N-(2-Hydroxypropyl)methacrylamide-based polymer conjugates with pH-controlled activation of doxorubicin for cell-specific or passive tumour targeting. Synthesis by RAFT polymerisation and physicochemical characterisation

• Published in: European journal of pharmaceutical sciences Vol. 41; no. 3; pp. 473 - 482
• Main Authors: Chytil, Petr, Etrych, Tomáš, Kříž, Jaroslav, Šubr, Vladimír, Ulbrich, Karel
• Format: Journal Article
• Language: English
• Published: Kindlington Elsevier B.V 20.11.2010; Elsevier
• Subjects: Acrylamides - chemistry; Antibiotics, Antineoplastic - chemistry; Antibiotics, Antineoplastic - pharmacology; Antibodies, Monoclonal; Biological and medical sciences; Cancer; Controlled drug release; Doxorubicin - chemistry; Doxorubicin - pharmacology; Drug carriers; Drug Carriers - chemistry; Drug Delivery Systems - methods; Drug targeting; General pharmacology; HPMA copolymers; Hydrogen-Ion Concentration; Kinetics; Medical sciences; Molecular Structure; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Polymerization; RAFT polymerisation; RAFT polymerisation; Drug carriers; Drug targeting; Controlled drug release; HPMA copolymers; Cancer; Antineoplastic agent; Targeting; Drug carrier; Activation; Doxorubicin; Alcohol polymer; Target; Chain transfer; Isomerases; pH; Drug; DNA topoisomerase (ATP-hydrolysing); Pharmaceutical technology; Enzyme; Controlled release form; Enzyme inhibitor; Topoisomerase II inhibitor; Malignant tumor; In vitro; Methacrylamide derivative polymer; Methacrylamide derivative copolymer; Antibiotic; Free radical polymerization; Preparation; Dosage form; Anthracyclins; Conjugated compound
• ISSN: 0928-0987; 1879-0720
• DOI: 10.1016/j.ejps.2010.08.003

Controlled radical reversible addition-fragmentation chain transfer (RAFT) polymerisation was used to prepare water-soluble polymer–drug carriers based on copolymers of N-(2-hydroxypropyl)methacrylamide (HPMA) with a hydrazide group-containing monomer, showing well-defined structure with narrow molecular weight distribution (approx. 1.1–1.2). The anticancer therapeutic doxorubicin was bound to the polymeric carrier by a hydrazone bond, enabling pH-controlled release under mildly acid conditions that mimics the environment in endosomes/lysosomes of tumour cells. RAFT polymerisation facilitated the synthesis of semitelechelic copolymers, which were used in the synthesis of monoclonal anti-CD20 antibody–polymer–drug conjugate designed for cell-specific tumour targeting. They were also used for producing a biodegradable high-molecular-weight graft polymer–drug conjugate that degrade in the presence of glutathione, which is designed for passive targeting to solid tumours. The conjugates exhibited well-defined structures with narrow molecular weight distributions of approx. 1.3 and pH-controlled drug release.