Safety Of Liposomes Research Articles

Licensed liposomal vaccines and adjuvants in the antigen delivery system.

Liposomes (LSs) are promising nanoparticles with unique properties such as controlled nanosize, large surface area, increased reactivity, and ability to undergo modification. Worldwide, licensed liposomal forms of antibiotics, hormones, antioxidants, cytostatics, ophthalmic drugs, etc., are available on the pharmaceutical market. This review focuses on the adjuvant properties of LSs in the production of vaccines (VACs). LS-VACs have the following advantages: antigens with low immunogenicity can become highly immunogenic; LSs can include both hydrophilic and hydrophobic antigens; LSs allow to achieve a prolonged specific action of antibodies; and LSs reduce the toxicity and pyrogenicity of encapsulated antigens and adjuvants. The immune response is influenced by the composition of the liposomal membrane, physicochemical characteristics of lipids, antigen localization in LSs, interaction of LSs with complement, and a number of proteins, which leads to opsonization. The major requirements for adjuvants are their ability to enhance the immune response, biodegradability, and elimination from the organism, and LSs fully meet these requirements. The effectiveness and safety of LSs as carriers in the antigen delivery system have been proven by the long-term clinical use of licensed vaccines against hepatitis A, influenza, herpes zoster, malaria, and COVID-19.

Physicochemical and Safety Evaluation of 5-Aminolevulinic Acid in Novel Liposomes as Carrier for Skin Delivery

In this study we successfully entrapped 5-aminolevulinic acid (ALA) in liposome, although it exists as a zwitter ion. A molar ratio of 2:1:2.5 phosphatidyle-thanolamine (PE)/cholesterol/sodium stearate represented the best condition to achieve high entrapment efficiency (29.37 ± 1.21%), and the average vehicle size was 133.6 ± 2.8 nm. After 32 days of storage, the vehicle sizes of formulations with PE series were still approximately less than 200 nm. The safety of liposomes was tested and ensured both with regard to cellular cytotoxicity and erythrocyte hemolysis. Safety studies showed that liposome formulations did not affect cell viability except when both potassium stearate and sodium oleate were added. Moreover, PE and PE/cholesterol did not damage human erythrocytes in this study. The range of the hemolytic effect caused by liposomes was 5 to 37% and the effect was dependent on the amount of sodium stearate added to the formulation. According to the release rates and skin penetration of ALA liposomes in vitro, PE/cholesterol/sodium stearate liposomes might increase skin penetration, and it was shown that penetration across the stratum–corneum (sc) layer was the rate-limiting process. Images from confocal laser scanning microscopy (CLSM) confirmed the great potency of liposomes for delivering ALA into skin.

HVJ-based non-viral gene transfer method: successful gene therapy using HGF and VEGF genes in experimental ischemia

VEGF and HGF are pleiotropic factors that regulate cell growth, cell motility, and morphogenesis of various types of cells. The receptors of these growth factors are expressed in neurons and endothelial cells, and are identified as neurotrophic, neuroprotective, and angiogenic factors. Indeed, gene therapy using viral vectors encoding the VEGF or HGF gene has been reported to be effective for preventing the expansion of ischemic injury. However, the safety issue of viral vectors is a major problem in clinical application. To overcome this problem, we have developed an HVJ-based non-viral vector, which achieves high-efficiency transfection rates of viral vectors with the safety of liposomes. This review discusses the feasibility of gene therapy using an HVJ-based non-viral vector containing the VEGF or HGF gene for cerebral ischemia.

Physicochemical specification of drug carrying liposomes for the quality control in the industrial production

Animal data of liposomal drugs in a laboratory environment are often not reproduced on industrial scale products. One of the most important reasons is in the fact that the colloid-chemical properties of the liposomes manufactured on a small scale are not reproduced in a large scale production. In this review, colloid chemical characterization of liposomes is introduced, fixed aqueous layer thickness (FALT) as an example, and its importance in a quality control of a liposomal product in an industrial scale production is shown. Methoxy-polyethylenglycol-diacylgricerol (PEG-DAG) with varying PEG chain length and acyl chains were synthesized, FALT of liposomes coated with PEG-DAG determined and tissue distribution in tumor bearing mice studied. The higher incorporation ratio of PEG-DAG into liposomal membrane was observed with PEG-DAG with short acyl chains (myristoyl) and a small PEG molecular weight (1000). The easier to be incorporated, the easier to be stripped in the serum. The disposition data in the mice well reflected the colliod chemical and in vitro data of the PEG liposomes. Galactosyl-carbonyl-propionyl-polyethyleneglycol-diacylglycerol (Gal-PEG-DAG) with oxyethylene number, n=10, 20 and 40 were synthesized. The exposure of galactosy residue beyond the fixed aqueous layer of liposomes coated with Gal-PEG-DAG was monitored by RCA lectin induced agglutination, half life in the blood and organ distribution after i.v. injection into rats determined and intrahepatic distribution studied. Only the liposomes containing Gal-PEG 10DAG aggregated with the lectin, indicating that only with this derivative the galactose group was adequately exposed. The Gal-PEG 10-DAG liposomes were cleared from plasma with a half life of 0.3 h. The plasma elimination could be attributed entirely to increased uptake by the liver. The increased liver uptake was almost entirely attributed to increased uptake by the non-parenchymal cell. Incorporation of PEG-DSPE in the Gal-PEG 10DAG liposomes caused (1) a 3-fold increase in blood circulation time, (2) a small but significant decrease in hepatic uptake after 20 h and (3) a significant shift in intrahepatic distribution in favor of the hepatocytes, comparable to that of the control liposomes. In conclusion, therapeutic efficacy and safety of liposomes can be controlled by their colloid chemical, more exactly, surface chemical properties. By setting up reasonable quality control specifications of the properties in the laboratory and examining the specifications satisfied in upscaling, the efficacy and safety are reproduced in a large scale product.

An importance of colloid chemical characterization of liposomes for DDS in a large scale production

Efficacy and safety data of liposomal drugs in a laboratory environment are often not reproduced on an industrial production scale. This is largely due to the fact that the colloid-chemical properties of the liposomes manufactured on a small scale are not reproduced in large scale production. Though the size and the electric charge of liposomes are measured and are adequately specified in relation to the bio-distributions in most developments of liposomes (1), uniformity of lipid components, exposure of bio-chemically important functional groups on the outer surface of liposomes (2), fixed aqueous layer thickness (FALT), number of the lipid bilayers, etc., are dependent upon the scale of production. Nevertheless these properties are not always exactly specified. Uniformity, especially of the functional groups on the membrane surface can be assessed chemically or bio-chemically with fractionated samples, and FALT can be easily determined through electro-chemical means (3). In this review, colloid chemical characterization of liposomes is introduced, FALT as an example, and its importance in a quality control of a liposomal product in an industrial scale production is shown. Methoxy-polyethyleneglycol-diacylglycerol (PEG-DAG) with varying PEG chain length and acyl chains were synthesized, FALT of liposomes coated with PEG-DAG determined and tissue distribution in tumor bearing mice. The higher incorporation ratio of PEG-DAG into liposomal membrane was observed with PEG-DAG with short acyl chains (myristoyl) and a small PEG molecular weight (1000). The easier to incorporate, the easier to be stripped in the serum. The disposition data in the rats well reflected the colloid chemical and in vitro data of the PEG liposomes. Galactosyl-carbonyl-propionyl-polyethyleneglycol-diacylglycerol (Gal-PEG-DAG) with oxyethylene number, n = 10, 20 and 40 were synthesized. The exposure of the galactose residue beyond the fixed aqueous layer of liposomes coated with Gal-PEG-DAG was monitored by a lectin, Ricinus communis agglutinin (RCA) induced agglutination, the half life in the blood after i.v. injection into rats, organ distribution determined and intrahepatic distribution studied. Only the liposomes containing the Gal-PEG10-DAG aggregated with the lectin, indicating that only with this derivative the galactose group was adequately exposed. The Gal-PEG10-DAG liposomes were cleared from the plasma with a half life of 0.3 h. The plasma elimination could be attributed entirely to increased uptake by the liver. The increased liver uptake was almost entirely attributed to increased uptake by the non-parenchymal cell. Incorporation of PEG-DSPE in to the Gal-PEG10-DAG liposomes caused 1) a three-fold increase in blood circulation time, 2) a small but significant decrease in hepatic uptake after 20 h and 3) a significant shift in intrahepatic distribution in favor of the hepatocytes, comparable to that of the control liposomes. In conclusion, therapeutic efficacy and safety of liposomes can be controlled by their colloid chemical, more exactly, surface chemical properties. By setting up reasonable quality control specification of the properties in laboratory and examining the specifications satisfied in upscaling, the efficacy and safety are reproduced in a large scale product.

Production and metabolism of cytotoxic phospholipids generated during incubation of liposomes with oxyhemoglobin.

It is now widely accepted that liposomes are useful drug delivery systems. The encapsulation of a drug inside liposomes often decreases the toxicity of the drug while maintaining or enhancing its efficacy. Liposomal drugs have many applications including anticancer, antiviral, antibacterial, antifungal, and anti-inflammatory therapy. It is therefore increasingly necessary to develop liposomal formulations that satisfy pharmaceutical demands for safety and stability in vivo. Many investigations have been performed to prepare liposomes that are stable in buffer, ‘but little information has been available concerning the stability and safety of liposomes after injection into the human body. Since they are used mostly to treat diseases, liposomes must be safe and stable under pathological conditions.KeywordsLiposomal DrugCytotoxic ProductLiposomal LipidConjugate Diene ConcentrationExtracellular PhospholipaseThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.