Skip to main content
SpringerLink
Log in

Acid-activatable doxorubicin prodrug micelles with folate-targeted and ultra-high drug loading features for efficient antitumor drug delivery

  • Biomaterials
  • Published:
Journal of Materials Science Aims and scope Submit manuscript

Abstract

Stimuli-responsive nanomedicine shows high therapeutic effects and low side effects to tumor cells and tissues, representing a preferable therapeutics for cancer therapy. Herein, we design an acid-stimuli-responsive doxorubicin polymeric prodrug (OM@DOX), and this amphiphilic prodrug has a unique chemical structure with prominent advantages, including high drug loading rate (as high as 61.5 wt%), pH-triggered drug release and targeted access to cells. This smart polymeric prodrug has a preferable size of ~40 nm and strong micellar stability in aqueous solution, which is benefited to the long blood circulation and efficient extravasation from tumor vessel. Moreover, the prodrug micelles showed a higher cytotoxicity against tumor cells (HeLa cells) than normal cells (L929 cells), likely suggesting the potential tumor-specific targeting ability. To render this prodrug micelles with targeting function, folic acid (FA) molecules conjugated prodrug (FA-OM@DOX) further showed selectively higher cytotoxicity to KB tumor cells (FA-receptor-positive) than A549 tumor cells (FA-receptor-negative). Considering the rapidly cell-penetrating ability and aforementioned features, we believe that the present prodrug strategy has the potential as a promising nanomedicine and providing inspired insights to design multifunctional drug delivery nanoplatforms.

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

Scheme1
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
Figure 10

Similar content being viewed by others

References

  1. Chen W, Zheng R, Zeng H, Zhang S (2015) Epidemiology of lung cancer in China. Thorac Cancer 6:209–215

    Article  Google Scholar 

  2. Tibbitt M, Dahlman J, Langer R (2016) Emerging frontiers in drug delivery. J Am Chem Soc 3:704–717

    Article  Google Scholar 

  3. Blum A, Kammeyer J, Rush A, Callmann C, Hahn M, Gianneschi N (2015) Stimuli-responsive nanomaterials for biomedical applications. J Am Chem Soc 137:2140–2154

    Article  Google Scholar 

  4. Ban Q, Bai T, Duan X, Kong J (2017) Noninvasive photothermal cancer therapy nanoplatforms via integrating nanomaterials and functional polymers. Biomater Sci 5:190–210

    Article  Google Scholar 

  5. Xu Z, Ma X, Gao Y, Hou M, Xue P, Li C, Kang Y (2017) Multifunctional silica nanoparticles as a promising theranostic platform for biomedical applications. Mater Chem Front 1:1257–1272

    Article  Google Scholar 

  6. Holohan C, Van Schaeybroeck S, Longley D, Johnston P (2013) Cancer drug resistance: an evolving paradigm. Nat Rev Cancer 13:714–726

    Article  Google Scholar 

  7. Mahmoudi M, Hofmann H, Rothen-Rutishauser B, Petri-Fink A (2012) Assessing the in vitro and in vivo toxicity of superparamagnetic iron oxide nanoparticles. Chem Rev 112:2323–2338

    Article  Google Scholar 

  8. Chen G, Qiu H, Prasad P, Chen X (2014) Upconversion nanoparticles: design, nanochemistry, and applications in theranostics. Chem Rev 114:5161–5214

    Article  Google Scholar 

  9. Tibbitt M, Dahlman J, Langer R (2016) Emerging frontiers in drug delivery. J Am Chem Soc 138:704–717

    Article  Google Scholar 

  10. Lu Y, Aimetti A, Langer R, Gu Z (2016) Bioresponsive materials. Nat Rev Mater 2:16075

    Article  Google Scholar 

  11. Kluza E, Jacobs I, Hectors S, Mayo K, Griffioen A, Strijkers G, Nicolay K (2012) Dual-targeting of αvβ3 and galectin-1 improves the specificity of paramagnetic/fluorescent liposomes to tumor endothelium in vivo. J Control Release 158:207–214

    Article  Google Scholar 

  12. Pattni B, Chupin V, Torchilin V (2015) New developments in liposomal drug delivery. Chem Rev 115:10938–10966

    Article  Google Scholar 

  13. Du J, Tang Y, Lewis A, Armes S (2011) Tailor-made dual pH-sensitive polymer-doxorubicin nanoparticles for efficient anticancer drug delivery. J Am Chem Soc 133:17560–17563

    Article  Google Scholar 

  14. Wang Y, Wang J, Han H, Liu J, Zhao H, Shen M, Xu Y, Xu J, Li L, Guo X (2016) Self-assembled micelles of N-phthaloylchitosan-g-poly (N-vinylcaprolactam) for temperature-triggered non-steroidal anti-inflammatory drug delivery. J Mater Sci 51:1591–1599. doi:10.1007/s10853-015-9482-2

    Article  Google Scholar 

  15. Lu S, Neoh K, Huang C, Shi Z, Kang E (2013) Polyacrylamide hybrid nanogels for targeted cancer chemotherapy via co-delivery of gold nanoparticles and MTX. J Colloid Interface Sci 412:46–55

    Article  Google Scholar 

  16. Yang C, Huang S, Wang X, Wang M (2016) Theranostic unimolecular micelles of highly fluorescent conjugated polymer bottlebrushes for far red/near infrared bioimaging and efficient anticancer drug delivery. Polym Chem 7:7455–7468

    Article  Google Scholar 

  17. Xu Z, Liu S, Liu H, Yang C, Kang Y, Wang M (2015) Unimolecular micelles of amphiphilic cyclodextrin-core star-like block copolymers for anticancer drug delivery. Chem Commun 51:15768–15771

    Article  Google Scholar 

  18. Wang C, Wei H, Tan N, Boydston A, Pun S (2016) Sunflower polymers for folate-mediated drug delivery. Biomacromolecules 17:69–75

    Article  Google Scholar 

  19. Zhang S, Xu J, Chen H, Song Z, Wu Y, Dai X, Kong J (2017) Acid-cleavable unimolecular micelles from amphiphilic star copolymers for triggered release of anticancer drugs. Macromol Biosci 17:1600258

    Article  Google Scholar 

  20. Chen F, Chen H, Duan X, Jia J, Kong J (2016) Molecularly imprinted polymers synthesized using reduction-cleavable hyperbranched polymers for doxorubicin hydrochloride with enhanced loading properties and controlled release. J Mater Sci 51:9367–9383. doi:10.1007/s10853-016-0183-2

    Article  Google Scholar 

  21. Duan X, Wu Y, Ma M, Du J, Zhang S, Chen H, Kong J (2017) Amphiphilic polymer–drug conjugates based on acid-sensitive 100% hyperbranched polyacetals for cancer therapy. J Mater Sci 52:9430–9440. doi:10.1007/s10853-017-1135-1

    Article  Google Scholar 

  22. Xu Z, Xue P, Gao Y, Liu S, Shi X, Hou M, Kang Y (2017) pH-responsive polymeric micelles based on poly(ethyleneglycol)-b-poly(2-(diisopropylamino) ethyl methacrylate) block copolymer for enhanced intracellular release of anticancer drugs. J Colloid Interface Sci 490:511–519

    Article  Google Scholar 

  23. Bui D, Maksimenko A, Desmaele D, Harrisson S, Vauthier C, Couvreur P, Nicolas J (2013) Polymer prodrug nanoparticles based on naturally occurring isoprenoid for anticancer therapy. Biomacromolecules 14:2837–2847

    Article  Google Scholar 

  24. Wang H, Sun D, Zhao N, Yang X, Shi Y, Li J, Su Z, Wei G (2014) Fabrication of alginate–gelatin crosslinked hydrogel microcapsules and evaluation of the microstructure and physico-chemical properties. J Mater Chem B 2:1362–1370

    Article  Google Scholar 

  25. Li H, Du J, Du X, Xu C, Sun C, Wang H, Cao Z, Yang X, Zhu Y, Nie S, Wang J (2016) Stimuli-responsive clustered nanoparticles for improved tumor penetration and therapeutic efficacy. Proc Natl Acad Sci USA 113:4164–4169

    Article  Google Scholar 

  26. Liow S, Dou Q, Kai D, Li C, Sugiarto S, Yu C, Kwok R, Chen X, Wu Y, Ong S, Kizhakeyil A, Verm N, Tang B, Loh X (2016) Long-term real-time in vivo drug release monitoring with AIE thermogelling polymer. Small 13:1603404

    Article  Google Scholar 

  27. Zhan F, Chen W, Wang Z, Lu W, Cheng R, Deng C, Meng F, Liu H, Zhong Z (2011) Acid-activatable prodrug nanogels for efficient intracellular doxorubicin release. Biomacromolecules 12:3612–3620

    Article  Google Scholar 

  28. Xu Z, Zhang K, Hou L, Wang D, Liu Y, Guan J, Zhang Y, Zhang H (2014) A novel nanoassembled doxorubicin prodrug with a high drug loading for anticancer drug delivery. J Mater Chem B 2:3433–3437

    Article  Google Scholar 

  29. Xu X, Wu J, Liu Y, Yu M, Zhao L, Zhu X, Bhasin S, Li Q, Ha E, Shi J, Farokhzad O (2016) Ultra-pH-responsive and tumor-penetrating nanoplatform for targeted siRNA delivery with robust anti-cancer efficacy. Angew Chem Int Ed 55:7091–7094

    Article  Google Scholar 

  30. Shi X, Ma X, Hou M, Gao Y, Bai S, Xiao B, Xue P, Kang Y, Xu Z, Li C (2017) pH-responsive unimolecular micelles based on amphiphilic star-like copolymer with high drug loading for effective drug delivery and cellular imaging. J Mater Chem B 5:6847–6859

    Article  Google Scholar 

  31. Hu X, Liu G, Li Y, Wang X, Liu S (2015) Cell-penetrating hyperbranched polyprodrug amphiphiles for synergistic reductive milieu-triggered drug release and enhanced magnetic resonance signals. J Am Chem Soc 137:362–368

    Article  Google Scholar 

  32. Xu Z, Liu Y, Kang J, Wang F (2015) Glutathione- and pH-responsive nonporous silica prodrug nanoparticles for controlled release and cancer therapy. Nanoscale 7:5859–5868

    Article  Google Scholar 

  33. Zhang X, Liu K, Huang Y, Xu J, Li J, Ma X, Li S (2014) Reduction-sensitive dual functional nanomicelles for improved delivery of paclitaxel. Bioconjug Chem 25:1689–1696

    Article  Google Scholar 

  34. Li Y, Xiao K, Zhu W, Deng W, Lam K (2014) Stimuli-responsive cross-linked micelles for on-demand drug delivery against cancers. Adv Drug Deliv Rev 66:58–73

    Article  Google Scholar 

  35. Duan X, Chen H, Fan L, Kong J (2016) Drug self-assembled delivery system with dual responsiveness for cancer chemotherapy. ACS Biomater Sci Eng 2:2347–2354

    Article  Google Scholar 

  36. Debbage P (2009) Targeted drugs and nanomedicine: present and future. Curr Pharm Des 15:153–172

    Article  Google Scholar 

  37. Li R, Feng F, Wang Y, Yang X, Yang X (2014) Folic acid-conjugated pH/temperature/redox multi-stimuli responsive polymer microspheres for delivery of anti-cancer drug. J Colloid Interface Sci 429:34–44

    Article  Google Scholar 

  38. Liu H, Xu Y, Wen S, Chen Q, Zheng L, Shen M, Zhao J, Zhang G, Shi X (2013) Targeted tumor computed tomography imaging using low-generation dendrimer-stabilized gold nanoparticles. Chem Eur J 19:6409–6416

    Article  Google Scholar 

  39. Xu Z, Hou M, Shi X, Gao Y, Xue P, Liu S, Kang Y (2017) Rapidly cell-penetrating and reductive milieu-responsive nanoaggregates assembled from an amphiphilic folate-camptothecin prodrug for enhanced drug delivery and controlled release. Biomater Sci 3:444–454

    Article  Google Scholar 

  40. Ross J, Chaudhuri P, Ratnam M (1994) Differential regulation of folate receptor isoforms in normal and malignant tissues in vivo and in established cell lines: physiological and clinical implications. Cancer 73:2432–2443

    Article  Google Scholar 

  41. Kang M, Yoo H, Kwon Y, Yoon H, Lee S, Kim S, Yeom D, Kang M, Choi Y (2015) Design of multifunctional liposomal nanocarriers for folate receptor-specific intracellular drug delivery. Mol Pharm 12:4200–4213

    Article  Google Scholar 

  42. Guo X, Shi C, Wang J, Di S, Zhou S (2013) pH-triggered intracellular release from actively targeting polymer micelles. Biomaterials 34:4544–4554

    Article  Google Scholar 

  43. Chen Y, Cao W, Zhou J, Pidhatika B, Xiong B, Huang L, Tian Q, Shu Y, Wen W, Hsing I, Wu H (2015) Poly(l-lysine)-graft-folic acid-coupled poly(2-methyl-2-oxazoline) (PLL-g-PMOXA-c-FA): a bioactive copolymer for specific targeting to folate receptor-positive cancer cells. ACS Appl Mater Interfaces 7:2919–2930

    Article  Google Scholar 

  44. Lu J, Zhao W, Huang Y, Liu H, Marquez R, Gibbs R, Li J, Venkataramanan R, Xu L, Li S (2014) Targeted delivery of doxorubicin by folic acid-decorated dual functional nanocarrier. Mol Pharm 11:4164–4178

    Article  Google Scholar 

  45. Wang H, Xu F, Li D, Liu X, Jin Q, Ji J (2013) Bioinspired phospholipid polymer prodrug as a pH responsive drug delivery system for cancer therapy. Polym Chem 4:2004–2010

    Article  Google Scholar 

  46. Xu Z, Wang D, Xu S, Liu 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

    Article  Google Scholar 

  47. Xu J, Tian K, Zhao X, Zhou T, Pei M, Liu P (2016) Fluorescent amphiphilic copolymer-based tumor theranostics for facile DOX-loading and tumor microenvironment-triggered release. Mater Des 105:333–340

    Article  Google Scholar 

  48. Zhang Y, Sun Y, Xu X, Zhu H, Huang L, Zhang X, Qi Y, Shen Y (2010) Radiosynthesis and micro-SPECT imaging of 99mTc-dendrimer poly(amido)-amine folic acid conjugate. Bioorg Med Chem Lett 20:927–931

    Article  Google Scholar 

  49. Xu Z, Shi X, Hou M, Xue P, Gao Y, Liu S, Kang Y (2017) Disassembly of amphiphilic small molecular prodrug with fluorescence switch induced by pH and folic acid receptors for targeted delivery and controlled release. Colloid Surf B 150:50–58

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported by a star-up Grant (SWU115058, SWU115059), Fundamental Research Funds for Central Universities from Southwest University (XDJK2016A010) and Chongqing Research Program of Basic Research and Frontier Technology (cstc2016jcyjA0078) and National Natural Science Foundation of China (51703187, 31671037, 21602073).

Author information

Authors and Affiliations

  1. Institute for Clean Energy and Advanced Materials, Faculty of Materials and Energy, Southwest University, Chongqing, 400715, People’s Republic of China

    Xiaoqian Ma, Xiaoxiao Shi, Shuang Bai, Yong-E Gao, Meili Hou & Zhigang Xu

  2. Department of Chemistry, Huaibei Normal University, Huaibei, Anhui, 235000, People’s Republic of China

    Man-Yi Han

  3. Chongqing Engineering Research Centre for Micro-Nano Biomedical Materials and Devices, Chongqing, 400715, People’s Republic of China

    Xiaoqian Ma, Xiaoxiao Shi, Shuang Bai, Yong-E Gao, Meili Hou & Zhigang Xu

Authors
  1. Xiaoqian Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaoxiao Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shuang Bai
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yong-E Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Meili Hou
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Man-Yi Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Zhigang Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zhigang Xu.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 3218 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ma, X., Shi, X., Bai, S. et al. Acid-activatable doxorubicin prodrug micelles with folate-targeted and ultra-high drug loading features for efficient antitumor drug delivery. J Mater Sci 53, 892–907 (2018). https://doi.org/10.1007/s10853-017-1546-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10853-017-1546-z

Keywords

Search

Navigation