Please wait a minute...
Frontiers of Materials Science

ISSN 2095-025X

ISSN 2095-0268(Online)

CN 11-5985/TB

Postal Subscription Code 80-974

2018 Impact Factor: 1.701

Front. Mater. Sci.    2019, Vol. 13 Issue (4) : 410-419    https://doi.org/10.1007/s11706-019-0475-y
RESEARCH ARTICLE
Synthesis of poly(ethylene glycol)-SS-poly(ε-caprolactone)-SS-poly(ethylene glycol) triblock copolymers via end-group conjugation and self-assembly for reductively responsive drug delivery
Junbo LI1(), Junting JIANG1, Biyu ZHOU1, Chaohuang NIU1, Wendi WANG1, Wenlan WU2
1. School of Chemical Engineering and Pharmaceutics, Henan University of Science and Technology, Luoyang 471023, China
2. School of Medicine, Henan University of Science and Technology, Luoyang 471023, China
 Download: PDF(2728 KB)   HTML
 Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks
Abstract

In this study, we describe a simple synthesis route to prepare triblock copolymers with disulfide-linkers, poly(ethylene glycol)-SS-poly(ε-caprolactone)-SS-poly(ethylene glycol) (PEG-SS-PCL-SS-PEG) for application in the reductively responsive release of doxorubicin (DOX). To synthesize PEG-SS-PCL-SS-PEG, two end-groups of PCL-diol were first modified with cystamine to introduce disulfide bonds and subsequently conjugated with PEG-NHS via carbodiimide chemistry. PEG-SS-PCL-SS-PEG fabricated into polymeric micelles with stable structure and different nanoscale sizes via adjusting the PCL chain length, showing obvious reductive responsiveness and fast drug release of encapsulated DOX in the presence of glutathione (GSH). Moreover, DOX-loaded PEG-SS-PCL-SS-PEG micelles exhibited higher therapeutic efficacy than reduction-insensitive PEG-b-PCL micelles in vitro. Thus, end-groups conjugation is a simple and straightforward strategy to introduce intelligent responsiveness in biocompatible block copolymers and improve their therapeutic efficacy.

Keywords poly-ε-caprolactone      poly(ethylene glycol)      block copolymer      reductive responsiveness      drug      release     
Corresponding Author(s): Junbo LI   
Online First Date: 07 November 2019    Issue Date: 04 December 2019
 Cite this article:   
Junbo LI,Junting JIANG,Biyu ZHOU, et al. Synthesis of poly(ethylene glycol)-SS-poly(ε-caprolactone)-SS-poly(ethylene glycol) triblock copolymers via end-group conjugation and self-assembly for reductively responsive drug delivery[J]. Front. Mater. Sci., 2019, 13(4): 410-419.
 URL:  
https://academic.hep.com.cn/foms/EN/10.1007/s11706-019-0475-y
https://academic.hep.com.cn/foms/EN/Y2019/V13/I4/410
Fig.1  Scheme 1 Schematic of PEG-SS-PCL-SS-PEG micelles for the intracellular release of DOX.
Fig.2  Scheme 2 Synthesis route of PEG-SS-PCL-SS-PEG: CDI, anhydrous dichloromethane (DCM), RT, 24 h (i); DMSO, pyridine, TEA, RT, 48 h (ii); TEA, anhydrous DCM, RT, 48 h (iii).
Fig.3  (A) 1H NMR spectra of PEG-SS-PCL-SS-PEG in CDCl3 and (B) GPC traces for PEG-SS-PCL-SS-PEG in CHCl3 at RT.
Fig.4  (a) The variation of I390/I377 with the CMC. Hydrodynamic diameter distributions f(Dh) and TEM images (inserted) of (b) PEG45-SS-PCL17-SS-PEG45, (c) PEG45-SS-PCL31-SS-PEG45 and (d) PEG45-SS-PCL44-SS-PEG45.
Fig.5  (a) Hydrodynamic diameter distribution f(Dh) and (b) TEM image of PEG45-SS-PCL17-SS-PEG45 micelles in PB containing 10 mmol·L−1 GSH.
Fig.6  (a) UV-vis spectra of DOX and DOX-loaded PEG45-SS-PCL17-SS-PEG45 micelles in PB. TEM images of DOX-loaded (b) PEG45-SS-PCL17-SS-PEG45 micelles, (c) PEG45-SS-PCL31-SS-PEG45 micelles and (d) PEG45-SS-PCL44-SS-PEG45 micelles.
Fig.7  In vitro DOX release profiles from PEG-SS-PCL-SS-PEG and PEG-b-PCL micelles in PBS (0.1 mol·L−1) at pH 7.4 (a) with or (b) without GSH (10?mmol·L−1).
Fig.8  Toxicity of HepG2 cells after incubation (a) with PEG45-b-PCL17 and PEG45-SS-PCL17-SS-PEG45 micelles and with (b) free DOX, DOX-loaded PEG45-b-PCL17 and PEG45-SS-PCL17-SS-PEG45 micelles for 24?h. Data are presented as the average (standard deviation n = 3).
Fig.9  (A) Fluorescence microscopy images of HepG2 cells incubated with free DOX (a), DOX-loaded PEG45-b-PCL17 (b), and PEG45-SS-PCL17-SS-PEG45 (c) micelles for 8 h. (B) The mean fluorescence intensity of HepG2 cells treated by PBS, empty micelles, DOX-loaded PEG45-b-PCL17 micelles or DOX-loaded PEG45-SS-PCL17-SS-PEG45 micelles, where the DOX concentration was 5 mg·L−1. Data are presented as the average (standard deviation (n = 3)).
1 S Popat, M O’Brien. Chemotherapy strategies in the treatment of small cell lung cancer. Anti-Cancer Drugs, 2005, 16(4): 361–372
https://doi.org/10.1097/00001813-200504000-00002 pmid: 15746572
2 D Liu, C Poon, K Lu, et al.. Self-assembled nanoscale coordination polymers with trigger release properties for effective anticancer therapy. Nature Communications, 2014, 5(1): 4182
https://doi.org/10.1038/ncomms5182 pmid: 24964370
3 C Poon, C He, D Liu, et al.. Self-assembled nanoscale coordination polymers carrying oxaliplatin and gemcitabine for synergistic combination therapy of pancreatic cancer. Journal of Controlled Release, 2015, 201: 90–99
https://doi.org/10.1016/j.jconrel.2015.01.026 pmid: 25620067
4 C He, D Liu, W Lin. Self-assembled nanoscale coordination polymers carrying siRNAs and cisplatin for effective treatment of resistant ovarian cancer. Biomaterials, 2015, 36: 124–133
https://doi.org/10.1016/j.biomaterials.2014.09.017 pmid: 25315138
5 C He, D Liu, W Lin. Self-assembled core‒shell nanoparticles for combined chemotherapy and photodynamic therapy of resistant head and neck cancers. ACS Nano, 2015, 9(1): 991–1003
https://doi.org/10.1021/nn506963h pmid: 25559017
6 C He, C Poon, C Chan, et al.. Nanoscale coordination polymers codeliver chemotherapeutics and siRNAs to eradicate tumors of cisplatin-resistant ovarian cancer. Journal of the American Chemical Society, 2016, 138(18): 6010–6019
https://doi.org/10.1021/jacs.6b02486 pmid: 27088560
7 X Li, Z Yang, K Yang, et al.. Self-assembled polymeric micellar nanoparticles as nanocarriers for poorly soluble anticancer drug ethaselen. Nanoscale Research Letters, 2009, 4(12): 1502–1511
https://doi.org/10.1007/s11671-009-9427-2 pmid: 20652138
8 D Xiong, N Yao, H Gu, et al.. Stimuli-responsive shell cross-linked micelles from amphiphilic four-arm star copolymers as potential nanocarriers for “pH/redox-triggered” anticancer drug release. Polymer, 2017, 114: 161–172
https://doi.org/10.1016/j.polymer.2017.03.002
9 H Cabral, K Kataoka. Progress of drug-loaded polymeric micelles into clinical studies. Journal of Controlled Release, 2014, 190: 465–476
https://doi.org/10.1016/j.jconrel.2014.06.042 pmid: 24993430
10 G S Kwon, K Kataoka. Block copolymer micelles as long-circulating drug vehicles. Advanced Drug Delivery Reviews, 2012, 64: 237–245
https://doi.org/10.1016/j.addr.2012.09.016
11 C Deng, Y Jiang, R Cheng, et al.. Biodegradable polymeric micelles for targeted and controlled anticancer drug delivery: Promises, progress and prospects. Nano Today, 2012, 7(5): 467–480
https://doi.org/10.1016/j.nantod.2012.08.005
12 Z Cao, Y Ma, C Sun, et al.. ROS-sensitive polymeric nanocarriers with red light-activated size shrinkage for remotely controlled drug release. Chemistry of Materials, 2017, 30: 517–515
https://doi.org/10.1021/acs.chemmater.7b04751
13 M L Adams, A Lavasanifar, G S Kwon. Amphiphilic block copolymers for drug delivery. Journal of Pharmaceutical Sciences, 2003, 92(7): 1343–1355
https://doi.org/10.1002/jps.10397 pmid: 12820139
14 Z Cao, Q Yu, H Xue, et al.. Nanoparticles for drug delivery prepared from amphiphilic PLGA zwitterionic block copolymers with sharp contrast in polarity between two blocks. Angewandte Chemie International Edition, 2010, 49(22): 3771–3776
https://doi.org/10.1002/anie.200907079 pmid: 20397173
15 X Zhu, M Fryd, B B Wayland. Kinetic-mechanistic studies of lipase-polymer micelle binding and catalytic degradation: Enzyme interfacial activation. Polymer Degradation and Stability, 2013, 98(6): 1173–1181
https://doi.org/10.1016/j.polymdegradstab.2013.03.016
16 L Zhao, C Wu, F Wang, et al.. Fabrication of biofunctional complex micelles with tunable structure for application in controlled drug release. Colloid & Polymer Science, 2014, 292(7): 1675–1683
https://doi.org/10.1007/s00396-014-3230-z
17 H Deng, J Liu, X Zhao, et al.. PEG-b-PCL copolymer micelles with the ability of pH-controlled negative-to-positive charge reversal for intracellular delivery of doxorubicin. Biomacromolecules, 2014, 15(11): 4281–4292
https://doi.org/10.1021/bm501290t pmid: 25325531
18 M Y Marzbali, A Y Khosroushahi. Polymeric micelles as mighty nanocarriers for cancer gene therapy: a review. Cancer Chemotherapy and Pharmacology, 2017, 79(4): 637–649
https://doi.org/10.1007/s00280-017-3273-1 pmid: 28314988
19 J Y Choi, R K Thapa, C S Yong, et al.. Nanoparticle-based combination drug delivery systems for synergistic cancer treatment. Journal of Pharmaceutical Investigation, 2016, 46(4): 325–339
https://doi.org/10.1007/s40005-016-0252-1
20 S Senapati, A K Mahanta, S Kumar, et al.. Controlled drug delivery vehicles for cancer treatment and their performance. Signal Transduction and Targeted Therapy, 2018, 3(1): 7
https://doi.org/10.1038/s41392-017-0004-3 pmid: 29560283
21 Y W Hu, Y Z Du, N Liu, et al.. Selective redox-responsive drug release in tumor cells mediated by chitosan based glycolipid-like nanocarrier. Journal of Controlled Release, 2015, 206: 91–100
https://doi.org/10.1016/j.jconrel.2015.03.018 pmid: 25796347
22 H Sun, B Guo, X Li, et al.. Shell-sheddable micelles based on dextran-SS-poly(ε-caprolactone) diblock copolymer for efficient intracellular release of doxorubicin. Biomacromolecules, 2010, 11(4): 848–854
https://doi.org/10.1021/bm1001069 pmid: 20205476
23 H Sun, B Guo, R Cheng, et al.. Biodegradable micelles with sheddable poly(ethylene glycol) shells for triggered intracellular release of doxorubicin. Biomaterials, 2009, 30(31): 6358–6366
https://doi.org/10.1016/j.biomaterials.2009.07.051 pmid: 19666191
24 Y Zhong, W Yang, H Sun, et al.. Ligand-directed reduction-sensitive shell-sheddable biodegradable micelles actively deliver doxorubicin into the nuclei of target cancer cells. Biomacromolecules, 2013, 14(10): 3723–3730
https://doi.org/10.1021/bm401098w pmid: 23998942
25 C Zhao, L Shao, J Lu, et al.. Triple redox responsive poly(ethylene glycol)-polycaprolactone polymeric nanocarriers for fine-controlled drug release. Macromolecular Bioscience, 2017, 17(4): 1600295
https://doi.org/10.1002/mabi.201600295 pmid: 27762492
26 Y Tao, H Zhao. Synthesis and self-assembly of amphiphilic tadpole-shaped block copolymer with disulfides at the junction points between cyclic PEG and linear PS. Polymer, 2017, 122: 52–59
https://doi.org/10.1016/j.polymer.2017.06.046
27 A Kumar, S V Lale, S Mahajan, et al.. ROP and ATRP fabricated dual targeted redox sensitive polymersomes based on pPEGMA-PCL-ss-PCL-pPEGMA triblock copolymers for breast cancer therapeutics. ACS Applied Materials & Interfaces, 2015, 7(17): 9211–9227
https://doi.org/10.1021/acsami.5b01731 pmid: 25838044
28 X Fan, X Wang, M Cao, et al.. “Y”-shape armed amphiphilic star-like copolymers: design, synthesis and dual-responsive unimolecular micelle formation for controlled drug delivery. Polymer Chemistry, 2017, 8(36): 5611
https://doi.org/10.1039/C7PY00999B
29 J Jiang, J Li, B Zhou, et al.. Fabrication of polymer micelles with Zwitterionic shell and biodegradable core for reductively responsive release of doxorubicin. Polymers, 2019, 11(6): 1019
https://doi.org/10.3390/polym11061019 pmid: 31181866
30 T Yan, D Li, J Li, et al.. Effective co-delivery of doxorubicin and curcumin using a glycyrrhetinic acid-modified chitosan-cystamine-poly(ε-caprolactone) copolymer micelle for combination cancer chemotherapy. Colloids and Surfaces B: Biointerfaces, 2016, 145: 526–538
https://doi.org/10.1016/j.colsurfb.2016.05.070 pmid: 27281238
31 P Davoodi, M P Srinivasan, C H Wang. Synthesis of intracellular reduction-sensitive amphiphilic polyethyleneimine and poly(ε-caprolactone) graft copolymer for on-demand release of doxorubicin and p53 plasmid DNA. Acta Biomaterialia, 2016, 39: 79–93
https://doi.org/10.1016/j.actbio.2016.05.003 pmid: 27154500
32 V P Torchilin. Structure and design of polymeric surfactant-based drug delivery systems. Journal of Controlled Release, 2001, 73(2‒3): 137–172
https://doi.org/10.1016/S0168-3659(01)00299-1 pmid: 11516494
33 Y Xu, L Wang, Y K Li, et al.. Reduction and pH dual-responsive nanoparticles based chitooligosaccharide-based graft copolymer for doxorubicin delivery. Colloids and Surfaces A: Physicochemical and Engineering Aspects, 2016, 497: 8–15
https://doi.org/10.1016/j.colsurfa.2016.01.049
34 Y Chen, W Zhang, Y Huang, et al.. In vivo biodistribution and anti-tumor efficacy evaluation of doxorubicin and paclitaxel-loaded pluronic micelles decorated with c(RGDyK) peptide. PLoS One, 2016, 11(3): e0149952
https://doi.org/10.1371/journal.pone.0149952 pmid: 26930626
35 S Mura, J Nicolas, P Couvreur. Stimuli-responsive nanocarriers for drug delivery. Nature Materials, 2013, 12(11): 991–1003
https://doi.org/10.1038/nmat3776 pmid: 24150417
[1] Yimin ZHOU, Qingni XU, Chaohua LI, Yuqi CHEN, Yueli ZHANG, Bo LU. Hollow mesoporous silica nanoparticles as nanocarriers employed in cancer therapy: A review[J]. Front. Mater. Sci., 2020, 14(4): 373-386.
[2] Xiao-Jing JI, Qiang CHENG, Jing WANG, Yan-Bin ZHAO, Zhuang-Zhuang HAN, Fen ZHANG, Shuo-Qi LI, Rong-Chang ZENG, Zhen-Lin WANG. Corrosion resistance and antibacterial effects of hydroxyapatite coating induced by polyacrylic acid and gentamicin sulfate on magnesium alloy[J]. Front. Mater. Sci., 2019, 13(1): 87-98.
[3] Zhenrong JIA, Xuefeng XIA, Xiaofeng WANG, Tengyi WANG, Guiying XU, Bei LIU, Jitong ZHOU, Fan LI. All-conjugated amphiphilic diblock copolymers for improving morphology and thermal stability of polymer/nanocrystals hybrid solar cells[J]. Front. Mater. Sci., 2018, 12(3): 225-238.
[4] Amina Ben MIHOUB, Boubakeur SAIDAT, Youssef BAL, Céline FROCHOT, Régis VANDERESSE, Samir ACHERAR. Development of new ionic gelation strategy: Towards the preparation of new monodisperse and stable hyaluronic acid/β-cyclodextrin-grafted chitosan nanoparticles as drug delivery carriers for doxorubicin[J]. Front. Mater. Sci., 2018, 12(1): 83-94.
[5] Mathew JOY, Srividhya J. IYENGAR, Jui CHAKRABORTY, Swapankumar GHOSH. Layered double hydroxide using hydrothermal treatment: morphology evolution, intercalation and release kinetics of diclofenac sodium[J]. Front. Mater. Sci., 2017, 11(4): 395-409.
[6] Lulu WEI, Beibei LU, Lin CUI, Xueying PENG, Jianning WU, Deqiang LI, Zhiyong LIU, Xuhong GUO. Folate-conjugated pH-responsive nanocarrier designed for active tumor targeting and controlled release of doxorubicin[J]. Front. Mater. Sci., 2017, 11(4): 328-343.
[7] Dongthanh NGUYEN,Wei WANG,Haibo LONG,Hongqiang RU. Facile and controllable preparation of mesoporous TiO2 using poly(ethylene glycol) as structure-directing agent and peroxotitanic acid as precursor[J]. Front. Mater. Sci., 2016, 10(4): 405-412.
[8] Lei LIU,Peng LIU. Synthesis strategies for disulfide bond-containing polymer-based drug delivery system for reduction-responsive controlled release[J]. Front. Mater. Sci., 2015, 9(3): 211-226.
[9] Ju LIANG,Wenlan WU,Junbo LI,Chen HAN,Shijie ZHANG,Jinwu GUO,Huiyun ZHOU. Synthesis and self-assembly of temperature and anion double responsive ionic liquid block copolymers[J]. Front. Mater. Sci., 2015, 9(3): 254-263.
[10] Peng WANG,Bin PI,Jin-Ning WANG,Xue-Song ZHU,Hui-Lin YANG. Preparation and properties of calcium sulfate bone cement incorporated with silk fibroin and Sema3A-loaded chitosan microspheres[J]. Front. Mater. Sci., 2015, 9(1): 51-65.
[11] Hui-Yun ZHOU,Pei-Pei CAO,Jie ZHAO,Zhi-Ying WANG,Jun-Bo LI,Fa-Liang ZHANG. Release behavior and kinetic evaluation of berberine hydrochloride from ethyl cellulose/chitosan microspheres[J]. Front. Mater. Sci., 2014, 8(4): 373-382.
[12] Yuan LIAN,Jian-Chao ZHAN,Kui-Hua ZHANG,Xiu-Mei MO. Fabrication and characterization of curcumin-loaded silk fibroin/P(LLA-CL) nanofibrous scaffold[J]. Front. Mater. Sci., 2014, 8(4): 354-362.
[13] Jing LI,Fang-Kui MA,Qi-Feng DANG,Xing-Guo LIANG,Xi-Guang CHEN. Glucose-conjugated chitosan nanoparticles for targeted drug delivery and their specific interaction with tumor cells[J]. Front. Mater. Sci., 2014, 8(4): 363-372.
[14] Ting-Ting GAO,Ming KONG,Xiao-Jie CHENG,Gui-Xue XIA,Yuan-Yuan GAO,Xi-Guang CHEN,Dong Su CHA,Hyun Jin PARK. A thermosensitive chitosan-based hydrogel for controlled release of insulin[J]. Front. Mater. Sci., 2014, 8(2): 142-149.
[15] Chong WANG,Min WANG. Electrospun multifunctional tissue engineering scaffolds[J]. Front. Mater. Sci., 2014, 8(1): 3-19.
Viewed
Full text


Abstract

Cited

  Shared   
  Discussed