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

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

References

[1] Popat S, O’Brien M. Chemotherapy strategies in the treatment of small cell lung cancer. Anti-Cancer Drugs, 2005, 16(4): 361–372

[2] Liu D, Poon C, Lu K, . Self-assembled nanoscale coordination polymers with trigger release properties for effective anticancer therapy. Nature Communications, 2014, 5(1): 4182

[3] Poon C, He C, Liu D, . Self-assembled nanoscale coordination polymers carrying oxaliplatin and gemcitabine for synergistic combination therapy of pancreatic cancer. Journal of Controlled Release, 2015, 201: 90–99

[4] He C, Liu D, Lin W. Self-assembled nanoscale coordination polymers carrying siRNAs and cisplatin for effective treatment of resistant ovarian cancer. Biomaterials, 2015, 36: 124–133

[5] He C, Liu D, Lin W. Self-assembled core‒shell nanoparticles for combined chemotherapy and photodynamic therapy of resistant head and neck cancers. ACS Nano, 2015, 9(1): 991–1003

[6] He C, Poon C, Chan C, . 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

[7] Li X, Yang Z, Yang K, . Self-assembled polymeric micellar nanoparticles as nanocarriers for poorly soluble anticancer drug ethaselen. Nanoscale Research Letters, 2009, 4(12): 1502–1511

[8] Xiong D, Yao N, Gu H, . 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

[9] Cabral H, Kataoka K. Progress of drug-loaded polymeric micelles into clinical studies. Journal of Controlled Release, 2014, 190: 465–476

[10] Kwon G S, Kataoka K. Block copolymer micelles as long-circulating drug vehicles. Advanced Drug Delivery Reviews, 2012, 64: 237–245

[11] Deng C, Jiang Y, Cheng R, . Biodegradable polymeric micelles for targeted and controlled anticancer drug delivery: Promises, progress and prospects. Nano Today, 2012, 7(5): 467–480

[12] Cao Z, Ma Y, Sun C, . ROS-sensitive polymeric nanocarriers with red light-activated size shrinkage for remotely controlled drug release. Chemistry of Materials, 2017, 30: 517–515

[13] Adams M L, Lavasanifar A, Kwon G S. Amphiphilic block copolymers for drug delivery. Journal of Pharmaceutical Sciences, 2003, 92(7): 1343–1355

[14] Cao Z, Yu Q, Xue H, . 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

[15] Zhu X, Fryd M, Wayland B B. Kinetic-mechanistic studies of lipase-polymer micelle binding and catalytic degradation: Enzyme interfacial activation. Polymer Degradation and Stability, 2013, 98(6): 1173–1181

[16] Zhao L, Wu C, Wang F, . Fabrication of biofunctional complex micelles with tunable structure for application in controlled drug release. Colloid & Polymer Science, 2014, 292(7): 1675–1683

[17] Deng H, Liu J, Zhao X, . 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

[18] Marzbali M Y, Khosroushahi A Y. Polymeric micelles as mighty nanocarriers for cancer gene therapy: a review. Cancer Chemotherapy and Pharmacology, 2017, 79(4): 637–649

[19] Choi J Y, Thapa R K, Yong C S, . Nanoparticle-based combination drug delivery systems for synergistic cancer treatment. Journal of Pharmaceutical Investigation, 2016, 46(4): 325–339

[20] Senapati S, Mahanta A K, Kumar S, . Controlled drug delivery vehicles for cancer treatment and their performance. Signal Transduction and Targeted Therapy, 2018, 3(1): 7

[21] Hu Y W, Du Y Z, Liu N, . Selective redox-responsive drug release in tumor cells mediated by chitosan based glycolipid-like nanocarrier. Journal of Controlled Release, 2015, 206: 91–100

[22] Sun H, Guo B, Li X, . Shell-sheddable micelles based on dextran-SS-poly(ε-caprolactone) diblock copolymer for efficient intracellular release of doxorubicin. Biomacromolecules, 2010, 11(4): 848–854

[23] Sun H, Guo B, Cheng R, . Biodegradable micelles with sheddable poly(ethylene glycol) shells for triggered intracellular release of doxorubicin. Biomaterials, 2009, 30(31): 6358–6366

[24] Zhong Y, Yang W, Sun H, . Ligand-directed reduction-sensitive shell-sheddable biodegradable micelles actively deliver doxorubicin into the nuclei of target cancer cells. Biomacromolecules, 2013, 14(10): 3723–3730

[25] Zhao C, Shao L, Lu J, . Triple redox responsive poly(ethylene glycol)-polycaprolactone polymeric nanocarriers for fine-controlled drug release. Macromolecular Bioscience, 2017, 17(4): 1600295

[26] Tao Y, Zhao H. 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

[27] Kumar A, Lale S V, Mahajan S, . 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

[28] Fan X, Wang X, Cao M, . “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

[29] Jiang J, Li J, Zhou B, . Fabrication of polymer micelles with Zwitterionic shell and biodegradable core for reductively responsive release of doxorubicin. Polymers, 2019, 11(6): 1019

[30] Yan T, Li D, Li J, . 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

[31] Davoodi P, Srinivasan M P, Wang C H. 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

[32] Torchilin V P. Structure and design of polymeric surfactant-based drug delivery systems. Journal of Controlled Release, 2001, 73(2‒3): 137–172

[33] Xu Y, Wang L, Li Y K, . 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

[34] Chen Y, Zhang W, Huang Y, . 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

[35] Mura S, Nicolas J, Couvreur P. Stimuli-responsive nanocarriers for drug delivery. Nature Materials, 2013, 12(11): 991–1003

Acknowledgements

This work was supported by the National Natural Science Foundation of China (Project U1704150) and the Scientific and Technological Projects of Henan Province (182102410017).

RIGHTS & PERMISSIONS

2019 Higher Education Press and Springer-Verlag GmbH Germany, part of Springer Nature