title: Tumor-targeted micelle-forming block copolymers for overcoming of multidrug resistance.
abstract: New amphiphilic diblock polymer nanotherapeutics serving simultaneously as a drug delivery system and an inhibitor of multidrug resistance were designed, synthesized, and evaluated for their physico-chemical and biological characteristics. The amphiphilic character of the diblock polymer, containing a hydrophilic block based on the N-(2-hydroxypropyl)methacrylamide copolymer and a hydrophobic poly(propylene oxide) block (PPO), caused self-assembly into polymer micelles with an increased hydrodynamic radius (Rhof approximately 15nm) in aqueous solutions. Doxorubicin (Dox), as a cytostatic drug, was bound to the diblock polymer through a pH-sensitive hydrazone bond, enabling prolonged circulation in blood, the delivery of Dox into a solid tumor and the subsequent stimuli-sensitive controlled release within the tumor mass and tumor cells at a decreased pH. The applicability of micellar nanotherapeutics as drug carriers was confirmed by an in vivo evaluation using EL4 lymphoma-bearing C57BL/6 mice. We observed significantly higher accumulation of micellar conjugates in a solid tumor because of the EPR effect compared with similar polymer-drug conjugates that do not form micellar structures or with the parent free drug. In addition, highly increased anti-tumor efficacy of the micellar polymer nanotherapeutics, even at a sub-optimal dose, was observed. The presence of PPO in the structure of the diblock polymer ensured, during in vitro tests on human and mouse drug-sensitive and resistant cancer cell lines, the inhibition of P-glycoprotein, one of the most frequently expressed ATP-dependent efflux pump that causes multidrug resistance. In addition, we observed highly increased rate of the uptake of the diblock polymer nanotherapeutics within the cells. We suppose that combination of unique properties based on MDR inhibition, stimuli sensitiveness (pH sensitive activation of drug), improved pharmacokinetics and increased uptake into the cells made the described polymer micelle a good candidate for investigation as potential drug delivery system.
authors.affiliation: Institute of Macromolecular Chemistry, Czech Academy of Sciences, Heyrovského nám. 2, 162 06 Prague, Czech Republic.
authors.forename: Alena
authors.initials: A
authors.lastname: Braunová
authors.affiliation: Institute of Macromolecular Chemistry, Czech Academy of Sciences, Heyrovského nám. 2, 162 06 Prague, Czech Republic.
authors.forename: Libor
authors.initials: L
authors.lastname: Kostka
authors.affiliation: Institute of Microbiology, Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic.
authors.forename: Ladislav
authors.initials: L
authors.lastname: Sivák
authors.affiliation: Institute of Macromolecular Chemistry, Czech Academy of Sciences, Heyrovského nám. 2, 162 06 Prague, Czech Republic.
authors.forename: Lucie
authors.initials: L
authors.lastname: Cuchalová
authors.affiliation: Institute of Macromolecular Chemistry, Czech Academy of Sciences, Heyrovského nám. 2, 162 06 Prague, Czech Republic.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Hvězdová
authors.affiliation: Institute of Macromolecular Chemistry, Czech Academy of Sciences, Heyrovského nám. 2, 162 06 Prague, Czech Republic.
authors.forename: Richard
authors.initials: R
authors.lastname: Laga
authors.affiliation: Institute of Macromolecular Chemistry, Czech Academy of Sciences, Heyrovského nám. 2, 162 06 Prague, Czech Republic.
authors.forename: Sergey
authors.initials: S
authors.lastname: Filippov
authors.affiliation: Institute of Macromolecular Chemistry, Czech Academy of Sciences, Heyrovského nám. 2, 162 06 Prague, Czech Republic.
authors.forename: Peter
authors.initials: P
authors.lastname: Černoch
authors.affiliation: Institute of Macromolecular Chemistry, Czech Academy of Sciences, Heyrovského nám. 2, 162 06 Prague, Czech Republic.
authors.forename: Michal
authors.initials: M
authors.lastname: Pechar
authors.affiliation: Institute of Macromolecular Chemistry, Czech Academy of Sciences, Heyrovského nám. 2, 162 06 Prague, Czech Republic.
authors.forename: Olga
authors.initials: O
authors.lastname: Janoušková
authors.affiliation: Institute of Microbiology, Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic.
authors.forename: Milada
authors.initials: M
authors.lastname: Šírová
authors.affiliation: Institute of Macromolecular Chemistry, Czech Academy of Sciences, Heyrovského nám. 2, 162 06 Prague, Czech Republic. Electronic address: etrych@imc.cas.cz.
authors.forename: Tomáš
authors.initials: T
authors.lastname: Etrych
mesh_terms: D000178:Acrylamides / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D004337:Drug Carriers / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D065546:Drug Liberation; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D008810:Mice, Inbred C57BL; D008823:Micelles; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011108:Polymers / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D011409:Propylene Glycols / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000178:Acrylamides; D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D008823:Micelles; D011108:Polymers; D011409:Propylene Glycols; C012504:polypropylene glycol; D004317:Doxorubicin; C032976:N-(2-hydroxypropyl)methacrylamide
keywords: EPR effect; HPMA copolymer; Micellar drug conjugate; Multidrug resistance; P-glycoprotein inhibitor; Poly(propylene oxide)