Liposomes: An Excellent Partner of Antiprotozoal Drug

Parasitic diseases such as malaria, leishmaniasis, and trypanosomiasis are still problems that threaten human health. About 30% of the world's population is infected with parasitic diseases. Most parasitic diseases do not trigger an immune response and thus no suitable vaccine can be found. Therefore, the treatment of parasitic diseases depends more on drug treatment. The disadvantage of traditional antiprotozoal drugs is that they cannot target cells. Repeated administration of large doses leads to multiple drug resistance and drug toxicity.

Taking into account the infection characteristics of protozoal diseases, the drug delivery system of antiprotozoal drugs should meet the following requirements:

1. Able to achieve oral administration;
2. Intracellular targeting, high drug loading rate, low toxicity, and low immunogenicity with the ability to protect the drug from being degraded before it enters the cell;
3. Improve the pharmacodynamic parameters of antiprotozoal drugs and reduce the administration cycle;
4. Transport the combination of antiprotozoal drugs and other substances flexibly;
5. The cost-benefit ratio;
6. Targeting Delivery of antiprotozoal drugs to achieve maximum efficacy and minimum adverse reactions.

• Liposome for Anti-malaria Drug

In the 1980s, scientists have prepared liposome formulations of antimalarial drugs such as quinine, chloroquine, primaquine, artemether, and artesunate. The pH gradient method is a good way to improve the encapsulation efficiency of antimalarials, especially for quinolones. The chloroquine PEGylated long-circulating liposome prepared by the pH gradient method released 30% of the drug within 6 hours at a pH of 7.4, and over 90% of the drug was released at a pH of 5.5. The artesunate liposomes prepared by using a buffer solution of pH 5 as the aqueous phase can reach almost 100% in the encapsulation efficiency, which can improve the stability of artesunate.

The relative oral bioavailability of artemether liposomes can reach 97.9%, while the artemether suspension is only 31.8%. Primaquine anionic liposomes prolong the plasma half-life of the drug, and the clearance rate is reduced by 8 times. About 50% of the injected drug is distributed in the liver, which is twice the free drug, and the spleen intake is increased by 3 times. The distribution in the lung, kidney, heart and brain is significantly reduced, thus decreasing the systemic toxicity of the drug. Scientists have prepared liposomes modified with monoclonal antibodies that specifically bind to erythrocytes infected with Plasmodium, and encapsulated with chloroquine, and then were injected into mice infected with Plasmodium. After administration for 4 days and 6 days, the cure rates were 75% and 90%, respectively, which means the liposome is not only effective against drug-sensitive plasmodium, but also effective against drug-resistant plasmodium.

• Liposome for Anti-leishmania Drug

Because Leishmania reproduces in macrophages, and macrophages are an important place for liposome elimination, liposomes are the most effective treatment for leishmaniasis.

The biological activity of sodium antimony gluconate liposomes against experimental leishmaniasis in hamsters is 700 times that of free drugs. The decomposition of Leishmania in Kupffer cells is clearly observed under the electron microscope, which fully reflects the broad prospects of liposome drug delivery system in the treatment of leishmaniasis. Sodium antimony gluconate liposomes are also effective against skin leishmaniasis.

In terms of macrophage drug uptake and targeting liver and spleen, cationic liposomes have more advantages than anionic and neutral liposomes. Cationic liposomes composed of phosphatidylcholine and stearylamine encapsulate sodium antimony gluconate, which can significantly reduce the amount of Leishmania in the liver. The mechanism may be the electrostatic effect of cationic liposomes and protozoan plasma membrane, which destroys the organelle structure and inhibit the oxygen consumption of the protozoa.

The macrophage membrane has receptors that recognize mannosyl, galactosyl, fucose residues and glucose residues of glycosides. Mannose modified urea antimony amine liposomes can more effectively deliver drugs to macrophages, and also more effectively reduce the amount of parasites in the spleen and drug toxicity. Glycoprotein-modified harmycin liposomes have a clearance rate of intracellular amastigo-protozoa that is twice that of ordinary liposomes and 10 times that of free drugs. Glycoprotein modified liposomes can completely eliminate the protozoa in the spleen, while ordinary liposomes can only partially eliminate them. Macrophage activating peptides, such as phagocytic peptides, are used to improve the targeting of anti-leishman drugs due to their preferential binding to the mononuclear macrophage system. There are Fc receptors on the surface of macrophages, and liposomes can be combined with some Fc antibodies such as immunoglobulins (Ig) to form immunoliposomes, which are used to treat Leieman’s disease. When sodium antimony gluconate is administered, the antibody has a synergistic effect against Leishman. Therefore, modified liposomes with this antibody can not only improve the targeting of macrophages, but also have anti-Leishman synergistic effects.

• a>Liposome for Anti-trypanosomiasis drug

Trypanosomal pathogens are distributed in general cells, not in the mononuclear macrophage system, so liposomes are rarely used in the treatment of trypanosomiasis. But blank cationic liposomes have the potential to resist trypanosomiasis. Cationic liposomes composed of phosphatidylcholine and stearylamine can kill trypanosomes within 30 minutes at a very low lipid concentration (100?mol/L) and have no toxicity to red blood cells. The mechanism may be to destroy plasma membrane stability of trypanosomes, while intervening in the dimensional mechanism of trypanosomal plasma membrane.

The second-generation nitroimidazole drug, etanterol, is prepared into pH-sensitive liposomes, which can avoid the endocytosis of lysosomes, significantly improve the cytoplasmic targeting of the drug, and clear 72% of trypanosomes in infected macrophages within 2 hours, while free drugs and ordinary liposomes do not have any antitrypanosomal activity. Arsenic compounds, such as melarsoprol, can be used to treat trypanosomal infections. Arsenic liposomes have significant anti-trypanosomal activity at lower concentrations, and their porous structure is very important for their anti-trypanosomal effects.

Richard J. Gray: Rich experience in drug delivery research and development and willing to share cutting-edge technologies.