Drug Delivery Systems Employing 1,4- or 1,6-Elimination:  Poly(ethylene glycol) Prodrugs of Amine-Containing Compounds

Abstract

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-lives and, in the case of anticancer agents, apparent tumor accumulation. Thus, we have successfully designed PEG conjugated specifiers or "triggers" as part of a double-prodrug strategy that relies, first, on enzymatic separation of PEG followed by the classical and rapid 1,4- or 1, 6-benzyl elimination reaction releasing the amine (drug) bound in the form of a carbamate. The prodrug trigger was comprised of ester, carbonate, carbamate, or amide bonds 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 prodrug. This modification led to longer circulating plasma half-lives of the final tripartate form. The "ortho" effect also had the beneficial effect of directing nucleophilic attack almost exclusively to the activated benzyl 6-position of the heterobifunctional intermediates. In vivo testing of the PEG daunorubicin prodrugs (transport forms) prepared in the course of this study 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 inhibition.

Lamellarin D Bioconjugates II: Synthesis and Cellular Internalization of Dendrimer and Nuclear Location Signal Derivatives

“…3, f1, f2, i1 and i2) N,N,N',N',N"-pentaacetic acid; EDC·HCl, N-(3-dimethylaminopropyl) 3 The ester bonds of the protected Lam-D conjugates were labile; hence, to avoid problems with hydrolysis, we minimized the deprotection steps after condensation. 4 The yield for the deprotection was 84% working on a 20-30 mg scale. However, the procedure could not be scaled up.…”

Prolonging the Action of Protein and Peptide Drugs by a Novel Approach of Reversible Polyethylene Glycol Modification

“…by employing detachable PEG chains) have been reported (11)(12)(13)(14)(15). They suffer, however, from major disadvantages including their dependence on enzymatic hydrolysis as the rate-determining step of PEG-parent molecule dissociation (11)(12)(13), potentially making the behavior of the molecules unpredictable and their utilization impractical because of steric considerations and inappropriate enzyme availability. An additional disadvantage is the nonspecific PEGylation of undesired protein/peptide functional moieties (e.g.…”

Releasable Conjugation of Polymers to Proteins

“…De-PEGylation releases 4-aminobenzyl alcohol, a byproduct reported to have low cytoxicity. 42 Since active azoreductases are not commercially available, the reconversion of the rPEGylated CPP−PNA was studied with a surrogate reducing agent, sodium dithionite. After incubation with this compound, disappearance of the PEGylated conjugate was observed with reappearance of the free CPP−PNA.…”