title: Multidrug PLA-PEG filomicelles for concurrent delivery of anticancer drugs-The influence of drug-drug and drug-polymer interactions on drug loading and release properties.
abstract: This study aimed to analyze the influence of drug-drug and drug-polymer interactions on drug loading and release properties of multidrug micelles. Three hydrophobic drugs-paclitaxel (Ptx), 17-AAG and rapamycin (Rap) were incorporated in poly(l-lactide)-poly(ethylene glycol) (PLA-PEG) filomicelles. Double loaded micelles containing Ptx and 17-AAG were used for the sake of comparison. (1)H NMR confirmed the effective incorporation of the various drugs in micelles, and HPLC allowed to determine the drug loading contents. FTIR was used to evaluate interactions between particular drugs and between drugs and copolymer. Ptx and 17-AAG present similar loading efficiencies in double loaded micelles probably due to interactions of drugs with each other and also with the copolymer. In contrast, unequal drug loading properties are observed for triple loaded micelles. Rapamycin shows very weak interactions with the copolymer, and displays the lowest loading efficiency. In vitro release of drugs from micelles was realized in pH 7.4 phosphate buffered saline at 37°C, and monitored by HPLC. Similar release profiles are observed for the three drugs: a strong burst followed by slower release. Nevertheless, Ptx release from micelles is significantly slower as compared to 17-AAG and Rap, probably due to interactions of NH and OH groups of Ptx with the carbonyl group of PLA. In vitro cytotoxicity of Ptx/17-AAG/Rap loaded micelles and a mixture of free drugs was determined. Drug loaded micelles exhibit advantageous effect of prolonged drug release and cytotoxic activity against Caco-2 cells, which makes them a promising solution for simultaneous drug delivery to solid tumors. Therefore, understanding of interactions within multidrug micelles should be a valuable approach for the development of concurrent delivery systems of anticancer drugs with tailored properties.
authors.affiliation: Centre of Polymer and Carbon Materials, Polish Academy of Sciences, Curie- Sklodowska 34 St., 41-819 Zabrze, Poland. Electronic address: kjelonek@cmpw-pan.edu.pl.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Jelonek
authors.affiliation: European Institute of Membranes, UMR CNRS 5635, University of Montpellier, Place Eugene Bataillon, 34095 Montpellier Cedex 5, France.
authors.forename: Suming
authors.initials: S
authors.lastname: Li
authors.affiliation: Centre of Polymer and Carbon Materials, Polish Academy of Sciences, Curie- Sklodowska 34 St., 41-819 Zabrze, Poland.
authors.forename: Bożena
authors.initials: B
authors.lastname: Kaczmarczyk
authors.affiliation: Centre of Polymer and Carbon Materials, Polish Academy of Sciences, Curie- Sklodowska 34 St., 41-819 Zabrze, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Marcinkowski
authors.affiliation: School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia, Katowice, Poland, Chair and Department of Biopharmacy, Jedności 8, Sosnowiec, Poland.
authors.forename: Arkadiusz
authors.initials: A
authors.lastname: Orchel
authors.affiliation: Centre of Polymer and Carbon Materials, Polish Academy of Sciences, Curie- Sklodowska 34 St., 41-819 Zabrze, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Musiał-Kulik
authors.affiliation: Centre of Polymer and Carbon Materials, Polish Academy of Sciences, Curie- Sklodowska 34 St., 41-819 Zabrze, Poland; School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia, Katowice, Poland, Chair and Department of Biopharmacy, Jedności 8, Sosnowiec, Poland.
authors.forename: Janusz
authors.initials: J
authors.lastname: Kasperczyk
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism*; D018938:Caco-2 Cells; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D016503:Drug Delivery Systems / Q000379:methods*; D004347:Drug Interactions / Q000502:physiology; D065546:Drug Liberation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008823:Micelles; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000378:metabolism*; D011108:Polymers / Q000008:administration & dosage / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D008823:Micelles; D011108:Polymers; C542623:monomethoxypolyethyleneglycol-polylactide block copolymer; D011092:Polyethylene Glycols
keywords: 17-AAG; Combination therapy; Multidrug micelles; PLA-PEG; Paclitaxel; Rapamycin