Limits...
Polymeric micelles in anticancer therapy: targeting, imaging and triggered release.

Oerlemans C, Bult W, Bos M, Storm G, Nijsen JF, Hennink WE - Pharm. Res. (2010)

Bottom Line: Micelle-based drug delivery, however, can be improved in different ways.Targeting ligands can be attached to the micelles which specifically recognize and bind to receptors overexpressed in tumor cells, and chelation or incorporation of imaging moieties enables tracking micelles in vivo for biodistribution studies.The combination of these approaches will further improve specificity and efficacy of micelle-based drug delivery and brings the development of a 'magic bullet' a major step forward.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiology and Nuclear Medicine, University Medical Center, Heidelberglaan 100, Utrecht, The Netherlands. C.Oerlemans@umcutrecht.nl

ABSTRACT
Micelles are colloidal particles with a size around 5-100 nm which are currently under investigation as carriers for hydrophobic drugs in anticancer therapy. Currently, five micellar formulations for anticancer therapy are under clinical evaluation, of which Genexol-PM has been FDA approved for use in patients with breast cancer. Micelle-based drug delivery, however, can be improved in different ways. Targeting ligands can be attached to the micelles which specifically recognize and bind to receptors overexpressed in tumor cells, and chelation or incorporation of imaging moieties enables tracking micelles in vivo for biodistribution studies. Moreover, pH-, thermo-, ultrasound-, or light-sensitive block copolymers allow for controlled micelle dissociation and triggered drug release. The combination of these approaches will further improve specificity and efficacy of micelle-based drug delivery and brings the development of a 'magic bullet' a major step forward.

Show MeSH

Related in: MedlinePlus

Schematic structure of NK012, consisting of PEG and partially modified polyglutamate. PEG is used to form the hydrophilic segment, and SN-38 was incorporated into the hydrophobic core of the micelle (33). Reproduced with permission from the American Association for Cancer Research.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2982955&req=5

Fig2: Schematic structure of NK012, consisting of PEG and partially modified polyglutamate. PEG is used to form the hydrophilic segment, and SN-38 was incorporated into the hydrophobic core of the micelle (33). Reproduced with permission from the American Association for Cancer Research.

Mentions: NK012 is a polymeric micellar formulation that consists of a block copolymer of PEG and polyglutamate (PGlu) conjugated with 7-ethyl-10-hydroxy-campothecin (SN-38) (6). SN-38 is a campotothecin analalog and acts as a DNA topoisomerase I inhibitor, but cannot be administered i.v. due to its water-insolubility and high toxicity. SN-38 is covalently coupled to the PGlu segment by the condensation reaction between the carboxylic acid of PGlu and the phenol of SN-38 using 1,3-diisopropylcarbodiimide and N,N-dimethylaminopyridine as coupling agent and catalyst, respectively. Consequently, the PGlu segment is rendered hydrophobically to induce micelle formation (Fig. 2) (26,33). Preclinical in vivo studies with NK012 showed potent antitumor activity in mice. A pharmacokinetic study revealed that the plasma area under the curve (AUC) of micellar SN-38 after i.v. administration (30 mg/kg) to HT-29 tumor-cell-bearing mice was around 200 times higher as compared to CPT-11 (which is hydrolyzed to SN-38 in the circulation) at a dose of 66.7 mg/kg. The IC50 values of NK012 were up to 5.8 times higher than those of free SN-38. In addition, the clearance of NK012 in the HT-29 tumors was significantly slower compared to CPT-11 and SN-38. The highest tumor-to-plasma concentration ratio of micellar SN-38 was up to 10 times higher compared to free SN-38. Moreover, NK012 clearance was significantly lower compared to CPT-11 (33,34). Furthermore, a combination of NK012 with 5-fluoruracil (5-FU) showed a significantly higher antitumor effect in human colon cancer xenografts compared to CPT-11/5-FU (35).Fig. 2


Polymeric micelles in anticancer therapy: targeting, imaging and triggered release.

Oerlemans C, Bult W, Bos M, Storm G, Nijsen JF, Hennink WE - Pharm. Res. (2010)

Schematic structure of NK012, consisting of PEG and partially modified polyglutamate. PEG is used to form the hydrophilic segment, and SN-38 was incorporated into the hydrophobic core of the micelle (33). Reproduced with permission from the American Association for Cancer Research.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2982955&req=5

Fig2: Schematic structure of NK012, consisting of PEG and partially modified polyglutamate. PEG is used to form the hydrophilic segment, and SN-38 was incorporated into the hydrophobic core of the micelle (33). Reproduced with permission from the American Association for Cancer Research.
Mentions: NK012 is a polymeric micellar formulation that consists of a block copolymer of PEG and polyglutamate (PGlu) conjugated with 7-ethyl-10-hydroxy-campothecin (SN-38) (6). SN-38 is a campotothecin analalog and acts as a DNA topoisomerase I inhibitor, but cannot be administered i.v. due to its water-insolubility and high toxicity. SN-38 is covalently coupled to the PGlu segment by the condensation reaction between the carboxylic acid of PGlu and the phenol of SN-38 using 1,3-diisopropylcarbodiimide and N,N-dimethylaminopyridine as coupling agent and catalyst, respectively. Consequently, the PGlu segment is rendered hydrophobically to induce micelle formation (Fig. 2) (26,33). Preclinical in vivo studies with NK012 showed potent antitumor activity in mice. A pharmacokinetic study revealed that the plasma area under the curve (AUC) of micellar SN-38 after i.v. administration (30 mg/kg) to HT-29 tumor-cell-bearing mice was around 200 times higher as compared to CPT-11 (which is hydrolyzed to SN-38 in the circulation) at a dose of 66.7 mg/kg. The IC50 values of NK012 were up to 5.8 times higher than those of free SN-38. In addition, the clearance of NK012 in the HT-29 tumors was significantly slower compared to CPT-11 and SN-38. The highest tumor-to-plasma concentration ratio of micellar SN-38 was up to 10 times higher compared to free SN-38. Moreover, NK012 clearance was significantly lower compared to CPT-11 (33,34). Furthermore, a combination of NK012 with 5-fluoruracil (5-FU) showed a significantly higher antitumor effect in human colon cancer xenografts compared to CPT-11/5-FU (35).Fig. 2

Bottom Line: Micelle-based drug delivery, however, can be improved in different ways.Targeting ligands can be attached to the micelles which specifically recognize and bind to receptors overexpressed in tumor cells, and chelation or incorporation of imaging moieties enables tracking micelles in vivo for biodistribution studies.The combination of these approaches will further improve specificity and efficacy of micelle-based drug delivery and brings the development of a 'magic bullet' a major step forward.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiology and Nuclear Medicine, University Medical Center, Heidelberglaan 100, Utrecht, The Netherlands. C.Oerlemans@umcutrecht.nl

ABSTRACT
Micelles are colloidal particles with a size around 5-100 nm which are currently under investigation as carriers for hydrophobic drugs in anticancer therapy. Currently, five micellar formulations for anticancer therapy are under clinical evaluation, of which Genexol-PM has been FDA approved for use in patients with breast cancer. Micelle-based drug delivery, however, can be improved in different ways. Targeting ligands can be attached to the micelles which specifically recognize and bind to receptors overexpressed in tumor cells, and chelation or incorporation of imaging moieties enables tracking micelles in vivo for biodistribution studies. Moreover, pH-, thermo-, ultrasound-, or light-sensitive block copolymers allow for controlled micelle dissociation and triggered drug release. The combination of these approaches will further improve specificity and efficacy of micelle-based drug delivery and brings the development of a 'magic bullet' a major step forward.

Show MeSH
Related in: MedlinePlus