Pathways and progress in improving drug delivery through the intestinal mucosa and blood-brain barriers

Abstract

One of the major hurdles in developing therapeutic agents is the difficulty in delivering drugs through the intestinal mucosa and blood-brain barriers (BBB). The goal here is to describe the general structures of the biological barriers and the strategies to enhance drug delivery across these barriers. Prodrug methods used to improve drug penetration via the transcellular pathway have been successfully developed, and some prodrugs have been used to treat patients. The use of transporters to improve absorption of some drugs (e.g., antiviral agents) has also been successful in treating patients. Other methods, including blocking the efflux pumps to improve transcellular delivery, and modulation of cell-cell adhesion in the intercellular junctions to improve paracellular delivery across biological barriers, are still in the investigational stage.

Figure 1

A diagram of the intestinal mucosa barrier. Drug molecules can pass through the barrier via transcellular and paracellular pathways. The molecules can passively diffuse through transcellular pathways by partitioning into the cellular membranes from the apical side to the basolateral side. The presence of efflux pumps can inhibit the transcellular passive diffusion of drug molecules. Nutrient transporters have also been used to carry drugs or drug conjugates across the biological barriers. Small ions and molecules can cross through barriers via paracellular pathways (intercellular junctions), but the presence of the tight junctions prevents drug molecules from passing through this pathway. Modulation of the protein-protein interactions in the intercellular junctions has been shown to improve paracellular permeation of drug molecules via the paracellular pathways.

Figure 1

A diagram of the intestinal mucosa barrier. Drug molecules can pass through the barrier via transcellular and paracellular pathways. The molecules can passively diffuse through transcellular pathways by partitioning into the cellular membranes from the apical side to the basolateral side. The presence of efflux pumps can inhibit the transcellular passive diffusion of drug molecules. Nutrient transporters have also been used to carry drugs or drug conjugates across the biological barriers. Small ions and molecules can cross through barriers via paracellular pathways (intercellular junctions), but the presence of the tight junctions prevents drug molecules from passing through this pathway. Modulation of the protein-protein interactions in the intercellular junctions has been shown to improve paracellular permeation of drug molecules via the paracellular pathways.

Figure 2

Illustration of drug to produg formation by chemical or enzymatic reaction. A produg is assembled by conjugating the drug to a promoiety to change the drug physicochemical properties. (A) After delivery, the enalapril prodrug can be converted to the parent drug (enalaprilate) by enzymatic reaction. (B) Heroin is a classic example prodrug of morphine. The acetyl ester groups protecting the hydroxyl group serve as the promoeity that change the physicochemical properties of heroin to favor brain uptake.

Figure 3

Formation of (A) phosphate and (B) ester prodrugs to improve drug solubility. (A) The salt of the phosphate prodrug of camptothecin is more soluble than camptothecin, and it can be converted to the parent camptothecin by phosphatase enzymes. (B) Irinotecan is an ester prodrug of camptothecin derivative, and the formation of diamine salts enhances drug solubility. The drug is converted to the parent drug by esterase enzymes.

Figure 4

The formation of cyclic peptide prodrugs using (A) acyloxyalkoxy and (B) phenylpropionic acid promoieties. The cyclic peptide prodrug is converted to the parent peptide by esterase enzymes (slow reaction) followed by a fast chemical reaction.

Figure 5

(A) Gal-2 and (B) NBD-abcavir are dimer prodrugs of galantamine and abcavir, respectively. Gal-2 can be converted to galantamine monomer by esterase while NBD-abcavir is converted to abcavir monomer upon reduction of the disulfide bond.

Figure 6

The structures of Zanamivir, Zan-L-Val, and Valacyclovir.