Natural and synthetic polymers as inhibitors of drug efflux pumps

Abstract

Inhibition of efflux pumps is an emerging approach in cancer therapy and drug delivery. Since it has been discovered that polymeric pharmaceutical excipients such as Tweens or Pluronics can inhibit efflux pumps, various other polymers have been investigated regarding their potential efflux pump inhibitory activity. Among them are polysaccharides, polyethylene glycols and derivatives, amphiphilic block copolymers, dendrimers and thiolated polymers. In the current review article, natural and synthetic polymers that are capable of inhibiting efflux pumps as well as their application in cancer therapy and drug delivery are discussed.

Fig. 1

Chemical structure of anionic gums: a gellan gum, b xanthan gum

Fig. 2

Chemical structure of alginates; consecutive M-residues (MMM), consecutive G-residues (GGG), alternating M and G-residues (MGM)

Fig. 3

Chemical structures of Tween® 80 and TPGS 1000

Fig. 4

Plasma curves of paclitaxel (ng/ml) in rats after oral administration of 25 mg/kg paclitaxel (open circle) and in combination with 50 mg/kg TPGS 1000 (filled circle). Figure adapted from (18)

Fig. 5

Plasma curves of Rho-123 (ng/ml) in rats after oral administration of 1.5 mg Rhodamine 123 in Pluronic® P85 tablets (filled circle), Myrj® 52 tablets (triangle) and chito–TBA/GSH tablets (filled square). Figure adapted from (48)

Fig. 6

Chemical structures of poloxamers (Pluronics®)

Fig. 7

Chemical structure of a polyamidoamine (PAMAM) dendrimer

Fig. 8

Structure of thiomers: a chitosan–thiobutylamidine (chito–TBA), b poly(acrylic acid)-cysteine (PAA-Cys)

Fig. 9

Schematic presentation of interactions between polymeric efflux pump inhibitors and efflux pumps; polymer (∧∧∧), ATP (triangle), drug (square); a inhibition mediated by ATP depletion, b inhibition mediated by interactions with the membrane, c bypassing drug efflux by a drug-polymer conjugate, d inhibition mediated by interfering with ATP-binding sites and e blocking of drug binding sites or other sites within the trans-membrane domains (TMB)