title: Biodegradable Micellar HPMA-Based Polymer-Drug Conjugates with Betulinic Acid for Passive Tumor Targeting.
abstract: Here, we present the synthesis, physicochemical, and preliminary biological characterization of micellar polymer-betulinic acid (BA) conjugates based on N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer carriers, enabling the controlled release of cytotoxic BA derivatives in solid tumors or tumor cells. Various HPMA copolymer conjugates differing in the structure of the spacer between the drug and the carrier were synthesized, all designed for pH-triggered drug release in tumor tissue or tumor cells. The high molecular weight of the micellar conjugates should improve the uptake of the drug in solid tumors due to the Enhanced permeability and retention (EPR) effect. Nevertheless, only the conjugate containing BA with methylated carboxyl groups enabled pH-dependent controlled release in vitro. Moreover, drug release led to the disassembly of the micellar structure, which facilitated elimination of the water-soluble HPMA copolymer carrier from the body by renal filtration. The methylated BA derivative and its polymer conjugate exhibited high cytostatic activity against DLD-1, HT-29, and HeLa carcinoma cell lines and enhanced tumor accumulation in HT-29 xenograft in mice.
authors.affiliation: Institute of Macromolecular Chemistry, The Czech Academy of Sciences , Heyrovsky Sq. 2, Prague 6, 162 06, Czech Republic.|St. Petersburg State Chemical Pharmaceutical Academy, 14 Prof. Popov St., St. Petersburg 197022, Russian Federation.
authors.forename: Ekaterina A
authors.initials: EA
authors.lastname: Lomkova
authors.affiliation: Institute of Macromolecular Chemistry, The Czech Academy of Sciences , Heyrovsky Sq. 2, Prague 6, 162 06, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Chytil
authors.affiliation: Institute of Macromolecular Chemistry, The Czech Academy of Sciences , Heyrovsky Sq. 2, Prague 6, 162 06, Czech Republic.
authors.forename: Olga
authors.initials: O
authors.lastname: Janoušková
authors.affiliation: Martin-Luther-University Halle-Wittenberg , Department of Internal Medicine IV, Oncology and Haematology, Ernst-Grube-Str. 40, 06120 Halle (Saale), Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mueller
authors.affiliation: Martin-Luther-University Halle-Wittenberg , Institute of Pharmacy, AG Pharmaceutical Technology, Wolfgang-Langenbeck-Str. 4, 06120 Halle (Saale), Germany.
authors.forename: Henrike
authors.initials: H
authors.lastname: Lucas
authors.affiliation: Institute of Macromolecular Chemistry, The Czech Academy of Sciences , Heyrovsky Sq. 2, Prague 6, 162 06, Czech Republic.
authors.forename: Sergey K
authors.initials: SK
authors.lastname: Filippov
authors.affiliation: Institute of Macromolecular Chemistry, The Czech Academy of Sciences , Heyrovsky Sq. 2, Prague 6, 162 06, Czech Republic.
authors.forename: Olga
authors.initials: O
authors.lastname: Trhlíková
authors.affiliation: St. Petersburg State Technological Institute (Technical University), 26 Moskovsky Pr., St. Petersburg, 190013, Russian Federation.
authors.forename: Pavel A
authors.initials: PA
authors.lastname: Aleshunin
authors.affiliation: St. Petersburg State Chemical Pharmaceutical Academy, 14 Prof. Popov St., St. Petersburg 197022, Russian Federation.|Institute of Macromolecular Compounds, Russian Academy of Sciences , 31 Bolshoy pr. VO, St. Petersburg 199004, Russian Federation.
authors.forename: Yury A
authors.initials: YA
authors.lastname: Skorik
authors.affiliation: Institute of Macromolecular Chemistry, The Czech Academy of Sciences , Heyrovsky Sq. 2, Prague 6, 162 06, Czech Republic.
authors.forename: Karel
authors.initials: K
authors.lastname: Ulbrich
authors.affiliation: Institute of Macromolecular Chemistry, The Czech Academy of Sciences , Heyrovsky Sq. 2, Prague 6, 162 06, Czech Republic.
authors.forename: Tomáš
authors.initials: T
authors.lastname: Etrych
mesh_terms: D000818:Animals; D063566:Biodegradable Plastics / Q000737:chemistry; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004317:Doxorubicin / Q000008:administration & dosage / Q000737:chemistry*; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry; D006801:Humans; D008689:Methacrylates / Q000008:administration & dosage / Q000737:chemistry*; D051379:Mice; D008823:Micelles; D009369:Neoplasms / Q000188:drug therapy*; D053978:Pentacyclic Triterpenes; D011108:Polymers / Q000008:administration & dosage / Q000737:chemistry; D014315:Triterpenes / Q000008:administration & dosage / Q000737:chemistry; D000094062:Betulinic Acid
chemical_list: D063566:Biodegradable Plastics; D004337:Drug Carriers; D008689:Methacrylates; D008823:Micelles; D053978:Pentacyclic Triterpenes; D011108:Polymers; D014315:Triterpenes; D004317:Doxorubicin; C032802:hydroxypropyl methacrylate; D000094062:Betulinic Acid