The Polar Lipid Fraction E from Sulfolobus acidocaldarius Can Be Used as Liposomal Drug Stabilizing Agents to Reduce the Leakage of the Antivascular Drug Combretastatin A4 Disodium Phosphate from Tetraether/Diester Hybrid Archaeosomes

Liposomes have many advantages as therapeutic capsules over free drugs such as small molecule drugs and nucleic acids. Cholesterol is commonly used as a membrane stabilizing agent in liposomal drugs (e.g., mRNA-lipid nanoparticle COVID-19 vaccines). However, due to the vulnerability of cholesterol to oxidation and the etiological role of cholesterol in many disorders, it is desirable to find an alternative means to stabilize liposomal membranes for drug delivery. In this study, we demonstrated that the polar lipid fraction E (PLFE), which contains exclusively bipolar tetraether macrocyclic lipids, isolated from the thermoacidophilic archaeon S. acidocaldarius can greatly stabilize the liposomal formulation of the anti-vascular drug, combretastatin A4 disodium phosphate (CA4P). Stability was assessed by determining the leakage rate constant k of entrapped CA4P fluorometrically. We found that, at 37 °C, PLFE decreases the k value monotonically from 1.54 × 10−2 s−1 for 100% 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC) liposomes to 3.4 × 10−5 s−1 for 100% PLFE archaeosomes, a change of k by two orders of magnitude. The changes in k of CA4P leakage are correlated well with the changes in liposomal CA4P’s cytotoxicity against MCF-7 breast cancer cells. We further showed that the reduction in spontaneous leakage of entrapped CA4P by PLFE can be attributed to the increased membrane surface charge and the increased membrane order and packing tightness in liposomes, as reflected by the zeta potential (−6.83 to −41.1 mV from 0 to 100 mol% PLFE) and diphenylhexatriene (DPH) fluorescence polarization (0.13 to 0.4 from 0 to 100 mol% PLFE) measurements. Moreover, we showed that PLFE slows down CA4P leakage more than cholesterol in POPC liposomes. These results together suggest that PLFE lipids can serve as an effective stabilizing agent for liposomal drugs and could potentially be useful for the optimization of liposomal CA4P for cancer treatment.

Liposomal drug delivery to manage nontuberculous mycobacterial pulmonary disease and other chronic lung infections

Nontuberculous mycobacterial (NTM) pulmonary disease is a chronic respiratory infection associated with declining lung function, radiological deterioration and significantly increased morbidity and mortality. Patients often have underlying lung conditions, particularly bronchiectasis and COPD. NTM pulmonary disease is difficult to treat because mycobacteria can evade host defences and antimicrobial therapy through extracellular persistence in biofilms and sequestration into macrophages. Management of NTM pulmonary disease remains challenging and outcomes are often poor, partly due to limited penetration of antibiotics into intracellular spaces and biofilms. Efficient drug delivery to the site of infection is therefore a key objective of treatment, but there is high variability in lung penetration by antibiotics. Inhalation is the most direct route of delivery and has demonstrated increased efficacy of antibiotics like amikacin compared with systemic administration. Liposomes are small, artificial, enclosed spherical vesicles, in which drug molecules can be encapsulated to provide controlled release, with potentially improved pharmacokinetics and reduced toxicity. They are especially useful for drugs where penetration of cell membranes is essential. Inhaled delivery of liposomal drug solutions can therefore facilitate direct access to macrophages in the lung where the infecting NTM may reside. A range of liposomal drugs are currently being evaluated in respiratory diseases.

Liposomal Nanomedicine: Applications for Drug Delivery in Cancer Therapy

The increasing prevalence of cancer, a disease in which rapid and uncontrollable cell growth causes complication and tissue dysfunction, is one of the serious and tense concerns of scientists and physicians. Nowadays, cancer diagnosis and especially its effective treatment have been considered as one of the biggest challenges in health and medicine in the last century. Despite significant advances in drug discovery and delivery, their many adverse effects and inadequate specificity and sensitivity, which usually cause damage to healthy tissues and organs, have been great barriers in using them. Limitation in the duration and amount of these therapeutic agents’ administration is also challenging. On the other hand, the incidence of tumor cells that are resistant to typical methods of cancer treatment, such as chemotherapy and radiotherapy, highlights the intense need for innovation, improvement, and development in antitumor drug properties. Liposomes have been suggested as a suitable candidate for drug delivery and cancer treatment in nanomedicine due to their ability to store drugs with different physical and chemical characteristics. Moreover, the high flexibility and potential of liposome structure for chemical modification by conjugating various polymers, ligands, and molecules is a significant pro for liposomes not only to enhance their pharmacological merits but also to improve the effectiveness of anticancer drugs. Liposomes can increase the sensitivity, specificity, and durability of these anti-malignant cell agents in the body and provide remarkable benefits to be applied in nanomedicines. We reviewed the discovery and development of liposomes focusing on their clinical applications to treat diverse sorts of cancers and diseases. How the properties of liposomal drugs can be improved and their opportunity and challenges for cancer therapy were also considered and discussed. Graphic abstract

"QUALITY BY DESIGN" IN LIPOSOMAL DRUGS CREATION

Nanobiotechnological preparations creation is one of the promising areas of modern pharmacy, since it allows creating products of a qualitatively new level. The procedure development, based on an understanding of the product characteristics and the technological process, confirmed by reliable scientific data. The article is devoted to the pharmaceutical development of liposomal drugs. On the basis of our own experience in the development of liposomal medicinal forms, as well as on the basis of literature data, the main components in their composition were detected and these components impact on the quality indicators of liposomes were studied. Individual lipids function in nanoparticle membrane and their interaction, which determines the stability both in the technological process and upon storage of the product, were considered. The advantages and disadvantages of cholesterol incorporation into liposomes with hydrophilic and hydrophobic active pharmaceutical ingredients were described. Cryoprotectors and buffer systems role in ensuring nanopreparation stability is discussed.

Efficacy of liposomal dosage forms and hyperosmolar salines in experimental pharmacotherapy of acute lung injury

Introduction: Hypertonic sodium chloride solutions and liposomal drugs with pulmotropic effect are of great interest for the treatment of acute lung injury (ALI). The results of the studies on the efficacy of hypertonic solutions and liposomes in ALI treatment are currently controversial.Materials and methods: For the experiment, liposomes with dexamethasone, N-acetylcysteine (NAC), aprotinin and dye Cyanine-7 (Cy-7) were obtained. A liposome analysis was performed by means of spectrophotometry. ALI was modeled in rats by the administration of the damaging agents into the trachea. The experimental agents were injected once intravenously after the modeling of ALI. For experimental therapy used liposomal agents, 7.5% hypertonic saline (HS) and HyperHAES solutions in the respective groups. The efficacy of the therapy was assessed by the survival of animals, functional indicators of the cardiovascular and respiratory systems, and by the lung-body ratio. The biodistribution of liposomes after intravenous administration was investigated in mice through using a fluorescent dye Cy-7. The biodistribution of liposomes with Cy-7 was assessed using bioimaging according to the fluorescence intensity of internal organs (lungs, liver, and kidneys) and blood, expressed as dye concentration according to the calibration dependence of dye concentrarion on fluorescence intensity.Results and discussion: All the studied liposomal drugs were effective for the pharmacological correction of ALI. Hypertonic solutions, unlike liposomal drugs, were less likely to prevent the development of pulmonary edema. All the studied therapeutic agents increased the survival rate of the laboratory animals with ALI. The most effective experimental agent was liposomal dexamethasone. The use of drugs in form of simple liposomes with average diameter of 350 nm provided for a higher concentration of the drug in the lungs within the first 40 minutes after intravenous administration.Conclusion: Intravenous administration of liposomal forms is promising for the pharmacotherapy of acute lung injury.

Pharmacokinetics and Pharmacodynamics Modeling and Simulation Systems to Support the Development and Regulation of Liposomal Drugs

Liposomal formulations have been developed to improve the therapeutic index of encapsulated drugs by altering the balance of on- and off-targeted distribution. The improved therapeutic efficacy of liposomal drugs is primarily attributed to enhanced distribution at the sites of action. The targeted distribution of liposomal drugs depends not only on the physicochemical properties of the liposomes, but also on multiple components of the biological system. Pharmacokinetic–pharmacodynamic (PK–PD) modeling has recently emerged as a useful tool with which to assess the impact of formulation- and system-specific factors on the targeted disposition and therapeutic efficacy of liposomal drugs. The use of PK–PD modeling to facilitate the development and regulatory reviews of generic versions of liposomal drugs recently drew the attention of the U.S. Food and Drug Administration. The present review summarizes the physiological factors that affect the targeted delivery of liposomal drugs, challenges that influence the development and regulation of liposomal drugs, and the application of PK–PD modeling and simulation systems to address these challenges.

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