoparticles, it is an important milestone in the development of nucleic acid drugs.

LNPs in COVID-19 mRNA Vaccines

The latest success story for lipid nanoparticles are the two FDA-approved COVID-19 messenger RNA (mRNA) vaccines using Pfizer/BioNTech and Moderna as delivery vehicles, which have been developed and marketed at an unmatched pace and have shown remarkable efficacy in pandemic virus prevention. The vaccine delivers an mRNA encoding the SARS-COV-2 spike protein to the cytoplasm of the host cell, where it is translated into the spike protein to act as an antigen that induces an immune response to the virus.

The mechanism of mRNA-LNP

FIG 2 The mechanism of action of mRNA-LNP

The composition of lipid nanoparticles used in the two mRNA vaccines is very similar. Both contain ionizable lipids that are positively charged at low pH to facilitate electrostatic complexation with mRNA, and neutral at physiological pH to facilitate mRNA delivery and release and reduce potential toxicity. Both contain PEGylated lipids to reduce antibody binding of serum proteins and clearance by phagocytes, thereby prolonging systemic circulation time.

Pfizer/BioNTech and Moderna's proprietary cationic lipids for COVID-19 vaccine lipid nanoparticles are ALC-0315 and SM-102, respectively. Both of these ionizable cationic lipids contain tertiary amines that are protonated and positively charged at low pH. The lipid's hydrocarbon chain links to biodegradable ester groups, allowing safe clearance after mRNA delivery. Cationic lipids used in mRNA vaccines contain hydrocarbon chain branches that optimize non-lamellar structure formation and mRNA delivery efficiency. PEGylated lipids are all PEG-2000 conjugates (PEG2000 DMG & PEG2000 DSPE). Lipid nanoparticles are prepared at low pH (pH 4.0), and the ionizable lipids are positively charged under acidic conditions and readily form complexes with mRNA. Use a microfluidic device to rapidly mix the aqueous solution containing the mRNA with the ethanolic solution containing the lipid mixture. When rapidly mixed, the components of the two fluids form nanoparticles and trap the negatively charged mRNA.

main excipients of mRNA COVID-19 vaccine

FIG 3 The main excipients of mRNA COVID-19 vaccine

LNP-based mRNA Vaccines And Therapies In Clinical Trials

mRNA vaccines and therapies hold great promise in the prevention and treatment of disease. Lipid nanoparticles can be used for intracellular delivery of mRNA to express virtually any desired protein in host cells. An important feature of mRNA-based therapies is the reduced risk of insertional mutations. Unlike DNA therapy, mRNA does not require the nucleus to function and does not integrate into the host genome, thus reducing the risk of carcinogenesis and mutagenesis and improving safety. In addition, mRNA is easier to standardize than DNA to produce and has good reproducibility.

mRNA vaccines have revolutionized vaccine development due to their high efficiency, short development cycles, and potentially low-cost production. Rapid development of mRNA vaccines would not have been possible without advances in lipid nanoparticle technology for nucleic acid delivery. Several mRNA vaccines based on lipid nanoparticles have entered clinical trials for various infectious diseases, such as nucleoside-modified mRNA vaccines against Zika virus, cytomegalovirus, tuberculosis and influenza. mRNA therapeutic vaccines have shown great potential in immunotherapy against melanoma, ovarian cancer, breast cancer and other solid tumors. Lipid nanoparticle carriers are critical for the successful delivery of mRNA to the cytosol of immune cells, especially antigen-presenting immune cells responsible for triggering the desired immune response.

Lipid nanoparticle mRNA drugs and vaccines in clinical trials

Table 2 Lipid nanoparticle mRNA drugs and vaccines in clinical trials

The use of mRNA to express therapeutic proteins holds promise for the treatment of a variety of diseases. Protein replacement therapy is a medical therapy that replaces or supplements a lacking or missing protein in a patient by engineering mRNA to encode a useful protein. Lipid nanoparticles are the carrier of choice for mRNA delivery to cells, but lipid nanoparticles-based mRNA drugs typically require repeated administration over a long period of time, thus requiring exhaustive safety analysis and testing.

As a professional PEG derivatives supplier, Biopharma PEG has been focusing on the development of a full range of medical applications and technologies for nanocarrier systems, including various types of nanoparticles, liposomes, micelles, etc. We are committed to providing a variety of PEG-liposome derivatives, including mPEG, DSPE lipids with different molecular weight and functional PEG. We can also produce and provide the some PEG products such as mPEG-N,N-Ditetradecylacetamide (ALC-0159) as ingredients used in COVID-19 vaccines. For more information, please visit website at PEGs for COVID-19 Vaccines.

Lipid Nanoparticles—From Liposomes to mRNA Vaccine Delivery, a Landscape of Research Diversity and Advancement

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[2]. Lipid Nanoparticles: Key Technology For mRNA Delivery
[3]. Lipid Nanoparticles for Drug and Vaccine Delivery
[4]. Overview of mRNA-Lipid Nanoparticle COVID-19 Vaccines
[5]. COVID-19 mRNA Vaccine Excipients - PEG Products Supply

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