Optimized thermosensitive liposomes for selective doxorubicin delivery: formulation development, quality analysis and bioactivity proof.

In our study we examined thermosensitive liposomal formulations (TL) from the perspective to minimize the general toxicity drawbacks of chemotherapy. The TL become active in response to local hyperthermia (LH), and remain inactive at physiological conditions. Here, we formulated novel doxorubicin loaded thermoliposomes (Dox-TL) with optimized characteristics and tested their biological activity in vitro. The liposomal membrane composition of Dox-TL and their preparation technology were adjusted for high drug loading and extended formulation stability. The 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC):1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC):cholesterol(Chol):1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[maleimide(polyethylene glycol)-2000] (ammonium salt) (DSPE-PEG-2000) in molar ratio 9:1:0.2:0.02:0.2 and drug/lipid weight ratio 0.13-0.20/1 composition has demonstrated best results. The freshly-prepared vesicles contained 94% doxorubicin. The Dox-TL, freeze-dried with 4% sucrose, maintained high level of encapsulated drug, remained stable in serum and prevented premature drug leakage. The Dox-TL proved to be significantly less toxic at 37°C than free Dox. In combination with local hyperthermia of 42.5°C Dox-TL were as effective as free Dox in cell survival, and even outperformed free Dox in proliferation activity suppression, colony proliferation rate, and cellular uptake. These findings represent a solid basis for a safer and more effective antitumor therapy.

[Nonenzymatic incorporation of prostaglandin A1 into phospholipids in rat liver microsomes]. / Nefermentativnoe vkliuchenie prostaglandina A1 v fosfolipidy mikrosom pecheni krysy.

The incorporation of [5,6(n)-3H]prostaglandin A1 (PGA1) and [1-14C]oleic acid into membrane phospholipids of rat liver microsomes was studied. It was shown that PGA1 is incorporated into phospholipids in a much lesser degree than oleic acid. PGA1 is incorporated into phosphatidylethanolamine and, in a lesser degree, into phosphatidylcholine and phosphatidylinositol + phosphatidylserine. The exogenous cofactors of fatty acid acylation (ATP, CoA, Mg2+) exert no marked influence on the incorporation of PGA1 into the phospholipids. PGA1 interacts with isolated rat liver phospholipids; the PGA1-phospholipid conjugate formed is not destroyed in the course of one- or two-dimensional thin-layer chromatography. On the other hand, PGA1 binding to unsaturated phosphatidylcholines is strictly dependent on the phospholipid oxidation index. It is concluded that PGA1 incorporation into rat liver phospholipids is a result of interaction of PGA1 with peroxidized phospholipids.