含有偶氮苯基的水溶性共聚物包覆的脂质体的光控释放行为

为了研究侧链含有偶氮苯基的水溶性共聚物的光异构化对脂质体内包容物的光控释放的影响，设计合成了Ｎ－异丙基丙烯酰胺和丙烯酰胺基偶氮苯的共聚物。     

Albendazole solution formulation via vesicle-to-micelle transition of phospholipid-surfactant aggregates

Objective: To reveal the physicochemical mechanisms governing the solubilization of albendazole in surfactant and phospholipid-surfactant solutions and, on this basis, to formulate clinically relevant dose of albendazole in solution suitable for parenteral delivery.

Significance: (1) A new drug delivery system for parenteral delivery of albendazole is proposed, offering high drug solubility and low toxicity of the materials used; (2) New insights on the role of surface curvature on albendazole solubilization in surfactant and surfactant-phospholipid aggregates are provided.

Methods: The effect of 17 surfactants and 6 surfactant-phospholipid mixtures on albendazole solubility was studied. The size of the colloidal aggregates was determined by light-scattering. The dilution stability of the proposed formulation was assessed by experiments with model human serum.

Results: Anionic surfactants increased very strongly drug solubility at pH?=?3 (up to 4?mg/mL) due to strong electrostatic attraction between the oppositely charged (at this pH) drug and surfactant molecules. This effect was observed with all anionic surfactants studied, including sodium dodecyl sulfate, double chain sodium dioctylsulfosuccinate (AOT), and the bile salt sodium taurodeoxycholate. The phospholipid-surfactant mixture of 40% sodium dipalmitoyl-phosphatidylglycerol +60% AOT provided highest albendazole solubilization (4.4?mg/mL), smallest colloidal aggregate size (11?nm) and was stable to dilution with model human serum at (and above) 1:12 ratio.

Conclusions: A new albendazole delivery system with high drug load and low toxicity of the materials used was developed. The high solubility of albendazole was explained with vesicle-to-micelle transition due to the larger interfacial curvature preferred for albendazole solubilization locus.     

Personalized Development of Antisense Oligonucleotides for Exon Skipping Restores Type XVII Collagen Expression in Junctional Epidermolysis Bullosa

Intermediate junctional epidermolysis bullosa caused by mutations in the COL17A1 gene is characterized by the frequent development of blisters and erosions on the skin and mucous membranes. The rarity of the disease and the heterogeneity of the underlying mutations renders therapy developments challenging. However, the high number of short in-frame exons facilitates the use of antisense oligonucleotides (AON) to restore collagen 17 (C17) expression by inducing exon skipping. In a personalized approach, we designed and tested three AONs in combination with a cationic liposomal carrier for their ability to induce skipping of COL17A1 exon 7 in 2D culture and in 3D skin equivalents. We show that AON-induced exon skipping excludes the targeted exon from pre-mRNA processing, which restores the reading frame, leading to the expression of a slightly truncated protein. Furthermore, the expression and correct deposition of C17 at the dermal–epidermal junction indicates its functionality. Thus, we assume AON-mediated exon skipping to be a promising tool for the treatment of junctional epidermolysis bullosa, particularly applicable in a personalized manner for rare genotypes.     

Liposomal Formulation of a PLA2-Sensitive Phospholipid–Allocolchicinoid Conjugate: Stability and Activity Studies In Vitro

To assess the stability and efficiency of liposomes carrying a phospholipase A2-sensitive phospholipid-allocolchicinoid conjugate (aC-PC) in the bilayer, egg phosphatidylcholine and 1-palmitoyl-2-oleoylphosphatidylglycerol-based formulations were tested in plasma protein binding, tubulin polymerization inhibition, and cytotoxicity assays. Liposomes L-aC-PC10 containing 10 mol. % aC-PC in the bilayer bound less plasma proteins and were more stable in 50% plasma within 4 h incubation, according to calcein release and FRET-based assays. Liposomes with 25 mol. % of the prodrug (L-aC-PC25) were characterized by higher storage stability judged by their hydrodynamic radius evolution yet enhanced deposition of blood plasma opsonins on their surface according to SDS-PAGE and immunoblotting. Notably, inhibition of tubulin polymerization was found to require that the prodrug should be hydrolyzed to the parent allocolchicinoid. The L-aC-PC10 and L-aC-PC25 formulations demonstrated similar tubulin polymerization inhibition and cytotoxic activities. The L-aC-PC10 formulation should be beneficial for applications requiring liposome accumulation at tumor or inflammation sites.     

Efficient intraliposomal entrapment of hydrophilic platinum oligonuclear complexes

A simple method for intraliposomal entrapment of platinum complexes is presented, where hydrophilic platinum oligonuclear complexes, 1-methyluracil green (MeUG), uridine green (UdG) and uridine blue (UdB), are included inside liposomes and allowed to react with bilayer lipids. The liposomes prepared in this method exhibit higher entrapment efficiency and higher distribution to organs (liver, kidney, spleen, lung) and blood (but not B16 cancer cells) than those prepared from mononuclear Pt complexes [cis-diamminedichloroplatinum, cis-diammine-1,1′-dicarboxylatocyclobutaneplatinum, and cis-dichloro-cis-dihydroxy-trans-bis(isopropylamine)platinum)].     

Whey Protein Isolate Coated Liposomes as Novel Carrier Systems for Astaxanthin

In this work, whey protein isolate (WPI)‐coated astaxanthin‐loaded liposomes are prepared by combining the fabrication of liposomes with the layer self‐assembly deposition technique. The physical properties of such composite carriers are evaluated by zeta potential, particle size, distribution, encapsulation efficiency, and morphology. WPI‐ coated astaxanthin‐loaded liposomes display homodisperse distribution and high encapsulation efficiency with a WPI coating layer surrounding the surface of conventional liposomes by the electrostatic interaction. Fourier transform infrared spectroscopy and X‐ray diffraction analysis reveal that WPI interacts with the lipid bilayer via hydrophobic forces and hydrogen bonding, which result in the successful coating. Based on experimental results of differential scanning calorimetry and thermogravimetric analysis, it is demonstrated that thermal stability of astaxanthin‐loaded liposomes benefits from the formation of surface modification of the WPI‐layer. In addition, the physical stability of WPI‐coated astaxanthin‐loaded liposomes under heating and light is significantly improved as compared with uncoated liposomes. This research might provide scientific guidance for the development of WPI‐coated liposomes as efficient carrier systems for bioactive substances in food and pharmaceutical industry. Practical Applications: To improve lipid membrane stability and to prevent the leakage of encapsulated astaxanthin, a novel carrier system based on WPI coated on the surface of liposomes is prepared through the layer self‐assembly deposition technique. This research suggests that WPI‐coated liposomes represent an effective and stable delivery system for astaxanthin. WPI‐coated liposomes could be developed as efficient carrier systems for bioactive compounds in the food and pharmaceutical industries.     

Efficient TGF-β1 Delivery to Articular Chondrocytes In Vitro Using Agro-Based Liposomes

The low efficiency in transfecting rat- and human-derived chondrocytes have been hampering developments in the field of cartilage biology. Transforming growth factor (TGF)-β1 has shown positive effects on chondrocytes, but its applications remain limited due to its short half-life, low stability and poor penetration into cartilage. Naturally derived liposomes have been shown to be promising delivery nanosystems due to their similarities with biological membranes. Here, we used agro-based rapeseed liposomes, which contains a high level of mono- and poly-unsaturated fatty acids, to efficiently deliver encapsulated TGF-β1 to rat chondrocytes. Results showed that TGF-β1 encapsulated in nano-sized rapeseed liposomes were safe for chondrocytes and did not induce any alterations of their phenotype. Furthermore, the controlled release of TGF-β1 from liposomes produced an improved response in chondrocytes, even at low doses. Altogether, these outcomes demonstrate that agro-based nanoliposomes are promising drug carriers.     

A-ring oxidation products from γ-irradiation of cholesterol in liposomes

γ-Irradiation of cholesterol in multilamellar vesicles (MLV) at 0–4°C causes oxidation of the A-ring. Two A-ring oxides formed in considerable amounts are cholest-4-en-3-one (10) and cholest-4-ene-3,6-dione (12) in addition to the usual B-ring oxides. Lesser amounts of cholesta-4,6-dien-3-one (11) are also generated. Compounds 10 and 12 were detected and measured in cholesterol irradiated at less than 0.5 kGy in liposomes containing saturated or unsaturated phospholipids. Lesser amounts of 10 and 12, as well as lesser amounts of other cholesterol oxides, were formed when a major constituent of the MLV was dilinoleoylphosphatidylcholine. Autoxidation of cholesterol in MLV also gave rise to small amounts of 10, 11 and 12.