Bioreducible block copolymers based on poly(ethylene glycol) and poly(γ-Benzyl L-Glutamate) for intracellular delivery of camptothecin

Thavasyappan Thambi, Hong Yeol Yoon, Kwang Meyung Kim, Ick Chan Kwon, Chang Kyoo Yoo, Jae Hyung Park

Research output: Contribution to journalArticle

110 Citations (Scopus)

Abstract

Poly(ethylene glycol)-b-poly(γ-benzyl l-glutamate)s bearing the disulfide bond (PEG-SS-PBLGs), which is specifically cleavable in intracellular compartments, were prepared via a facile synthetic route as a potential carrier of camptothecin (CPT). Diblock copolymers with different lengths of PBLG were synthesized by ring-opening polymerization of benzyl glutamate N-carboxy anhydride in the presence of a PEG macroinitiator (PEG-SS-NH 2). Owing to their amphiphilic nature, the copolymers formed spherical micelles in an aqueous condition, and their particle sizes (20-125 nm in diameter) were dependent on the block length of PBLG. Critical micelle concentrations of the copolymers were in the range 0.005-0.065 mg/mL, which decreased as the block length of PBLG increased. CPT, chosen as a model anticancer drug, was effectively encapsulated up to 12 wt % into the hydrophobic core of the micelles by the solvent casting method. It was demonstrated by the in vitro optical imaging technique that the fluorescence signal of doxorubicin, quenched in the PEG-SS-PBLG micelles, was highly recovered in the presence of glutathione (GSH), a tripeptide reducing disulfide bonds in the cytoplasm. The micelles released CPT completely within 20 h under 10 mM GSH, whereas only 40% of CPT was released from the micelles in the absence of GSH. From the in vitro cytotoxicity test, it was found that CPT-loaded PEG-SS-PBLG micelles showed higher toxicity to SCC7 cancer cells than CPT-loaded PEG-b-PBLG micelles without the disulfide bond. Microscopic observation demonstrated that the disulfide-containing micelle could effectively deliver the drug into nuclei of SCC7 cells. These results suggest that PEG-SS-PBLG diblock copolymer is a promising carrier for intracellular delivery of CPT.

Original languageEnglish
Pages (from-to)1924-1931
Number of pages8
JournalBioconjugate Chemistry
Volume22
Issue number10
DOIs
Publication statusPublished - 2011 Oct 19
Externally publishedYes

Fingerprint

Camptothecin
Ethylene Glycol
Micelles
Polyethylene glycols
Block copolymers
Disulfides
Bearings (structural)
Copolymers
poly-gamma-benzyl-L-glutamate
Critical micelle concentration
Ring opening polymerization
Cytotoxicity
Optical Imaging
Pharmaceutical Preparations
Doxorubicin
Cell Nucleus
Glutathione
Toxicity
Particle Size
Glutamic Acid

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Organic Chemistry
  • Pharmaceutical Science
  • Biomedical Engineering
  • Pharmacology

Cite this

Bioreducible block copolymers based on poly(ethylene glycol) and poly(γ-Benzyl L-Glutamate) for intracellular delivery of camptothecin. / Thambi, Thavasyappan; Yoon, Hong Yeol; Kim, Kwang Meyung; Kwon, Ick Chan; Yoo, Chang Kyoo; Park, Jae Hyung.

In: Bioconjugate Chemistry, Vol. 22, No. 10, 19.10.2011, p. 1924-1931.

Research output: Contribution to journalArticle

Thambi, Thavasyappan ; Yoon, Hong Yeol ; Kim, Kwang Meyung ; Kwon, Ick Chan ; Yoo, Chang Kyoo ; Park, Jae Hyung. / Bioreducible block copolymers based on poly(ethylene glycol) and poly(γ-Benzyl L-Glutamate) for intracellular delivery of camptothecin. In: Bioconjugate Chemistry. 2011 ; Vol. 22, No. 10. pp. 1924-1931.
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abstract = "Poly(ethylene glycol)-b-poly(γ-benzyl l-glutamate)s bearing the disulfide bond (PEG-SS-PBLGs), which is specifically cleavable in intracellular compartments, were prepared via a facile synthetic route as a potential carrier of camptothecin (CPT). Diblock copolymers with different lengths of PBLG were synthesized by ring-opening polymerization of benzyl glutamate N-carboxy anhydride in the presence of a PEG macroinitiator (PEG-SS-NH 2). Owing to their amphiphilic nature, the copolymers formed spherical micelles in an aqueous condition, and their particle sizes (20-125 nm in diameter) were dependent on the block length of PBLG. Critical micelle concentrations of the copolymers were in the range 0.005-0.065 mg/mL, which decreased as the block length of PBLG increased. CPT, chosen as a model anticancer drug, was effectively encapsulated up to 12 wt {\%} into the hydrophobic core of the micelles by the solvent casting method. It was demonstrated by the in vitro optical imaging technique that the fluorescence signal of doxorubicin, quenched in the PEG-SS-PBLG micelles, was highly recovered in the presence of glutathione (GSH), a tripeptide reducing disulfide bonds in the cytoplasm. The micelles released CPT completely within 20 h under 10 mM GSH, whereas only 40{\%} of CPT was released from the micelles in the absence of GSH. From the in vitro cytotoxicity test, it was found that CPT-loaded PEG-SS-PBLG micelles showed higher toxicity to SCC7 cancer cells than CPT-loaded PEG-b-PBLG micelles without the disulfide bond. Microscopic observation demonstrated that the disulfide-containing micelle could effectively deliver the drug into nuclei of SCC7 cells. These results suggest that PEG-SS-PBLG diblock copolymer is a promising carrier for intracellular delivery of CPT.",
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AB - Poly(ethylene glycol)-b-poly(γ-benzyl l-glutamate)s bearing the disulfide bond (PEG-SS-PBLGs), which is specifically cleavable in intracellular compartments, were prepared via a facile synthetic route as a potential carrier of camptothecin (CPT). Diblock copolymers with different lengths of PBLG were synthesized by ring-opening polymerization of benzyl glutamate N-carboxy anhydride in the presence of a PEG macroinitiator (PEG-SS-NH 2). Owing to their amphiphilic nature, the copolymers formed spherical micelles in an aqueous condition, and their particle sizes (20-125 nm in diameter) were dependent on the block length of PBLG. Critical micelle concentrations of the copolymers were in the range 0.005-0.065 mg/mL, which decreased as the block length of PBLG increased. CPT, chosen as a model anticancer drug, was effectively encapsulated up to 12 wt % into the hydrophobic core of the micelles by the solvent casting method. It was demonstrated by the in vitro optical imaging technique that the fluorescence signal of doxorubicin, quenched in the PEG-SS-PBLG micelles, was highly recovered in the presence of glutathione (GSH), a tripeptide reducing disulfide bonds in the cytoplasm. The micelles released CPT completely within 20 h under 10 mM GSH, whereas only 40% of CPT was released from the micelles in the absence of GSH. From the in vitro cytotoxicity test, it was found that CPT-loaded PEG-SS-PBLG micelles showed higher toxicity to SCC7 cancer cells than CPT-loaded PEG-b-PBLG micelles without the disulfide bond. Microscopic observation demonstrated that the disulfide-containing micelle could effectively deliver the drug into nuclei of SCC7 cells. These results suggest that PEG-SS-PBLG diblock copolymer is a promising carrier for intracellular delivery of CPT.

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