Facile construction of dual-bioresponsive biodegradable micelles with superior extracellular stability and activated intracellular drug release

Wei Chen, Fenghua Meng, Ru Cheng, Chao Deng, Jan Feijen, Zhiyuan Zhong

Research output: Contribution to journalArticleAcademicpeer-review

66 Citations (Scopus)

Abstract

It is still a major challenge for targeted cancer chemotherapy to design stable biodegradable micellar drug delivery systems which show a rapid and complete intracellular drug release. Here, reversibly core-crosslinked pH-responsive biodegradable micelles were developed based on poly(ethylene glycol)-poly(2,4,6-trimethoxybenzylidene-pentaerythritol carbonate-co-pyridyl disulfide carbonate) [PEG-P(TMBPEC-co-PDSC)] copolymers and investigated for intracellular doxorubicin (DOX) release. PEG-P(TMBPEC-co-PDSC) copolymers formed micelles with a small size of 58.6 nm were readily crosslinked by the addition of dithiothreitol (DTT). Notably, in vitro release studies showed that under physiological conditions only ca. 19.9% of DOX was released from the reversibly crosslinked micelles in 24 h at a low micelle concentration of 40 μg/mL. The release of DOX was accelerated at pH 5.0 or in the presence of 10 mM glutathione (GSH) at pH 7.4, in which 64.2% and 44.1% of DOX was released, respectively, in 24 h. The drug release was further boosted at pH 5.0 and 10 mM GSH, with 98.8% of DOX released in 12 h. Moreover, DOX release was also facilitated by a 4 h incubation at pH 5.0 followed by incubation at pH 7.4 with 10 mM GSH. Confocal microscopy indicated that DOX was delivered and released into the nuclei of RAW 264.7 cells following a 12 h incubation with DOX-loaded reversibly crosslinked micelles. MTT assays revealed that DOX-loaded reversibly crosslinked micelles had much higher antitumor activity than irreversibly crosslinked controls, with low IC50 values of 1.65 and 1.14 μg/mL for HeLa and RAW 264.7 cells, respectively, following a 48 h incubation. The blank crosslinked micelles had a low cytotoxicity of up to a concentration of 0.8 mg/mL. These reversibly crosslinked pH-sensitive biodegradable micelles with superior extracellular stability but activated intracellular drug release provide a novel platform for tumor-targeting drug delivery.
Original languageUndefined
Pages (from-to)125-133
JournalJournal of controlled release
Volume210
DOIs
Publication statusPublished - 2015

Keywords

  • IR-99966
  • METIS-315343

Cite this

@article{83f261dbb98e473497437e9653cb9bc6,
title = "Facile construction of dual-bioresponsive biodegradable micelles with superior extracellular stability and activated intracellular drug release",
abstract = "It is still a major challenge for targeted cancer chemotherapy to design stable biodegradable micellar drug delivery systems which show a rapid and complete intracellular drug release. Here, reversibly core-crosslinked pH-responsive biodegradable micelles were developed based on poly(ethylene glycol)-poly(2,4,6-trimethoxybenzylidene-pentaerythritol carbonate-co-pyridyl disulfide carbonate) [PEG-P(TMBPEC-co-PDSC)] copolymers and investigated for intracellular doxorubicin (DOX) release. PEG-P(TMBPEC-co-PDSC) copolymers formed micelles with a small size of 58.6 nm were readily crosslinked by the addition of dithiothreitol (DTT). Notably, in vitro release studies showed that under physiological conditions only ca. 19.9{\%} of DOX was released from the reversibly crosslinked micelles in 24 h at a low micelle concentration of 40 μg/mL. The release of DOX was accelerated at pH 5.0 or in the presence of 10 mM glutathione (GSH) at pH 7.4, in which 64.2{\%} and 44.1{\%} of DOX was released, respectively, in 24 h. The drug release was further boosted at pH 5.0 and 10 mM GSH, with 98.8{\%} of DOX released in 12 h. Moreover, DOX release was also facilitated by a 4 h incubation at pH 5.0 followed by incubation at pH 7.4 with 10 mM GSH. Confocal microscopy indicated that DOX was delivered and released into the nuclei of RAW 264.7 cells following a 12 h incubation with DOX-loaded reversibly crosslinked micelles. MTT assays revealed that DOX-loaded reversibly crosslinked micelles had much higher antitumor activity than irreversibly crosslinked controls, with low IC50 values of 1.65 and 1.14 μg/mL for HeLa and RAW 264.7 cells, respectively, following a 48 h incubation. The blank crosslinked micelles had a low cytotoxicity of up to a concentration of 0.8 mg/mL. These reversibly crosslinked pH-sensitive biodegradable micelles with superior extracellular stability but activated intracellular drug release provide a novel platform for tumor-targeting drug delivery.",
keywords = "IR-99966, METIS-315343",
author = "Wei Chen and Fenghua Meng and Ru Cheng and Chao Deng and Jan Feijen and Zhiyuan Zhong",
year = "2015",
doi = "10.1016/j.jconrel.2015.05.273",
language = "Undefined",
volume = "210",
pages = "125--133",
journal = "Journal of controlled release",
issn = "0168-3659",
publisher = "Elsevier",

}

Facile construction of dual-bioresponsive biodegradable micelles with superior extracellular stability and activated intracellular drug release. / Chen, Wei; Meng, Fenghua; Cheng, Ru; Deng, Chao; Feijen, Jan; Zhong, Zhiyuan.

In: Journal of controlled release, Vol. 210, 2015, p. 125-133.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Facile construction of dual-bioresponsive biodegradable micelles with superior extracellular stability and activated intracellular drug release

AU - Chen, Wei

AU - Meng, Fenghua

AU - Cheng, Ru

AU - Deng, Chao

AU - Feijen, Jan

AU - Zhong, Zhiyuan

PY - 2015

Y1 - 2015

N2 - It is still a major challenge for targeted cancer chemotherapy to design stable biodegradable micellar drug delivery systems which show a rapid and complete intracellular drug release. Here, reversibly core-crosslinked pH-responsive biodegradable micelles were developed based on poly(ethylene glycol)-poly(2,4,6-trimethoxybenzylidene-pentaerythritol carbonate-co-pyridyl disulfide carbonate) [PEG-P(TMBPEC-co-PDSC)] copolymers and investigated for intracellular doxorubicin (DOX) release. PEG-P(TMBPEC-co-PDSC) copolymers formed micelles with a small size of 58.6 nm were readily crosslinked by the addition of dithiothreitol (DTT). Notably, in vitro release studies showed that under physiological conditions only ca. 19.9% of DOX was released from the reversibly crosslinked micelles in 24 h at a low micelle concentration of 40 μg/mL. The release of DOX was accelerated at pH 5.0 or in the presence of 10 mM glutathione (GSH) at pH 7.4, in which 64.2% and 44.1% of DOX was released, respectively, in 24 h. The drug release was further boosted at pH 5.0 and 10 mM GSH, with 98.8% of DOX released in 12 h. Moreover, DOX release was also facilitated by a 4 h incubation at pH 5.0 followed by incubation at pH 7.4 with 10 mM GSH. Confocal microscopy indicated that DOX was delivered and released into the nuclei of RAW 264.7 cells following a 12 h incubation with DOX-loaded reversibly crosslinked micelles. MTT assays revealed that DOX-loaded reversibly crosslinked micelles had much higher antitumor activity than irreversibly crosslinked controls, with low IC50 values of 1.65 and 1.14 μg/mL for HeLa and RAW 264.7 cells, respectively, following a 48 h incubation. The blank crosslinked micelles had a low cytotoxicity of up to a concentration of 0.8 mg/mL. These reversibly crosslinked pH-sensitive biodegradable micelles with superior extracellular stability but activated intracellular drug release provide a novel platform for tumor-targeting drug delivery.

AB - It is still a major challenge for targeted cancer chemotherapy to design stable biodegradable micellar drug delivery systems which show a rapid and complete intracellular drug release. Here, reversibly core-crosslinked pH-responsive biodegradable micelles were developed based on poly(ethylene glycol)-poly(2,4,6-trimethoxybenzylidene-pentaerythritol carbonate-co-pyridyl disulfide carbonate) [PEG-P(TMBPEC-co-PDSC)] copolymers and investigated for intracellular doxorubicin (DOX) release. PEG-P(TMBPEC-co-PDSC) copolymers formed micelles with a small size of 58.6 nm were readily crosslinked by the addition of dithiothreitol (DTT). Notably, in vitro release studies showed that under physiological conditions only ca. 19.9% of DOX was released from the reversibly crosslinked micelles in 24 h at a low micelle concentration of 40 μg/mL. The release of DOX was accelerated at pH 5.0 or in the presence of 10 mM glutathione (GSH) at pH 7.4, in which 64.2% and 44.1% of DOX was released, respectively, in 24 h. The drug release was further boosted at pH 5.0 and 10 mM GSH, with 98.8% of DOX released in 12 h. Moreover, DOX release was also facilitated by a 4 h incubation at pH 5.0 followed by incubation at pH 7.4 with 10 mM GSH. Confocal microscopy indicated that DOX was delivered and released into the nuclei of RAW 264.7 cells following a 12 h incubation with DOX-loaded reversibly crosslinked micelles. MTT assays revealed that DOX-loaded reversibly crosslinked micelles had much higher antitumor activity than irreversibly crosslinked controls, with low IC50 values of 1.65 and 1.14 μg/mL for HeLa and RAW 264.7 cells, respectively, following a 48 h incubation. The blank crosslinked micelles had a low cytotoxicity of up to a concentration of 0.8 mg/mL. These reversibly crosslinked pH-sensitive biodegradable micelles with superior extracellular stability but activated intracellular drug release provide a novel platform for tumor-targeting drug delivery.

KW - IR-99966

KW - METIS-315343

U2 - 10.1016/j.jconrel.2015.05.273

DO - 10.1016/j.jconrel.2015.05.273

M3 - Article

VL - 210

SP - 125

EP - 133

JO - Journal of controlled release

JF - Journal of controlled release

SN - 0168-3659

ER -