title: N-alkylation of poloxamines modulates micellar assembly and encapsulation and release of the antiretroviral efavirenz.
abstract: Poloxamines (X-shaped poly(ethylene oxide)-poly(propylene oxide) (PEO-PPO) diblocks connected to a central ethylenediamine group) were N-methylated and N-allylated with the aim of widening their versatility as drug nanocarriers. The self-aggregation properties of various derivatives, covering a wide range of molecular weights and EO/PO ratios, were thoroughly investigated. The cytocompatibility of different modified poloxamines was compared to that of the pristine counterparts by MTT and LDH assays. The most hydrophilic varieties were highly cytocompatible even at concentrations of 5%. Toward the optimization of the oral pharmacotherapy of the Human Immunodeficiency Virus (HIV) infection in pediatric patients, the encapsulation and in vitro delivery of efavirenz (EFV), a lipophilic first-line antiretroviral drug, were evaluated. Pristine and N-alkylated poloxamines behaved as highly efficient EFV solubilizers enhancing the aqueous solubility of the drug between 166 and 7426-times. EFV promotes self-micellization of poloxamines; their tiny structural modification (i.e., just one methyl- or allyl-group) being able to regulate drug/micellar core interaction. Despite the physical stability of the micelles against dilution in physiological mimicking fluids, the N-alkylated derivatives were slightly more prone to disassembly promoting EFV release from the micellar reservoir. For all the derivatives evaluated, the in vitro release fitted zero-order kinetics and was sustained for at least 24 h. These findings point out N-alkylated poloxamines as promising nanocarriers for oral or parenteral drug delivery.
authors.affiliation: Department of Pharmaceutical Technology, University of Buenos Aires, Buenos Aires, Argentina; National Science Research Council (CONICET), Buenos Aires, Argentina.
authors.forename: Diego A
authors.initials: DA
authors.lastname: Chiappetta
authors.forename: Carmen
authors.initials: C
authors.lastname: Alvarez-Lorenzo
authors.forename: Ana
authors.initials: A
authors.lastname: Rey-Rico
authors.forename: Pablo
authors.initials: P
authors.lastname: Taboada
authors.forename: Angel
authors.initials: A
authors.lastname: Concheiro
authors.forename: Alejandro
authors.initials: A
authors.lastname: Sosnik
mesh_terms: D000284:Administration, Oral; D000478:Alkylation; D000480:Alkynes; D000818:Animals; D044966:Anti-Retroviral Agents / Q000008:administration & dosage / Q000737:chemistry*; D041702:BALB 3T3 Cells; D048588:Benzoxazines / Q000008:administration & dosage / Q000737:chemistry*; D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D003521:Cyclopropanes; D004337:Drug Carriers; D004339:Drug Compounding; D004355:Drug Stability; D005029:Ethylenediamines / Q000737:chemistry* / Q000633:toxicity; D007700:Kinetics; D051379:Mice; D008823:Micelles; D008956:Models, Chemical; D053758:Nanoparticles; D011092:Polyethylene Glycols / Q000737:chemistry* / Q000633:toxicity; D011108:Polymers / Q000737:chemistry* / Q000633:toxicity; D011409:Propylene Glycols / Q000737:chemistry* / Q000633:toxicity; D012995:Solubility; D013500:Surface Tension; D013678:Technology, Pharmaceutical / Q000379:methods
chemical_list: D000480:Alkynes; D044966:Anti-Retroviral Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D004337:Drug Carriers; D005029:Ethylenediamines; D008823:Micelles; D011108:Polymers; D011409:Propylene Glycols; C012504:polypropylene glycol; D011092:Polyethylene Glycols; C098320:efavirenz