Skip to main content
SpringerLink
Log in

pH-responsive release of paclitaxel from hydrazone-containing biodegradable micelles

  • Original Contribution
  • Published:
Colloid and Polymer Science Aims and scope Submit manuscript

Abstract

Many tumor cells have acidic microenvironment that can be exploited for the design of pH-responsive drug delivery systems. In this work, well-defined pH-sensitive and biodegradable polymeric micelles were prepared and evaluate as carrier of paclitaxel (PTX). A diblock copolymer constituting of a poly(ethylene glycol) (PEG) and a polycaprolactone (PCL) segment linked by a pH-sensitive hydrazone bond (Hyd), which was denoted as mPEG-Hyd-PCL, was synthesized. The copolymer was assembled to micelles with mean diameters about 100 nm. The mean diameters and size distribution of the hydrazone-containing micelles increased obviously in mildly acidic environments while kept unchanged in the neutral. No significant change in size was found on polymeric micelles without hydrazone (mPEG-PCL). PTX was loaded into micelles, and the anticancer drug released from mPEG-Hyd-PCL micelles was promoted by the increased acidity. In vitro cytotoxicity study showed that the PTX-loaded mPEG-Hyd-PCL micelles exhibited significantly enhanced cytotoxicity against HepG2 cells compared to the non-sensitive mPEG-PCL micelles. These results suggest that hydrazone-containing copolymer micelles with pH sensitivity and biodegradability show excellent potential as carriers of anticancer drugs.

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

Scheme 1
Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Kataoka K, Harada A, Nagasaki Y (2001) Block copolymer micelles for drug delivery: design, characterization and biological significance. Adv Drug Deliv Rev 47:113–131

    Article  CAS  Google Scholar 

  2. Sakai-Kato K, Nishiyama N, Kozaki M, Nakanishi T, Matsuda Y, Hirano M, Hanada H, Hisada S, Onodera H, Harashima H, Matsumura Y, Kataoka K, Goda Y, Okuda H, Kawanishi T (2015) General considerations regarding the in vitro and in vivo properties of block copolymer micelle products and their evaluation. J Control Release 210:76–83

    Article  CAS  Google Scholar 

  3. Cho H, Lai TC, Tomoda K, Kwon GS (2015) Polymeric micelles for multi-drug delivery in cancer. AAPS PharmSciTech 16:10–20

    Article  CAS  Google Scholar 

  4. Cabral H, Kataoka K (2014) Progress of drug-loaded polymeric micelles into clinical studies. J Control Release 190:465–476

    Article  CAS  Google Scholar 

  5. Eetezadi S, Ekdawi SN, Allen C (2015) The challenges facing block copolymer micelles for cancer therapy: in vivo barriers and clinical translation. Adv Drug Deliv Rev 91:7–22

    Article  CAS  Google Scholar 

  6. Makino J, Cabral H, Miura Y, Matsumoto Y, Wang M, Kinoh H, Mochida Y, Nishiyama N, Kataoka K (2015) cRGD-installed polymeric micelles loading platinum anticancer drugs enable cooperative treatment against lymph node metastasis. J Control Release 220:783–791

    Article  CAS  Google Scholar 

  7. Hrubý M, Koňák Č, Ulbrich K (2005) Polymeric micellar pH-sensitive drug delivery system for doxorubicin. J Control Release 103:137–148

    Article  Google Scholar 

  8. Huang F, Cheng R, Meng F, Deng C, Zhong Z (2015) Micelles based on acid degradable poly(acetal urethane): preparation, pH-sensitivity, and triggered intracellular drug release. Biomacromolecules 16:2228–2236

    Article  CAS  Google Scholar 

  9. Ma Y, Fan X, Li L (2016) pH-sensitive polymeric micelles formed by doxorubicin conjugated prodrugs for co-delivery of doxorubicin and paclitaxel. Carbohydrate Polym 137:19–29

    Article  CAS  Google Scholar 

  10. Akimoto J, Nakayama M, Okano T (2014) Temperature-responsive polymeric micelles for optimizing drug targeting to solid tumors. J Control Release 193:2–8

    Article  CAS  Google Scholar 

  11. Deng B, Ma P, Xie Y (2015) Reduction-sensitive polymeric nanocarriers in cancer therapy: a comprehensive review. Nanoscale 7:12773–12795

    Article  CAS  Google Scholar 

  12. Cheng R, Meng F, Deng C, Zhong Z (2015) Bioresponsive polymeric nanotherapeutics for targeted cancer chemotherapy. Nano Today 10:656–670

    Article  CAS  Google Scholar 

  13. Webb BA, Chimenti M, Jacobson MP, Barber DL (2011) Dysregulated pH: a perfect storm for cancer progression. Nat Rev Cancer 11:671–677

    Article  CAS  Google Scholar 

  14. Ulbrich K, Šubr V (2010) Structural and chemical aspects of HPMA copolymers as drug carriers. Adv Drug Deliv Rev 62:150–166

    Article  CAS  Google Scholar 

  15. Ba Y, Fukushima S, Harada A, Kataoka K (2003) Design of environment-sensitive supramolecular assemblies for intracellular drug delivery: polymeric micelles that are responsive to intracellular pH change. Angew Chem Int Ed 42:4640–4643

    Article  Google Scholar 

  16. Hu X, Liu S, Huang Y, Chen X, Jing X (2010) Biodegradable block copolymer-doxorubicin conjugates via different linkages: preparation, characterization, and in vitro evaluation. Biomacromolecules 11:2094–2102

    Article  CAS  Google Scholar 

  17. Chen W, Meng F, Cheng R, Zhong Z (2010) pH-sensitive degradable polymersomes for triggered release of anticancer drugs: a comparative study with micelles. J Control Release 142:40–46

    Article  CAS  Google Scholar 

  18. Ding C, Gu J, Qu X, Yang Z (2009) Preparation of multifunctional drug carrier for tumor-specific uptake and enhanced intracellular delivery through the conjugation of weak acid labile linker. Bioconjug Chem 20:1163–1170

    Article  CAS  Google Scholar 

  19. Gillies ER, Goodwin AP, Fréchet JMJ (2004) Acetals as pH-sensitive linkages for drug delivery. Bioconjug Chem 15:1254–1263

    Article  CAS  Google Scholar 

  20. Lu J, Li N, Xu Q, Ge J, Lu J, Xia X (2010) Acetals moiety contained pH-sensitive amphiphilic copolymer self-assembly used for drug carrier. Polymer 51:1709–1715

    Article  CAS  Google Scholar 

  21. Tang R, Ji W, Panus D, Palumbo RN, Wang C (2011) Block copolymer micelles with acid-labile ortho ester side-chains: synthesis, characterization, and enhanced drug delivery to human glioma cells. J Control Release 151:18–27

    Article  CAS  Google Scholar 

  22. Cheng J, Ji R, Gao SJ, Du F, Li Z (2012) Facile synthesis of acid-labile polymers with pendent ortho esters. Biomacromolecules 13:173–179

    Article  CAS  Google Scholar 

  23. Cao J, Su T, Zhang L, Liu R, Wang G, He B, Gu Z (2014) Polymeric micelles with citraconic amide as pH-sensitive bond in backbone for anticancer drug delivery. Int J Pharm 471:28–36

    Article  CAS  Google Scholar 

  24. Zhou L, Yu L, Ding M, Li J, Tan H (2011) Synthesis and characterization of pH-sensitive biodegradable polyurethane for potential drug delivery applications. Macromolecules 44:857–864

    Article  CAS  Google Scholar 

  25. Koutroumanis KP, Holdich RG, Georgiadou S (2013) Synthesis and micellization of a pH-sensitive diblock copolymer for drug delivery. Int J Pharm 455:5–13

    Article  CAS  Google Scholar 

  26. Xiong M, Tang L, Wang J (2011) Synthesis and properties 0f diblock copolymers of poly(ethylene glycol) and poly(2-methoxyethyl ethylene phosphate) for enhanced paclitaxel solubility. Acta Polym Sin 11:853–860

    Article  Google Scholar 

  27. Ahmad Z, Shah A, Siddiq M, Kraatz HB (2014) Polymeric micelles as drug delivery vehicles. RSC Adv 4:17028–17038

    Article  CAS  Google Scholar 

  28. Xu Z, Zhu S, Wang M, Li Y, Shi P (2014) Delivery of paclitaxel using PEGylated graphene oxide as a nanocarrier. ACS Appl Mater Interfaces 7:1355–1363

    Article  Google Scholar 

  29. Zheng H, Hua D, Bai R (2007) Controlled/living free-radical copolymerization of 4-(azidocarbonyl) phenyl methacrylate with methyl acrylate under 60Co γ-ray irradiation. Polymer Chemistry J Polym Sci 245:2609–2616

    Article  Google Scholar 

  30. Ahmad Z, Tang Z, Shah A, Zhang D, Zhang Y (2014) Cisplatin loaded methoxy poly (ethylene glycol)-block-poly (L-glutamic acid-co-L-phenylalanine) nanoparticles against human breast cancer cell. Macromol Biosci 14:1337–1345

    Article  CAS  Google Scholar 

  31. Hong BX, Ou JL, Li XF, Ye QJ, Feng CJ (2014) Preparation of doxorubicin-loading sodium alginate nanoparticles and their in vitro release. Central South Pharmacy 12:451–456

    CAS  Google Scholar 

  32. Maeda H, Matsumura Y (2011) EPR effect based drug design and clinical outlook for enhanced cancer chemotherapy. Adv Drug Deliv Rev 63:129–130

    Article  CAS  Google Scholar 

  33. Baish JW, Stylianopoulos T, Lanning RM, Kamoun WS, Fukumura D, Munn LL, Jain RK (2011) Scaling rules for diffusive drug delivery in tumor and normal tissues. Proc Natl Acad Sci U S A 108:1799–1803

    Article  CAS  Google Scholar 

  34. Engin K, Leeper DB, Cater JR, Thistlethwaite AJ, Tupchong L, McFarlane JD (1995) Extracellular ph distribution in human tumors. Int J Hypertherm 11:211–216

    Article  CAS  Google Scholar 

  35. McAuliffe G, Roberts L, Roberts S (2002) Paclitaxel administration and its effects on clinically relevant human cancer and non cancer cell lines. Biotechnol Lett 24:959–964

    Article  CAS  Google Scholar 

  36. Gagandeep S, Novikoff PM, Ott M, Gupta S (1999) Paclitaxel shows cytotoxic activity in human hepatocellular carcinoma cell lines. Cancer Lett 136:109–118

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Natural Science Foundation of China (NSFC 51375142), Research Fund for Excellent Young College Teachers of Henan Province, and a key project funded by the Education Department of Henan Province.

Author information

Author notes

  1. Shiyong Song

    Present address: Institute of Pharmacy, Henan University, North Jinming Rd, Kaifeng, 475004, China

Authors and Affiliations

  1. Institute of Pharmacy, Henan University, North Jinming Rd, Kaifeng, 475004, China

    Peilan Qi, Yongqiang Bu, Jing Xu, Benkai Qin & Shujuan Luan

Authors
  1. Peilan Qi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yongqiang Bu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jing Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Benkai Qin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shujuan Luan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shiyong Song
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shiyong Song.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Figure S1

(DOCX 143 kb)

Figure S2

(DOCX 32 kb)

Figure S3

(DOCX 36 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Qi, P., Bu, Y., Xu, J. et al. pH-responsive release of paclitaxel from hydrazone-containing biodegradable micelles. Colloid Polym Sci 295, 1–12 (2017). https://doi.org/10.1007/s00396-016-3968-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00396-016-3968-6

Keywords

Search

Navigation