Drug delivery systems employing 1,4-or 1,6-elimination: Poly(ethylene glycol) prodrugs of amine-containing compounds

A general methodology for synthesizing poly(ethylene glycol) (PEG) prodrugs of amino-containing compounds has been developed and constitutes the basis for solubilization of insoluble drugs, extending plasma circulating half-l ives and, in the case of anticancer agents, apparent tumor accumulation. Th us, we have successfully designed PEG conjugated specifiers or "triggers" a s part of a double-prodrug strategy that relies, first, on enzymatic separa tion of PEG followed by the classical and rapid 1,4- or 1,6-benzyl eliminat ion reaction releasing the amine (drug) bound in the form of a carbamate. T he prodrug trigger was comprised of ester, carbonate, carbamate, or amide b onds in order to secure predictable rates of hydrolysis. Further refinement of the hydrolysis was accomplished by the introduction of steric hindrance through the use of ortho substituents on the benzyl component of the prodr ug. This modification led to longer circulating plasma half-lives of the fi nal tripartate form. The "ortho" effect also had the beneficial effect of d irecting nucleophilic attack almost exclusively to the activated benzyl B-p osition of the heterobifunctional intermediates. In vivo testing of the PEG daunorubicin prodrugs (transport forms) prepared in the course of this stu dy ultimately identified the type 1 carbamate (34b), with a circulating t(1 /2) of 4 h, as the most effective derivative for solid tumor growth inhibit ion.