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 phase I/II clinical trial as anticancer agents. These include N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-doxorubicin (PK1, FCE28068), HPMA copolymer-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 conjugate to liver for the treatment of primary and secondary liver cancer. Promising early clinical results with lysosomotropic conjugates has stimulated significant interest in this field. Ongoing research is developing (1) conjugates containing drugs that could otherwise not progress due to poor solubility or uncontrollable toxicity; (2) conjugates of agents directed against novel targets; and (3) two-step combinations such as polymer-directed enzyme prodrug therapy (PDEPT) and polymer-enzyme liposome therapy (PELT) that can cause explosive liberation of drug from either polymeric prodrugs or liposomes within the tumour interstitium. Moreover, bioresponsive polymer-based constructs able to promote endosomal escape and thus intracytoplasmic delivery of macromolecular drugs (peptides, proteins and oligonucleotides) are also under study.
Duncan
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Centre for Polymer Therapeutics, Welsh School of Pharmacy, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff CF10 3XF, Wales, UK. duncanr@cf.ac.uk
Gac-Breton
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Keane
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Musila
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Satchi
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Searle
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D000178:Acrylamides / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D004317:Doxorubicin / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D004337:Drug Carriers; D016503:Drug Delivery Systems; D005079:Excipients; D005688:Galactosamine / Q000008:administration & dosage / Q000494:pharmacology; D008081:Liposomes; D008689:Methacrylates; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000494:pharmacology; D011108:Polymers / Q000737:chemistry*; D011355:Prodrugs / Q000008:administration & dosage*
D000178:Acrylamides; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D004337:Drug Carriers; D005079:Excipients; C438845:HPMA coploymer-doxorubicin-galactosamine; C438846:HPMA copolymer-platinate; D008081:Liposomes; D008689:Methacrylates; D009944:Organoplatinum Compounds; D011108:Polymers; D011355:Prodrugs; D005688:Galactosamine; D004317:Doxorubicin; C032802:hydroxypropyl methacrylate