Skip to main content
SpringerLink
Log in

Novel amphiphilic PEG-hydroxycamptothecin conjugates as glutathione-responsive prodrug nanocapsules for cancer chemotherapy

  • Research Paper
  • Published:
Journal of Nanoparticle Research Aims and scope Submit manuscript

Abstract

A series of novel hydroxycamptothecin (HCPT) conjugates (13a–14d), which contained a polyethylene glycol moiety and disulfide bond, were designed and synthesized in five to six steps, with overall yields of 20–39%. The anticancer activities and toxicities of these new conjugates were evaluated using an in vitro MTT assay in K562, HepG2, and HT-29 cell lines and HUVECs. The conjugates displayed enhanced antitumor activity and reduced toxicity in comparison with their parent molecule, HCPT. Among these conjugates, compound 13a exhibited 100-fold better selectivity to the tumor cells than to HUVECs. TEM and DLS experiments demonstrated that 13a formed nanosized micelles with a diameter of approximately 200 nm in aqueous solution and that the conjugate could undergo glutathione-responsive degradation to release HCPT at the tumor site. The improved potency and reduced toxicity of these conjugates may be caused by the enhanced permeation and retention (EPR) effect of nanoparticles.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Scheme 1
Scheme 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Blanco E, Hsiao A, Ruiz-Esparza GU, Landry MG, Meric-Bernstam F, Ferrari M (2011) Molecular-targeted nanotherapies in cancer: enabling treatment specificity. Mol Oncol 5:492–503. doi:10.1016/j.molonc.2011.10.005

    Article  Google Scholar 

  • Cheetham AG, Zhang P, Lin YA, Lock LL, Cui H (2013) Supramolecular nanostructures formed by anticancer drug assembly. J Am Chem Soc 135:2907–2910. doi:10.1021/ja3115983

    Article  Google Scholar 

  • Chen W, Shi Y, Feng H, Du M, Zhang JZ, Hu J, Yang D (2012) Preparation of copolymer paclitaxel covalently linked via a disulfide bond and its application on controlled drug delivery. J Phys Chem B 116:9231–9237. doi:10.1021/jp303260f

    Article  Google Scholar 

  • Denison TA, Bae YH (2012) Tumor heterogeneity and its implication for drug delivery. J Control Release 164:187–191. doi:10.1016/j.jconrel.2012.04.014

    Article  Google Scholar 

  • Gao Y et al (2011) Controlled intracellular release of doxorubicin in multidrug-resistant cancer cells by tuning the shell-pore sizes of mesoporous silica nanoparticles. ACS Nano 5:9788–9798. doi:10.1021/nn2033105

    Article  Google Scholar 

  • Jackson AW, Fulton DA (2012) Triggering polymeric nanoparticle disassembly through the simultaneous. Application of Two Different Stimuli Macromolecules 45:2699–2708

    Google Scholar 

  • Kamaly N, Xiao Z, Valencia PM, Radovic-Moreno AF, Farokhzad OC (2012) Targeted polymeric therapeutic nanoparticles: design, development and clinical translation. Chem Soc Rev 41:2971–3010. doi:10.1039/c2cs15344k

    Article  Google Scholar 

  • Li XQ et al (2011) Self-assembling nanomicelles of a novel camptothecin prodrug engineered with a redox-responsive release mechanism. Chem Commun (Camb) 47:8647–8649. doi:10.1039/c1cc12495a

    Article  Google Scholar 

  • Lu J et al (2015) The self-assembling camptothecin-tocopherol prodrug: an effective approach for formulating camptothecin. Biomaterials 62:176–187. doi:10.1016/j.biomaterials.2015.05.046

    Article  Google Scholar 

  • Maeda H, Matsumura Y (2011) EPR effect based drug design and clinical outlook for enhanced cancer chemotherapy. Adv Drug Deliv Rev 63:129–130. doi:10.1016/j.addr.2010.05.001

    Article  Google Scholar 

  • Matsumura Y (2011) Preclinical and clinical studies of NK012, an SN-38-incorporating polymeric micelles, which is designed based on EPR effect. Adv Drug Deliv Rev 63:184–192. doi:10.1016/j.addr.2010.05.008

    Article  Google Scholar 

  • Mullen DG, Banaszak Holl MM (2011) Heterogeneous ligand-nanoparticle distributions: a major obstacle to scientific understanding and commercial translation. Acc Chem Res 44:1135–1145. doi:10.1021/ar1001389

    Article  Google Scholar 

  • Nalwa HS (2011) Encyclopedia of nanoscience and nanotechnology, 15-volume set (Vols. 11–25) 2011.

  • Ryu JH, Chacko RT, Jiwpanich S, Bickerton S, Babu RP, Thayumanavan S (2010) Self-cross-linked polymer nanogels: a versatile nanoscopic drug delivery platform. J Am Chem Soc 132:17227–17235. doi:10.1021/ja1069932

    Article  Google Scholar 

  • Tai W, Mo R, Lu Y, Jiang T, Gu Z (2014) Folding graft copolymer with pendant drug segments for co-delivery of anticancer drugs. Biomaterials 35:7194–7203. doi:10.1016/j.biomaterials.2014.05.004

    Article  Google Scholar 

  • Veronese FM, Pasut G (2005) PEGylation, successful approach to drug delivery. Drug Discov Today 10:1451–1458. doi:10.1016/S1359-6446(05)03575-0

    Article  Google Scholar 

  • Wang J et al (2013) Tumor redox heterogeneity-responsive prodrug nanocapsules for cancer chemotherapy. Adv Mater 25:3670–3676. doi:10.1002/adma.201300929

    Article  Google Scholar 

  • Wei H, Schellinger JG, Chu DS, Pun SH (2012) Neuron-targeted copolymers with sheddable shielding blocks synthesized using a reducible, RAFT-ATRP double-head agent. J Am Chem Soc 134:16554–16557. doi:10.1021/ja3085803

    Article  Google Scholar 

  • Xing T, Mao C, Lai B, Yan L (2012) Synthesis of disulfide-cross-linked polypeptide nanogel conjugated with a near-infrared fluorescence probe for direct imaging of reduction-induced drug release. ACS Appl Mater Interfaces 4:5662–5672. doi:10.1021/am301600u

    Article  Google Scholar 

  • Xu Z, Wang D, Xu S, Liu X, Zhang X, Zhang H (2014) Preparation of a camptothecin prodrug with glutathione-responsive disulfide linker for anticancer drug delivery. Chem Asian J 9:199–205. doi:10.1002/asia.201301030

    Article  Google Scholar 

  • Zheng ZB, Zhu G, Tak H, Joseph E, Eiseman JL, Creighton DJ (2005) N-(2-hydroxypropyl)methacrylamide copolymers of a glutathione (GSH)-activated glyoxalase i inhibitor and DNA alkylating agent: synthesis, reaction kinetics with GSH, and in vitro antitumor activities. Bioconjug Chem 16:598–607. doi:10.1021/bc0499634

    Article  Google Scholar 

  • Zhou L et al (2011) Endosomal pH-activatable poly(ethylene oxide)-graft-doxorubicin prodrugs: synthesis, drug release, and biodistribution in tumor-bearing mice. Biomacromolecules 12:1460–1467. doi:10.1021/bm101340u

    Article  Google Scholar 

Download references

Acknowledgements

The authors are thankful to the Research Centre of Modern Analytical Technology, Tianjin University of Science and Technology, for NMR measurements and MALDI-TOF analysis.

Author information

Authors and Affiliations

  1. Key Laboratory of Industrial Fermentation Microbiology of Ministry of Education, Tianjin University of Science and Technology, Tianjin, 300457, China

    Na Guo, Tiantian Hao, Xiuzhuan Shang, Tianle Zhang, Huan Liu, Qian Zhang, Jing Wang, Du Jiang, Yao Rong, Yuou Teng & Peng Yu

  2. China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, Tianjin University of Science and Technology, Tianjin, 300457, China

    Na Guo, Tiantian Hao, Xiuzhuan Shang, Tianle Zhang, Huan Liu, Qian Zhang, Jing Wang, Du Jiang, Yao Rong, Yuou Teng & Peng Yu

Authors
  1. Na Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tiantian Hao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiuzhuan Shang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tianle Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Huan Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Qian Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jing Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Du Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yao Rong
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yuou Teng
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Peng Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peng Yu.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Funding

This work was supported by the National Natural Science Foundation of China (No. 81302649) and Natural Science Foundation of Tianjin City (14JCQNJC13200 and 16JCTPJC46000).

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Guo, N., Hao, T., Shang, X. et al. Novel amphiphilic PEG-hydroxycamptothecin conjugates as glutathione-responsive prodrug nanocapsules for cancer chemotherapy. J Nanopart Res 19, 205 (2017). https://doi.org/10.1007/s11051-017-3897-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11051-017-3897-4

Keywords

Search

Navigation