title: Optimized thermosensitive liposomes for selective doxorubicin delivery: formulation development, quality analysis and bioactivity proof.
abstract: 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.
authors.affiliation: Blokhin Oncological Research Center, Kashirskoje Shosse 24, 115478 Moscow, Russia; Department of Pharmaceutics and Biopharmacy, Philipps University, Ketzerbach 63, D-35037 Marburg, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Levacheva
authors.affiliation: Department of Pharmaceutics and Biopharmacy, Philipps University, Ketzerbach 63, D-35037 Marburg, Germany. Electronic address: olga.samsonova@staff.uni-marburg.de.
authors.forename: O
authors.initials: O
authors.lastname: Samsonova
authors.affiliation: Blokhin Oncological Research Center, Kashirskoje Shosse 24, 115478 Moscow, Russia.
authors.forename: E
authors.initials: E
authors.lastname: Tazina
authors.affiliation: Department of Pharmaceutics and Biopharmacy, Philipps University, Ketzerbach 63, D-35037 Marburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Beck-Broichsitter
authors.affiliation: Blokhin Oncological Research Center, Kashirskoje Shosse 24, 115478 Moscow, Russia.
authors.forename: S
authors.initials: S
authors.lastname: Levachev
authors.affiliation: Department of Pharmaceutics and Biopharmacy, Philipps University, Ketzerbach 63, D-35037 Marburg, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Strehlow
authors.affiliation: Blokhin Oncological Research Center, Kashirskoje Shosse 24, 115478 Moscow, Russia.
authors.forename: M
authors.initials: M
authors.lastname: Baryshnikova
authors.affiliation: Blokhin Oncological Research Center, Kashirskoje Shosse 24, 115478 Moscow, Russia.
authors.forename: N
authors.initials: N
authors.lastname: Oborotova
authors.affiliation: Blokhin Oncological Research Center, Kashirskoje Shosse 24, 115478 Moscow, Russia.
authors.forename: A
authors.initials: A
authors.lastname: Baryshnikov
authors.affiliation: Department of Pharmaceutics and Biopharmacy, Philipps University, Ketzerbach 63, D-35037 Marburg, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Bakowsky
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D002850:Chromatography, Gel; D003451:Cryoprotective Agents / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology*; D016503:Drug Delivery Systems / Q000592:standards*; D005612:Freeze Drying; D005615:Freezing; D008055:Lipids / Q000737:chemistry; D008081:Liposomes / Q000737:chemistry* / Q000648:ultrastructure; D008546:Melanoma, Experimental; D051379:Mice; D010316:Particle Size; D013696:Temperature
chemical_list: D001672:Biocompatible Materials; D003451:Cryoprotective Agents; D008055:Lipids; D008081:Liposomes; D004317:Doxorubicin
keywords: Antitumor therapy; Doxorubicin; Stability; Thermosensitive liposomes