Polymer conjugates of the highly potent cytostatic drug 2-pyrrolinodoxorubicin

• Published in: European journal of pharmaceutical sciences 2011-01, Vol.42 (1), p.156-163
• Main Authors: Studenovsky, M., Ulbrich, K., Ibrahimova, M., Rihova, B.
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics, Antineoplastic - administration & dosage; Antibiotics, Antineoplastic - adverse effects; Antibiotics, Antineoplastic - chemical synthesis; Antibiotics, Antineoplastic - chemistry; Antibiotics, Antineoplastic - therapeutic use; Anticancer agents; Biological and medical sciences; Cell Line, Tumor; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Doxorubicin - administration & dosage; Doxorubicin - adverse effects; Doxorubicin - analogs & derivatives; Doxorubicin - chemical synthesis; Doxorubicin - chemistry; Doxorubicin - therapeutic use; Drug Carriers - chemical synthesis; Drug Carriers - chemistry; Female; General pharmacology; Humans; Lymphoma, T-Cell - drug therapy; Lymphoma, T-Cell - pathology; Medical sciences; Mice; Molecular Structure; Multidrug resistance; pH-controlled release; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Polymer conjugates; Polymethacrylic Acids - chemical synthesis; Polymethacrylic Acids - chemistry; Pyrroles - administration & dosage; Pyrroles - adverse effects; Pyrroles - chemical synthesis; Pyrroles - chemistry; Pyrroles - therapeutic use; Solubility; Tumor drug delivery; Xenograft Model Antitumor Assays
• ISSN: 0928-0987; 1879-0720
• DOI: 10.1016/j.ejps.2010.11.006

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.