title: A comprehensive mathematical model of drug release kinetics from nano-liposomes, derived from optimization studies of cationic PEGylated liposomal doxorubicin formulations for drug-gene delivery.
abstract: This study focuses on the development of a universal mathematical model for drug release kinetics from liposomes to allow in silico prediction of optimal conditions for fine-tuned controlled drug release. As a prelude for combined siRNA-drug delivery, nanoliposome formulations were optimized using various mole percentages of a cationic lipid (1,2-dioleoyl-3-trimethylammonium-propane, DOTAP) in the presence or absence of 3 mol% distearoyl phosphoethanolamine, polyethylene glycol (PEG-2000mDSPE). Outcome parameters were particle size, zeta potential, entrapment efficiency, in vitro drug release, and tumor cell kill efficiency. The optimized formula (containing 20% DOTAP with 3% DSPE-mPEG(2000) was found to be stable for six months, with round-shaped particles without aggregate formation, an average diameter of 71 nm, a suitable positive charge, and 89% drug encapsulation efficiency (EE). The 41% drug release during 6 h confirmed controlled release. Furthermore, the release profiles as functions of pH and temperature were investigated and the kinetics of the drug release could adequately be fitted to Korsmeyer-Peppas' model by multiple regression analysis. The statistical parameters confirmed good conformity of final models. Functionality of the novel cationic liposome formulations (± DOX) was tested on osteosarcoma (OS) cell lines. Increased OS cell toxicity (1.3-fold) was observed by the DOX-loaded vs. the free DOX. A feasibility pilot showed that siRNA could be loaded efficiently as well. In conclusion, we have established a predictive mathematical model for the fine-tuning of controlled drug release from liposomal formulations, while creating functional drug-delivery liposomes with potential for siRNA co-delivery to increase specificity and efficacy.
authors.affiliation: a Department of Life Science Engineering, Faculty of New Sciences & Technologies , University of Tehran , Tehran , Iran.|b Department of Oral and Maxillofacial Surgery , VU University Medical Center, MOVE Research Institute Amsterdam , Amsterdam , Netherlands.
authors.forename: Fateme
authors.initials: F
authors.lastname: Haghiralsadat
authors.affiliation: b Department of Oral and Maxillofacial Surgery , VU University Medical Center, MOVE Research Institute Amsterdam , Amsterdam , Netherlands.|c Department of Biotechnology and Pharmaceutical Engineering, School of Chemical Engineering, College of Engineering , University of Tehran , Tehran , Iran.
authors.forename: Ghasem
authors.initials: G
authors.lastname: Amoabediny
authors.affiliation: b Department of Oral and Maxillofacial Surgery , VU University Medical Center, MOVE Research Institute Amsterdam , Amsterdam , Netherlands.|d Department of Orthopedic Surgery , VU University Medical Center, MOVE Research Institute Amsterdam , Amsterdam , Netherlands.
authors.forename: Marco N
authors.initials: MN
authors.lastname: Helder
authors.affiliation: c Department of Biotechnology and Pharmaceutical Engineering, School of Chemical Engineering, College of Engineering , University of Tehran , Tehran , Iran.
authors.forename: Samira
authors.initials: S
authors.lastname: Naderinezhad
authors.affiliation: e Research and Clinical Center for Infertility, Shahid Sadoughi University of Medical Sciences , Yazd , Iran.
authors.forename: Mohammad Hasan
authors.initials: MH
authors.lastname: Sheikhha
authors.affiliation: c Department of Biotechnology and Pharmaceutical Engineering, School of Chemical Engineering, College of Engineering , University of Tehran , Tehran , Iran.
authors.forename: Tymour
authors.initials: T
authors.lastname: Forouzanfar
authors.affiliation: f Oral Cell Biology and Functional Anatomy , VU University , Amsterdam , North Holland , Netherlands.
authors.forename: Behrouz
authors.initials: B
authors.lastname: Zandieh-Doulabi
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology; D004337:Drug Carriers / Q000737:chemistry*; D004339:Drug Compounding; D065546:Drug Liberation; D006801:Humans; D007700:Kinetics; D008081:Liposomes / Q000737:chemistry*; D008956:Models, Chemical; D049329:Nanostructures / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000737:chemistry* / Q000235:genetics; D014162:Transfection
chemical_list: D004337:Drug Carriers; D008081:Liposomes; D034741:RNA, Small Interfering; D011092:Polyethylene Glycols; D004317:Doxorubicin
keywords: Cationic liposome; drug release kinetics; mathematical modelling; siRNA delivery; thermo and pH sensitivity