Skip to main content


Log in

Hyaluronic acid-based drug nanocarriers as a novel drug delivery system for cancer chemotherapy: A systematic review

  • Review article
  • Published:
DARU Journal of Pharmaceutical Sciences Aims and scope Submit manuscript


Chemotherapy is the most common treatment strategy for cancer patients. Nevertheless, limited drug delivery to cancer cells, intolerable toxicity, and multiple drug resistance are constant challenges of chemotherapy. Novel targeted drug delivery strategies by using nanoparticles have attracted much attention due to reducing side effects and increasing drug efficacy. Therefore, the most important outcome of this study is to answer the question of whether active targeted HA-based drug nanocarriers have a significant effect on improving drug delivery to cancer cells.

This study aimed to systematically review studies on the use of hyaluronic acid (HA)-based nanocarriers for chemotherapy drugs. The two databases MagIran and SID from Persian databases as well as international databases PubMed, WoS, Scopus, Science Direct, Embase, as well as Google Scholar were searched for human studies and cell lines and/or xenograft mice published without time limit until 2020. Keywords used to search included Nanoparticle, chemotherapy, HA, Hyaluronic acid, traditional medicine, natural medicine, chemotherapeutic drugs, natural compound, cancer treatment, and cancer. The quality of the studies was assessed by the STROBE checklist. Finally, studies consistent with inclusion criteria and with medium- to high-quality were included in the systematic review.

According to the findings of studies, active targeted HA-based drug nanocarriers showed a significant effect on improving drug delivery to cancer cells. Also, the use of lipid nanoparticles with a suitable coating of HA have been introduced as biocompatible drug carriers with high potential for targeted drug delivery to the target tissue without affecting other tissues and reducing side effects. Enhanced drug delivery, increased therapeutic efficacy, increased cytotoxicity and significant inhibition of tumor growth, as well as high potential for targeted chemotherapy are also reported to be benefits of using HA-based nanocarriers for tumors with increased expression of CD44 receptor.

Graphical abstract

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

Access this article

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

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

Data availability

Datasets are available through the corresponding author upon reasonable request.



Scientific Information Database


Medical Subject Headings


Web of Science


Preferred Reporting Items for Systematic Reviews and Meta-Analysis


Hyaluronic acid


  1. Wang H, Naghavi M, Allen C, Barber RM, Bhutta ZA, Carter A, et al. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015. The lancet. 2016;388(10053):1459–544.

    Article  Google Scholar 

  2. Zheng PP, Li J, Kros JM. Breakthroughs in modern cancer therapy and elusive cardiotoxicity: Critical research-practice gaps, challenges, and insights. Med Res Rev. 2018;38(1):325–76.

    Article  CAS  PubMed  Google Scholar 

  3. Bray F, Ferlay J, Soerjomataram I, Siegel R, Torre L, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries (vol 68, pg 394, 2018). CA-A Cancer J Clin. 2020;70(4):313.

    Article  Google Scholar 

  4. Blagosklonny MV. Target for cancer therapy: proliferating cells or stem cells. Leukemia. 2006;20(3):385–91.

    Article  CAS  PubMed  Google Scholar 

  5. Otto T, Sicinski P. Cell cycle proteins as promising targets in cancer therapy. Nat Rev Cancer. 2017;17(2):93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Visconti R, Della Monica R, Grieco D. Cell cycle checkpoint in cancer: a therapeutically targetable double-edged sword. J Exp Clin Cancer Res. 2016;35(1):1–8.

    Article  Google Scholar 

  7. Gillet J-P, Gottesman MM. Mechanisms of multidrug resistance in cancer. Multi-drug resistance in cancer. Methods Mol Biol. 2010;596:47–76.

  8. Schirrmacher V. From chemotherapy to biological therapy: A review of novel concepts to reduce the side effects of systemic cancer treatment. Int J Oncol. 2019;54(2):407–19.

    CAS  PubMed  Google Scholar 

  9. Strebhardt K, Ullrich A. Paul Ehrlich’s magic bullet concept: 100 years of progress. Nat Rev Cancer. 2008;8(6):473–80.

    Article  CAS  PubMed  Google Scholar 

  10. Zhuang Y, Deng H, Su Y, He L, Wang R, Tong G, et al. Aptamer-functionalized and backbone redox-responsive hyperbranched polymer for targeted drug delivery in cancer therapy. Biomacromol. 2016;17(6):2050–62.

    Article  CAS  Google Scholar 

  11. Wu G, Wang Z, Bian X, Du X, Wei C. Folate-modified doxorubicin-loaded nanoparticles for tumor-targeted therapy. Pharm Biol. 2014;52(8):978–82.

    Article  CAS  PubMed  Google Scholar 

  12. Qi X, Fan Y, He H, Wu Z. Hyaluronic acid-grafted polyamidoamine dendrimers enable long circulation and active tumor targeting simultaneously. Carbohyd Polym. 2015;126:231–9.

    Article  CAS  Google Scholar 

  13. Yang B, Ni X, Chen L, Zhang H, Ren P, Feng Y, et al. Honokiol-loaded polymeric nanoparticles: an active targeting drug delivery system for the treatment of nasopharyngeal carcinoma. Drug Delivery. 2017;24(1):660–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Bae Y, Kataoka K. Intelligent polymeric micelles from functional poly (ethylene glycol)-poly (amino acid) block copolymers. Adv Drug Deliv Rev. 2009;61(10):768–84.

    Article  CAS  PubMed  Google Scholar 

  15. Mashayekhi S, Rasoulpoor S, Shabani S, Esmaeilizadeh N, Serati-Nouri H, Sheervalilou R, et al. Curcumin-loaded mesoporous silica nanoparticles/nanofiber composites for supporting long-term proliferation and stemness preservation of adipose-derived stem cells. Int J Pharm. 2020;587:119656.

    Article  CAS  PubMed  Google Scholar 

  16. Chen W, Zhong P, Meng F, Cheng R, Deng C, Feijen J, et al. Redox and pH-responsive degradable micelles for dually activated intracellular anticancer drug release. J Control Release. 2013;169(3):171–9.

    Article  CAS  PubMed  Google Scholar 

  17. Kapoor A, Kumar S. Cancer stem cell: A rogue responsible for tumor development and metastasis. Indian J Cancer. 2014;51(3):282.

    Article  PubMed  Google Scholar 

  18. Sanità G, Carrese B, Lamberti A. Nanoparticle Surface Functionalization: How to Improve Biocompatibility and Cellular Internalization. Front Mol Biosci. 2020;7:587012.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Cho H-J, Yoon I-S, Yoon HY, Koo H, Jin Y-J, Ko S-H, et al. Polyethylene glycol-conjugated hyaluronic acid-ceramide self-assembled nanoparticles for targeted delivery of doxorubicin. Biomaterials. 2012;33(4):1190–200.

    Article  CAS  PubMed  Google Scholar 

  20. Zhong Y, Zhang J, Cheng R, Deng C, Meng F, Xie F, et al. Reversibly crosslinked hyaluronic acid nanoparticles for active targeting and intelligent delivery of doxorubicin to drug resistant CD44+ human breast tumor xenografts. J Control Release. 2015;205:144–54.

    Article  CAS  PubMed  Google Scholar 

  21. Yin S, Huai J, Chen X, Yang Y, Zhang X, Gan Y, et al. Intracellular delivery and antitumor effects of a redox-responsive polymeric paclitaxel conjugate based on hyaluronic acid. Acta Biomater. 2015;26:274–85.

    Article  CAS  PubMed  Google Scholar 

  22. Xiong H, Du S, Ni J, Zhou J, Yao J. Mitochondria and nuclei dual-targeted heterogeneous hydroxyapatite nanoparticles for enhancing therapeutic efficacy of doxorubicin. Biomaterials. 2016;94:70–83.

    Article  CAS  PubMed  Google Scholar 

  23. Sun B, Deng C, Meng F, Zhang J, Zhong Z. Robust, active tumor-targeting and fast bioresponsive anticancer nanotherapeutics based on natural endogenous materials. Acta Biomater. 2016;45:223–33.

    Article  CAS  PubMed  Google Scholar 

  24. Teng C, Chai Z, Yuan Z, Ren L, Lin C, Yan Z, et al. Desirable pegylation for improving tumor selectivity of hyaluronic acid-based nanoparticles via low hepatic captured, long circulation times and cd44 receptor-mediated tumor targeting. Nanomed Nanotechnol Biol Med. 2020;24:102105.

    Article  CAS  Google Scholar 

  25. Freag MS, Elnaggar YS, Abdelmonsif DA, Abdallah OY. Layer-by-layer-coated lyotropic liquid crystalline nanoparticles for active tumor targeting of rapamycin. Nanomedicine. 2016;11(22):2975–96.

    Article  CAS  PubMed  Google Scholar 

  26. Kesharwani P, Banerjee S, Padhye S, Sarkar FH, Iyer AK. Hyaluronic acid engineered nanomicelles loaded with 3, 4-difluorobenzylidene curcumin for targeted killing of CD44+ stem-like pancreatic cancer cells. Biomacromol. 2015;16(9):3042–53.

    Article  CAS  Google Scholar 

  27. Suh MS, Shen J, Kuhn LT, Burgess DJ. Layer-by-layer nanoparticle platform for cancer active targeting. Int J Pharm. 2017;517(1–2):58–66.

    Article  CAS  PubMed  Google Scholar 

  28. Lu B, Xiao F, Wang Z, Wang B, Pan Z, Zhao W, et al. Redox-sensitive Hyaluronic Acid Polymer Prodrug Nanoparticles for Enhancing Intracellular Drug Self-Delivery and Targeted Cancer Therapy. ACS Biomater Sci Eng. 2020.

  29. Mizrahy S, Goldsmith M, Leviatan-Ben-Arye S, Kisin-Finfer E, Redy O, Srinivasan S, et al. Tumor targeting profiling of hyaluronan-coated lipid based-nanoparticles. Nanoscale. 2014;6(7):3742–52.

    Article  CAS  PubMed  Google Scholar 

  30. Li J, Li M, Tian L, Qiu Y, Yu Q, Wang X, et al. Facile strategy by hyaluronic acid functional carbon dot-doxorubicin nanoparticles for CD44 targeted drug delivery and enhanced breast cancer therapy. Int J Pharmac. 2020;578:119122.

    Article  CAS  Google Scholar 

  31. Upadhyay KK, Mishra AK, Chuttani K, Kaul A, Schatz C, Le Meins J-F, et al. The in vivo behavior and antitumor activity of doxorubicin-loaded poly (γ-benzyl l-glutamate)-block-hyaluronan polymersomes in Ehrlich ascites tumor-bearing BalB/c mice. Nanomedicine: Nanotechnol Biol Med. 2012;8(1):71–80.

    Article  CAS  Google Scholar 

  32. Lu B, Xiao F, Wang Z, Wang B, Pan Z, Zhao W, et al. Redox-Sensitive Hyaluronic Acid Polymer Prodrug Nanoparticles for Enhancing Intracellular Drug Self-Delivery and Targeted Cancer Therapy. ACS Biomater Sci Eng. 2020;6(7):4106–15.

    Article  CAS  PubMed  Google Scholar 

  33. Arpicco S, Milla P, Stella B, Dosio F. Hyaluronic acid conjugates as vectors for the active targeting of drugs, genes and nanocomposites in cancer treatment. Molecules. 2014;19(3):3193–230.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Mattheolabakis G, Milane L, Singh A, Amiji MM. Hyaluronic acid targeting of CD44 for cancer therapy: from receptor biology to nanomedicine. J Drug Target. 2015;23(7–8):605–18.

    Article  CAS  PubMed  Google Scholar 

  35. Dosio F, Arpicco S, Stella B, Fattal E. Hyaluronic acid for anticancer drug and nucleic acid delivery. Adv Drug Deliv Rev. 2016;97:204–36.

    Article  CAS  PubMed  Google Scholar 

  36. Sun C-Y, Zhang B-B, Zhou J-Y. Light-activated drug release from a hyaluronic acid targeted nanoconjugate for cancer therapy. Journal of Materials Chemistry B. 2019;7(31):4843–53.

    Article  CAS  PubMed  Google Scholar 

  37. Wu P, Sun Y, Dong W, Zhou H, Guo S, Zhang L, et al. Enhanced anti-tumor efficacy of hyaluronic acid modified nanocomposites combined with sonochemotherapy against subcutaneous and metastatic breast tumors. Nanoscale. 2019;11(24):11470–83.

    Article  CAS  PubMed  Google Scholar 

  38. Bazak R, Houri M, El Achy S, Kamel S, Refaat T. Cancer active targeting by nanoparticles: a comprehensive review of literature. J Cancer Res Clin Oncol. 2015;141(5):769–84.

    Article  CAS  PubMed  Google Scholar 

  39. Liu L, Liu Y, Li J, Du G, Chen J. Microbial production of hyaluronic acid: current state, challenges, and perspectives. Microb Cell Fact. 2011;10(1):1–9.

    Article  CAS  Google Scholar 

  40. Pedrosa SS, Gama M. Hyaluronic acid and its application in nanomedicine. Carbohydrates Appl Med. 2014:55–89.

  41. Misra S, Hascall VC, Atanelishvili I, Moreno Rodriguez R, Markwald RR, Ghatak S. Utilization of glycosaminoglycans/proteoglycans as carriers for targeted therapy delivery. Int J Cell Biol. 2015;2015:537560.

  42. Huang G, Huang H. Application of hyaluronic acid as carriers in drug delivery. Drug Deliv. 2018;25(1):766–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Goodison S, Urquidi V, Tarin D. CD44 cell adhesion molecules. Molecular pathology : MP. 1999;52(4):189–96.

    Article  CAS  PubMed Central  Google Scholar 

  44. Kaya G, Rodriguez I, Jorcano JL, Vassalli P, Stamenkovic I. Selective suppression of CD44 in keratinocytes of mice bearing an antisense CD44 transgene driven by a tissue-specific promoter disrupts hyaluronate metabolism in the skin and impairs keratinocyte proliferation. Genes Dev. 1997;11(8):996–1007.

    Article  CAS  PubMed  Google Scholar 

  45. Naor D, Nedvetzki S, Golan I, Melnik L, Faitelson Y. CD44 in cancer. Crit Rev Clin Lab Sci. 2002;39(6):527–79.

    Article  CAS  PubMed  Google Scholar 

  46. Kim JH, Moon MJ, Kim DY, Heo SH, Jeong YY. Hyaluronic acid-based nanomaterials for cancer therapy. Polymers. 2018;10(10):1133.

    Article  PubMed Central  Google Scholar 

  47. Wan L, Jiao J, Cui Y, Guo J, Han N, Di D, et al. Hyaluronic acid modified mesoporous carbon nanoparticles for targeted drug delivery to CD44-overexpressing cancer cells. Nanotechnology. 2016;27(13):135102.

    Article  PubMed  Google Scholar 

  48. Nie W, Zhang B, Yan X, Su L, Wang Sh, Han G, Han D. Degraded Hyaluronic Acid-Modified Magnetic Nanoparticles. J Nanomater. 2020;2020:1–8.

    Article  CAS  Google Scholar 

  49. Yang Y, Yang Y, Xie X, Xu X, Xia X, Wang H, et al. Dual stimulus of hyperthermia and intracellular redox environment triggered release of siRNA for tumor-specific therapy. Int J Pharm. 2016;506(1–2):158–73.

    Article  CAS  PubMed  Google Scholar 

  50. Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P), , et al. elaboration and explanation. BMJ. 2015;2015:349.

    Google Scholar 

  51. Oommen OP, Garousi J, Sloff M, Varghese OP. Tailored doxorubicin-H yaluronan conjugate as a potent anticancer glyco-D rug: an alternative to prodrug approach. Macromol Biosci. 2014;14(3):327–33.

    Article  CAS  PubMed  Google Scholar 

  52. Liu Q, Li J, Pu G, Zhang F, Liu H, Zhang Y. Co-delivery of baicalein and doxorubicin by hyaluronic acid decorated nanostructured lipid carriers for breast cancer therapy. Drug Delivery. 2016;23(4):1364–8.

    Article  CAS  PubMed  Google Scholar 

  53. Zhang B, Zhang Y, Yu D. Lung cancer gene therapy: Transferrin and hyaluronic acid dual ligand-decorated novel lipid carriers for targeted gene delivery. Oncol Rep. 2017;37(2):937–44.

    Article  CAS  PubMed  Google Scholar 

Download references


by the Student Research Committee of Kermanshah University of Medical Sciences.


Not applicable.

Author information

Authors and Affiliations



SHR and NS and KM contributed to the design. MM and EV and FA and MJ prepared the manuscript. SD and SHR assisted in designing the study, and helped in the, interpretation of the study. All authors have read and approved the content of the manuscript.

Corresponding author

Correspondence to Masoud Mohammadi.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no conflict of interest.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Salari, N., Mansouri, K., Valipour, E. et al. Hyaluronic acid-based drug nanocarriers as a novel drug delivery system for cancer chemotherapy: A systematic review. DARU J Pharm Sci 29, 439–447 (2021).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: