Polymer-drug conjugates, PDEPT and PELT: basic principles for design and transfer from the laboratory to clinic

There are now at least seven polymer-drug conjugates that have entered phas e I/II clinical trial as anticancer agents. These include N-(2-hydroxypropy l)methacrylamide (HPMA) copolymer-doxorubicin (PK1, FCE28068), HPMA copolym er-paclitaxel (PNU 166945), HPMA copolymer-camptothecin, PEG-camptothecin, polyglutamic acid-paclitaxel an HPMA copolymer-platinate (AP5280) and also an HPMA copolymer-doxorubicin conjugate bearing additionally galactosamine (PK2, FCE28069). The galactosamine is used as a means to target the conjuga te to liver for the treatment of primary and secondary liver cancer. Promis ing early clinical results with lysosomotropic conjugates has stimulated si gnificant interest in this field. Ongoing research is developing (1) conjug ates containing drugs that could otherwise not progress due to poor solubil ity or uncontrollable toxicity; (2) conjugates of agents directed against n ovel targets; and (3) two-step combinations such as polymer-directed enzyme prodrug therapy (PDEPT) and polymer-enzyme liposome therapy (PELT) that ca n cause explosive liberation of drug from either polymeric prodrugs or lipo somes within the tumour interstitium. Moreover, bioresponsive polymer-based constructs able to promote enclosomal escape and thus intracytoplasmic del ivery of macromolecular drugs (peptides, proteins and oligonucleotides) are also under study. (C) 2001 Elsevier Science B.V. All rights reserved.