title: Polypeptide conjugates of D-penicillamine and idarubicin for anticancer therapy.
abstract: We investigated anticancer therapy with a novel combination of D-penicillamine (D-pen) and Idarubicin (Ida) in a synthetic dual drug conjugate (DDC). D-pen and Ida were covalently linked to poly(α)-L-glutamic acid (PGA) via reducible disulfide and acid-sensitive hydrazone bonds, respectively. The DDCs showed cell uptake and sustained release of the bound drugs in conditions mimicking the intracellular release media (10mM glutathione and pH 5.2). The in-vitro cytotoxicity of DDCs was comparable to unconjugated Ida in several sensitive and resistant cancer cell lines and correlated with the rate of cell uptake. In a single equivalent-dose pharmacokinetic study, DDCs enhanced the drug exposure by 7-fold and prolonged the plasma circulation half-life (t(1/2)) by 5-fold over unconjugated Ida. The therapeutic index of DDCs was 2-3-fold higher than unconjugated drugs. DDCs caused 89% tumor growth inhibition compared to 60% by unconjugated Ida alone and led to significant enhancement in the median survival (17%) of athymic nu/nu mice bearing NCI-H460 tumor xenografts.
authors: Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599-7362, USA.
authors: Saurabh
authors: S
authors: Wadhwa
authors: Russell J
authors: RJ
authors: Mumper
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D006801:Humans; D015255:Idarubicin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010396:Penicillamine / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D010455:Peptides; D011099:Polyglutamic Acid / Q000737:chemistry; D014018:Tissue Distribution; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D010455:Peptides; D011099:Polyglutamic Acid; D010396:Penicillamine; D015255:Idarubicin