Drug Modifications To Enhance Transport Across Biological Barriers

Several methods have been explored to improve drug permeation across biological barriers.1'44-47 One method involves chemical modification of drug entities such as prodrugs and peptidomimetics. Another method is to design a formulation that enhances drug permeation through the biological barriers.

2.5.1. Prodrugs and Structural Modifications

A prodrug approach has been utilized to optimize drugs; a prodrug is defined as a chemical derivative that is inactive pharmacologically until it is converted in vivo to the active drug moiety. Recently, a targeted prodrug design has emerged in which prodrugs have been used to target membrane transporters or enzymes.45 This method improves oral drug absorption or site-specific drug delivery. Extensive knowledge of the structure, the distribution within biological barriers, and substrate specificities is needed to target a desired transporter.

Prodrug strategies have been very successful with small molecules; however, the use of prodrugs for peptides has been less frequent.44 The cyclic peptide prodrug approach has been shown to improve membrane permeation. In this method, the

N and C termini of the peptide are connected via a linker to form a cyclic peptide. The linker can be cleaved by esterase to release the peptide. The cyclic peptide prodrug formation increases the intramolecular hydrogen bonding and lowers the hydrogen-bonding potential to water molecules as solvent. In addition, the lipophi-licity of the cyclic prodrug increases, which shifts its transport from paracellular to transcellular.48 It has also been reported that cyclic peptides are less susceptible to amino- and carboxypeptidases than linear peptides because the amino and carboxy terminals are protected from these enzymes.44

Peptide structural modification has been applied to improve membrane permeation of peptides. Metabolism of peptide pharmaceuticals can occur in various regions along the route to oral absorption, and inhibition of this degradation is advantageous in enhancing drug delivery. To improve enzymatic stability, peptides have been converted to peptidomimetics. In this case, the peptide bond is converted to its bioisostere, which is stable to proteolytic enzymes. Other structural modification strategies to improve membrane permeation of peptides include lipidization, halogenation, glycosylation, cationization, and conjugation to polymers.46

2.5.2. Formulations

Peptide absorption can be improved by designing an optimal formulation.47'49 Several methods to enhance peptide absorption have been suggested, including addition of ion-pairing and complexation molecules, nonsurfactant membrane permeation enhancers, surfactant adjuvants, or combinations of these additives.47 Addition of perturbants of tight junctions such as cytoskeletal agents, oxidants, hormones, calcium chelators, and bacterial toxins the formulation has been investigated to improve drug permeation.49 Another novel delivery system involves the use of mucoadhesives to enhance drug delivery because of their long retention time at the targeted mucosal membrane; lectins have been identified as potential carriers for peptides in an oral mucoadhesive system.1 Coadministration of peptides with inhibitors of metabolizing enzymes has also been suggested to increase oral absorp-tion.47,50,51

Modulation of the intercellular junctions by inhibiting the cadherin-cadherin interaction at the adherens junction has also been investigated. Peptides derived from the sequence of the extracellular domain of E-cadherin have been shown to modulate the intercellular junction of bovine brain microvessel endothelial cell (BBMEC) and Madin-Darby canine kidney (MDCK) cell monolayers. These peptides enhance the paracellular penetration of marker molecules such as 14C-mannitol and lower the transepithelial resistance of the monolayers.52-55 The use of these cadherin-derived peptides as adjuvants to enhance paracellular permeability of drugs is still under investigation.

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