Polypeptide conjugates of d-penicillamine and idarubicin for anticancer therapy

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 (10 mM 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 (t1/2) 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.