title: Polymer conjugates of the highly potent cytostatic drug 2-pyrrolinodoxorubicin.
abstract: This paper describes the synthesis and biological evaluation of a conjugate of the highly cytotoxic drug 2-pyrrolinodoxorubicin (p-DOX) with an N-(2-hydroxypropyl)methacrylamide copolymer (PHPMA) as a water-soluble biocompatible polymer carrier, utilizing the advantageous concept of polymer-drug conjugates. The conjugate of p-DOX with HPMA copolymer (PHPMA/p-DOX) was prepared by reacting the PHPMA/DOX conjugate, where the DOX was bound via a hydrazone bond, with 4-iodobutyraldehyde. The hydrazone bond between the polymer and drug is susceptible to pH-controlled hydrolysis, enabling prolonged stability in circulation and fast p-DOX release under conditions mimicking the intracellular environment. The in vitro cytostatic activity of free p-DOX was in accordance with literature, whereas its PHPMA conjugate exhibited a 1.3- to 5-fold lower cytotoxicity, depending on the cancer cell line, when compared to the free p-DOX. This is in qualitative agreement with the data obtained for DOX and its HPMA copolymer conjugates. On mice bearing T-cell EL4 lymphoma, no tumor suppression was observed from the free p-DOX at a subtoxic dose of 0.1 mg/kg, whereas the PHPMA/p-DOX conjugate significantly inhibited the initial tumor growth at approximately equitoxic doses of 0.4 and 0.8 mg p-DOX eq/kg. However, moderately elevated doses of the p-DOX equivalent in the conjugate caused toxic effects, making accurate dosage setting essential.
authors.affiliation: Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, Heyrovsky Sq. 2, Prague 6, Czech Republic. studenovsky@imc.cas.cz
authors.forename: M
authors.initials: M
authors.lastname: Studenovsky
authors.forename: K
authors.initials: K
authors.lastname: Ulbrich
authors.forename: M
authors.initials: M
authors.lastname: Ibrahimova
authors.forename: B
authors.initials: B
authors.lastname: Rihova
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D004337:Drug Carriers / Q000138:chemical synthesis* / Q000737:chemistry; D005260:Female; D006801:Humans; D016399:Lymphoma, T-Cell / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D015394:Molecular Structure; D011109:Polymethacrylic Acids / Q000138:chemical synthesis* / Q000737:chemistry; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D012995:Solubility; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D011109:Polymethacrylic Acids; D011758:Pyrroles; C098751:AN 204; C011533:Duxon; D004317:Doxorubicin