Shell-sheddable micelles based on dextran-SS-poly(epsilon-caprolactone) diblock copolymer for efficient intracellular release of doxorubicin.
Reduction-responsive biodegradable micelles were developed from disulfide-linked dextran-b-poly(epsilon-caprolactone) diblock copolymer (Dex-SS-PCL) and applied for triggered release of doxorubicin (DOX) in vitro and inside cells. Dex-SS-PCL was readily synthesized by thiol-disulfide exchange reaction between dextran orthopyridyl disulfide (Dex-SS-py, 6000 Da) and mercapto PCL (PCL-SH, 3100 Da). Dynamic light scattering (DLS) measurements showed that Dex-SS-PCL yielded micelles with an average size of about 60 nm and a low polydispersity index (PDI 0.1-0.2) in PB (50 mM, pH 7.4). Interestingly, these micelles formed large aggregates rapidly in response to 10 mM dithiothreitol (DTT), most likely due to shedding of the dextran shells through reductive cleavage of the intermediate disulfide bonds. DOX could be efficiently loaded into the micelles with a drug loading efficiency of about 70%. Notably, the in vitro release studies revealed that Dex-SS-PCL micelles released DOX quantitatively in 10 h under a reductive environment, mimicking that of the intracellular compartments such as cytosol and the cell nucleus, whereas only about 27% DOX was released from reduction insensitive Dex-PCL micelles in 11.5 h under otherwise the same conditions and about 20% DOX released from Dex-SS-PCL micelles in 20 h under the nonreductive conditions. The cell experiments using fluorescence microscopy and confocal laser scanning microscopy (CLSM) showed clearly that DOX was rapidly released to the cytoplasm as well as to the cell nucleus. MTT studies revealed a markedly enhanced drug efficacy of DOX-loaded Dex-SS-PCL micelles as compared to DOX-loaded reduction-insensitive Dex-PCL micelles. These reduction-responsive biodegradable micelles have appeared highly promising for the targeted intracellular delivery of hydrophobic chemotherapeutics in cancer therapy.
Sun
Huanli
H
Biomedical Polymers Laboratory and Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, 215123, People's Republic of China.
Guo
Bingnan
B
Li
Xiaoqing
X
Cheng
Ru
R
Meng
Fenghua
F
Liu
Haiyan
H
Zhong
Zhiyuan
Z
D000903:Antibiotics, Antineoplastic / Q000737:chemistry*; D004317:Doxorubicin / Q000737:chemistry*; D004337:Drug Carriers / Q000138:chemical synthesis / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008823:Micelles; D011091:Polyesters / Q000737:chemistry*; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry*; D017550:Spectroscopy, Fourier Transform Infrared
D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D008823:Micelles; D011091:Polyesters; D011108:Polymers; C016240:polycaprolactone; D004317:Doxorubicin