Development of HPMA copolymer-anticancer conjugates: clinical experience and lessons learnt.
The concept of polymer-drug conjugates was proposed more than 30 years ago, and an N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer conjugate of doxorubicin covalently bound to the polymer backbone by a Gly-Phe-Leu-Gly peptidyl linker (FCE28068) became the first synthetic polymer-based anticancer conjugate to enter clinical trial in 1994. This conjugate arose from rational design attempting to capitalise on passive tumour targeting by the enhanced permeability and retention effect and, at the cellular level, lysosomotropic drug delivery to improve therapeutic index. Early clinical results were promising, confirming activity in chemotherapy refractory patients and the safety of HPMA as a new polymer platform. Subsequent Phase I/II trials have investigated an HPMA copolymer-based conjugate containing a doxorubicin and additionally galactose as a targeting moiety to promote liver targeting (FCE28069), and also HPMA copolymer conjugates of paclitaxel (PNU 166945), camptothecin (PNU 166148) and two platinates (AP5280 and AP5346- ProLindac). The preclinical and clinical observations made in these, and clinical studies with other polymer conjugates, should shape the development of next generation anticancer polymer therapeutics.
Duncan
Ruth
R
School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff CF10 3AT, UK. duncanr@cf.ac.uk
D000178:Acrylamides / Q000737:chemistry*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002986:Clinical Trials as Topic; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems; D004353:Drug Evaluation, Preclinical; D006801:Humans; D050997:Nanomedicine / Q000379:methods
D000178:Acrylamides; D000970:Antineoplastic Agents; D004337:Drug Carriers; C032976:N-(2-hydroxypropyl)methacrylamide