Targeted prodrug design to optimize drug delivery

Abstract

Classical prodrug design often represents a nonspecific chemical approach to mask undesirable drug properties such as limited bioavailability, lack of site specificity, and chemical instability. On the other hand, targeted prodrug design represents a new strategy for directed and efficient drug delivery. Particularly, targeting the prodrugs to a specific enzyme or a specific membrane transporter, or both, has potential as a selective drug delivery system in cancer chemotherapy or as an efficient oral drug delivery system. Site-selective targeting with prodrugs can be further enhanced by the simultaneous use of gene delivery to express the requisite enzymes or transporters. This review highlights evolving strategies in targeted prodrug design, including antibody-directed enzyme prodrug therapy, genedirected enzyme prodrug therapy, and peptide transporter-associated prodrug therapy.

Cyclization-activated Prodrugs

“…The prodrug approach has been widely used to improve delivery of drugs to their site of action by modulation of physico-chemical properties that affect absorption or by targeting to specific enzymes or membrane transporters [2,[3][4][5]. Most of the prodrugs that are now in clinical use require enzymatic catalysis in order to be converted into the parent drug.…”

Identification of a Human Valacyclovirase

“…Prodrugs are designed to be inactive until in vivo activation to the parent drug, and hence reliable in vivo activation of the prodrug is considered critical for their pharmacological activity (1). Identification of the mechanism of in vivo activation of prodrugs is important for prodrug design and for investigating clinical applications.…”

“…For example, the anti-cancer prodrug, CPT-11 (irinotecan), a carbamate derivative of 7-ethyl-10-hydroxycamptothecin, is converted to its active metabolite, 7-ethyl-10-hydroxycamptothecin by human carboxylesterases. The efficiency of hydrolysis varies depending on isoforms such that carboxylesterase 2 (hCE2) 1 and intestinal carboxylesterase (hiCE) are more efficient activators than human liver carboxylesterase 1 (hCE1) (2)(3)(4). The angiotensin-converting enzyme inhibitor temocapril, an ester prodrug, is rapidly hydrolyzed by carboxylesterase to the active temocaprilat.…”

Purification by p-aminobenzoic acid (PABA)-affinity chromatography and the functional reconstitution of the nateglinide/H+ cotransport system in the rat intestinal brush-border membrane

“…One of the major problems is the poor permeability through the intestinal mucosa. The use of transporter function offers the possibility of delivering a drug to the target organ, avoiding distribution to other organs (thereby reducing the risk of toxic effects), controlling the elimination process, and improving oral bioavailability [21,22]. Intestinal PEPT1 has been utilized to improve the intestinal absorption of poorly absorbed and pharmacologically active agents by chemically converting them to substrates for PEPT1 [5,23].…”