title: Curcumin loaded pH-sensitive hybrid lipid/block copolymer nanosized drug delivery systems.
abstract: Curcumin is a perspective drug candidate with pleiotropic antineoplastic activity, whose exceptionally low aqueous solubility and poor pharmacokinetic properties have hampered its development beyond the preclinical level. A possible approach to overcome these limitations is the encapsulation of curcumin into nano-carriers, incl. liposomes. The present contribution is focused on feasibility of using hybrid pH-sensitive liposomes, whereby curcumin is entrapped as a free drug and as a water soluble inclusion complex with PEGylated tert-butylcalix[4]arene, which allows the drug to occupy both the phospholipid membranes and the aqueous core of liposomes. The inclusion complexes were encapsulated in dipalmithoylphosphathydilcholine:cholesterol liposomes, whose membranes were grafted with a poly(isoprene-b-acrylic acid) diblock copolymer to confer pH-sensitivity. The liposomes were characterized by DLS, ζ-potential measurements, cryo-TEM, curcumin encapsulation efficacy, loading capacity, and in vitro release as a function of pH. Free and formulated curcumin were further investigated for cytotoxicity, apoptosis-induction and caspase-8, and 9 activation in chemosensitive HL-60 and its resistant sublines HL-60/Dox and HL-60/CDDP. Formulated curcumin was superior cytotoxic and apoptogenic agent vs. the free drug. The mechanistic assay demonstrated that the potent proapoptotic effects of pH-sensitive liposomal curcumin presumably mediated via recruitment of both extrinsic and intrinsic apoptotic pathways in both HL-60 and HL-60/CDDP cells.
authors.affiliation: Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University of Sofia, 2 Dunav Str., 1000 Sofia, Bulgaria.
authors.forename: Ivelina
authors.initials: I
authors.lastname: Jelezova
authors.affiliation: Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, Medical University of Sofia, 2 Dunav Str., 1000 Sofia, Bulgaria.
authors.forename: Elena
authors.initials: E
authors.lastname: Drakalska
authors.affiliation: Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, Medical University of Sofia, 2 Dunav Str., 1000 Sofia, Bulgaria. Electronic address: dmomekova@yahoo.com.
authors.forename: Denitsa
authors.initials: D
authors.lastname: Momekova
authors.affiliation: Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University of Sofia, 2 Dunav Str., 1000 Sofia, Bulgaria.
authors.forename: Natalia
authors.initials: N
authors.lastname: Shalimova
authors.affiliation: Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University of Sofia, 2 Dunav Str., 1000 Sofia, Bulgaria.
authors.forename: Georgi
authors.initials: G
authors.lastname: Momekov
authors.affiliation: Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University of Sofia, 2 Dunav Str., 1000 Sofia, Bulgaria.
authors.forename: Spiro
authors.initials: S
authors.lastname: Konstantinov
authors.affiliation: Institute of Polymers, Bulgarian Academy of Sciences, Sofia, Bulgaria.
authors.forename: Stanislav
authors.initials: S
authors.lastname: Rangelov
authors.affiliation: Theoretical and Physical Chemistry Institute, National Hellenic Research Foundation, 48 Vassileos Constantinou Avenue, 11635 Athens, Greece.
authors.forename: Stergios
authors.initials: S
authors.lastname: Pispas
mesh_terms: D015060:1,2-Dipalmitoylphosphatidylcholine / Q000737:chemistry; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis; D047250:Calixarenes / Q000737:chemistry; D002470:Cell Survival / Q000187:drug effects; D002784:Cholesterol / Q000737:chemistry; D003474:Curcumin / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D016503:Drug Delivery Systems; D018922:HL-60 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008081:Liposomes; D049329:Nanostructures / Q000008:administration & dosage / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D008081:Liposomes; C525100:para-tert-butylcalix(4)arene; D047250:Calixarenes; D015060:1,2-Dipalmitoylphosphatidylcholine; D011092:Polyethylene Glycols; D002784:Cholesterol; D003474:Curcumin
keywords: Apoptosis; Curcumin; Inclusion complex; Poly(isoprene-b-acrylic acid); Polyoxyethylated tert-buthylcalix[4]arenes; pH-sensitive hybrid liposomes