As an artificially prepared drug delivery system, liposomes are micro-spherical carriers formed by encapsulating active ingredients within a lipid bilayer. This type of preparation can effectively accumulate drugs at the lesion site and avoid metabolic loss of activity during drug circulation. Compared with traditional pharmaceutical preparations, liposome preparations have the characteristics of high efficiency, low toxicity and targeting. In recent years, the global liposome market has developed rapidly, and the types and sales of liposome drugs have continued to increase. So far, a variety of liposome drugs have been approved for marketing. In view of this, this article reviews the classification and clinical applications of liposomes, aiming to provide reference for the rational clinical use of liposome preparations and the development of new drugs.
Figure 1. Liposomes smart delivery systems. (Dymek M, et al.; 2022)
Classification of Liposomes
According to the formulation and mode of action of the preparation, liposomes can be roughly divided into ordinary liposomes, environmentally sensitive liposomes, long-circulation liposomes, active targeting liposomes, multifunctional liposomes, etc.
Ordinary liposomes are only composed of phospholipids and cholesterol and are easily phagocytosed by the monocyte-macrophage system (MPS) after entering the body. In the 1980s, studies have discovered that liposomes of pentavalent antimony compounds can be used to treat macrophage system diseases such as leishmaniasis. However, ordinary liposomes easily aggregate and fuse with each other in the body, making it difficult to ensure sustained and stable release. Therefore, it is necessary to modify the surface of liposomes to change their pharmacokinetic process in the body. As a result, new liposomes have been developed one after another.
- Environmentally Sensitive Liposomes
After environment-sensitive liposomes enter the body, they can be induced in specific tissues due to changes in the dynamic microenvironment (such as pH, enzymes) or by artificially controlling the physical environment of the target tissue (such as photosensitivity, temperature sensitivity, magnetic response, etc.) Release the drug.
- Long Circulating Liposomes
The surface of long-circulating liposomes is covered with inert polymer molecules such as oligosaccharides, glycoproteins, polysaccharides and synthetic polymers, which can extend their half-life in the circulation system. Among them, polyethylene glycol (PEG) has the advantages of being non-toxic, non-immunogenic, non-antigenic, and easily soluble in water, and is a commonly used polymer.
- Active Targeting Liposomes
There are certain specific overexpressed receptors on the surface of tumor cells or blood vessels, such as folate receptors, human epidermal growth factor receptor 2, transferrin receptors, etc. These receptors are usually closely related to the growth and proliferation of tumors. Targeting receptors highly expressed in tumor tissues, liposomes modified with corresponding ligands are designed to become nanocarriers targeting tumor tissues, accumulation of drugs in tumor cells through selective cell binding or receptor-mediated endocytosisActive targeting liposomes are divided into two categories: antibody-targeting ligand modification and non-antibody-targeting modification.
Clinical Applications of Liposomes
As a mature drug delivery carrier, liposomes have been widely used in the preparation of various preparations such as anti-tumor, anti-infection, and vaccines.
Anti-tumor treatment is the most widely used area for liposomal preparations. Since the US FDA approved doxorubicin liposomes for the treatment of Kaposi's sarcoma, ovarian cancer and breast cancer in 1995, a variety of liposomal formulations for anti-tumor treatment have been marketed. By incorporating cytotoxic drugs into liposome formulations, they have passive or active tumor targeting properties and can reduce drug toxicity to non-target organs. Two main mechanisms of passive targeting are currently being investigated: (1) The high permeability and long retention effect (EPR) is used to retain the drug in the tumor tissue, thereby achieving the purpose of passive targeting. (2) Utilising the charge characteristics of nanoparticles to induce passive targeting.
As a relatively mature targeting technology, passive targeting liposomes have been successfully used in many marketed anti-tumor drugs such as doxorubicin liposomes, doxorubicin liposomes, and mitoxantrone liposomes. As mentioned above, active targeting liposomes use targeting substances to modify liposomes and achieve drug accumulation in tumor cells through selective cell binding or receptor-mediated endocytosis. CPX-351, the world's first active-targeted dual-drug-loaded liposome, was approved for marketing in the United States in 2017 for the treatment of acute myeloid leukemia secondary to and associated with myelodysplastic syndrome-related cytogenetic abnormalities. This preparation pioneered the encapsulation of two cytotoxic drugs, cytarabine and daunorubicin, into nano-delivery carriers through two different loading technologies, while using anionic phosphatidylglycerol coupled to the liposome surface to interact with leukemia cells. Binds to CD36 and CD91 ligands, preferentially enters leukemia cells through active uptake, and finally releases the drug in the nucleus. This release method completely achieves targeting of leukemia cells, ensuring efficacy while reducing cytotoxicity to normal hematopoietic stem cells.
The lipid-containing formulation of the broad-spectrum antifungal drug Amphotericin B (AmB) is the most classic and successful case of liposome formulation development. After entering the body, AmB partially binds to human cells, causing haemolysis, kidney damage and other adverse reactions. Lipid-containing formulations of AmB are phagocytosed by MPS and accumulate in the liver and spleen, thereby reducing binding to cholesterol on the renal tubular cell membrane and reducing nephrotoxicity. Preclinical studies have shown that AmB lipid formulations have higher peak plasma concentrations and areas under the curve compared to equal doses of free AmB, suggesting that AmB lipid formulations have greater therapeutic potential. There are currently three formulations of AmB lipid preparations on the market, including AmB lipid complex, AmB cholesterol sulphate complex and AmB liposome. These three preparations differ in particle size, structure, lipid composition, AmB concentration, etc., resulting in certain differences in tissue distribution, plasma concentration, macrophage uptake rate and concentration at the site of infection. As the toxicity of lipid-containing preparations to human cells is much lower than that of pure AmB preparations, the clinically acceptable dose is higher than that of pure AmB preparations and can be used in patients with impaired renal function. Inhaled liposomal antimicrobials are another type of liposome that has made significant progress in recent years. Liposomes deliver drugs to alveolar macrophages through phagocytosis to enhance the therapeutic effect of drugs on intracellular infections. Amikacin liposomes for inhalation, which have been used clinically, use neutral liposomes to encapsulate positively charged amikacin, preventing the drug from direct contact with negatively charged sputum and allowing it to penetrate the network structure of the Pseudomonas aeruginosa biofilm in sputum.
With the continuous advancement of immunology and bioengineering technology, new vaccines such as subunit vaccines, nucleic acid vaccines, and polysaccharide conjugate vaccines have made rapid progress. Liposomes are used to construct a new vaccine adjuvant delivery system, which can protect the key component of the vaccine - the long-term and slow release of pathogen antigens, and enhance the immunogenicity of the vaccine. Studies have shown that certain liposomes themselves have unique immune-stimulating functions and can induce broad-spectrum acquired immunity in the body under special conditions. For example, liposomes containing monophosphate lipid A can trigger the body's helper T cell 1 immune response and rarely produce intolerable side effects. Some products using this technology for herpes zoster virus vaccines.
mRNA vaccines are third-generation vaccines. Compared with previous-generation vaccines such as attenuated, inactivated, and recombinant subunit vaccines, mRNA vaccines do not require cell culture or animal-derived substrates and are synthesized quickly. It only takes a few weeks from gene sequencing to production. It has played an important role in epidemic prevention and control. However, the single-stranded structure of mRNA is extremely unstable and difficult to deliver through the negatively charged cell membrane, so it needs to be wrapped in special liposome nanoparticles and delivered to the cytoplasm. A system consisting of SARS-CoV-2 spike glycoprotein mRNA and liposome nanoparticles wrapped in an outer layer is used in the SARS-CoV-2 vaccine. The vaccine received marketing approval from the US FDA in August 2021 and is currently approved for use in more than 140 countries around the world.
References
- Dymek M, Sikora E. Liposomes as biocompatible and smart delivery systems - the current state. Adv Colloid Interface Sci. 2022, 309:102757.
- Guimarães D, et al.; Design of liposomes as drug delivery system for therapeutic applications. Int J Pharm. 2021, 601:120571.
