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Natural and synthetic polymers as inhibitors of drug efflux pumps.

Werle M - Pharm. Res. (2007)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Technology, Leopold-Franzens University Innsbruck, Innrain 52, 6020, Innsbruck, Austria. martin.werle@uibk.ac.at

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.

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Chemical structure of a polyamidoamine (PAMAM) dendrimer
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Fig7: Chemical structure of a polyamidoamine (PAMAM) dendrimer

Mentions: Dendrimers (dendritic polymers) are fully synthetic macromolecules with a defined structure. From a core located in the center of the dendrimer, branched repeat units emanate. The surface can display functional groups such as primary amines or hydroxyl groups. Exemplarily, the structure of a polyamidoamine (PAMAM) dendrimer is shown in Fig. 7. The first dendrimers have been described nearly 30 years ago (65). Dendrimers are used as delivery systems for potent anticancer drugs (66), in gene delivery and in imaging (67,68). There is some evidence that dendrimers might be interesting tools for the delivery of efflux pumps substrates. D’Emanuele et al. showed that the conjugation of the P-gp substrate propranolol to generation 3 (G3) and lauroyl-G3 PAMAM dendrimers improved apical to basolateral transport and decreased basolateral to apical transport through Caco-2 monolayers. The mechanism responsible for this behaviour was attributed to a circumvention of P-gp transport rather than to P-gp inhibition, because in the presence of the well known P-gp inhibitor cyclosporine A, no further improvement of propranolol transport was observed (69). However, it has been shown that the transport of efflux pump substrates in the presence of dendrimers was improved without conjugating the substrate to the dendrimer. The accumulation of vinblastine and doxorubicin using gut sacs was improved about three- and fourfold in the presence of a G3 dendrimer. These results might indicate a possible efflux pump inhibition (35).Fig. 7


Natural and synthetic polymers as inhibitors of drug efflux pumps.

Werle M - Pharm. Res. (2007)

Chemical structure of a polyamidoamine (PAMAM) dendrimer
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2265773&req=5

Fig7: Chemical structure of a polyamidoamine (PAMAM) dendrimer
Mentions: Dendrimers (dendritic polymers) are fully synthetic macromolecules with a defined structure. From a core located in the center of the dendrimer, branched repeat units emanate. The surface can display functional groups such as primary amines or hydroxyl groups. Exemplarily, the structure of a polyamidoamine (PAMAM) dendrimer is shown in Fig. 7. The first dendrimers have been described nearly 30 years ago (65). Dendrimers are used as delivery systems for potent anticancer drugs (66), in gene delivery and in imaging (67,68). There is some evidence that dendrimers might be interesting tools for the delivery of efflux pumps substrates. D’Emanuele et al. showed that the conjugation of the P-gp substrate propranolol to generation 3 (G3) and lauroyl-G3 PAMAM dendrimers improved apical to basolateral transport and decreased basolateral to apical transport through Caco-2 monolayers. The mechanism responsible for this behaviour was attributed to a circumvention of P-gp transport rather than to P-gp inhibition, because in the presence of the well known P-gp inhibitor cyclosporine A, no further improvement of propranolol transport was observed (69). However, it has been shown that the transport of efflux pump substrates in the presence of dendrimers was improved without conjugating the substrate to the dendrimer. The accumulation of vinblastine and doxorubicin using gut sacs was improved about three- and fourfold in the presence of a G3 dendrimer. These results might indicate a possible efflux pump inhibition (35).Fig. 7

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Technology, Leopold-Franzens University Innsbruck, Innrain 52, 6020, Innsbruck, Austria. martin.werle@uibk.ac.at

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.

Show MeSH