Skip to main content
SpringerLink
Log in

In situ-forming and pH-responsive hydrogel based on chitosan for vaginal delivery of therapeutic agents

  • Delivery Systems
  • Original Research
  • Published:
Journal of Materials Science: Materials in Medicine Aims and scope Submit manuscript

Abstract

One of the important routes of drug administration for localized delivery of contraceptives and cervical cancer treatment agents is vaginal canal. Due to the low pH of vagina, a pH-responsive drug delivery system was developed. This hydrogel was synthesized based on a mucoadhesive biopolymer, chitosan (CS), that promotes the interaction between the hydrogel and mucosal surface of the vagina, potentially increasing the residence time of the system. This injectable hydrogel was formed via acid-labile Schiff-base linkages between free amine groups and aldehyde functionalities on modified chitosan. A novel approach was taken to add aldehyde functionalities to chitosan using a two-step reaction. Two types of slow and fast degrading hydrogels were prepared and loaded with iron (II) gluconate dihydrate, a non-hormonal spermicide, and doxorubicin hydrochloride, an anti-cancer drug. The release profiles of these drugs at different pH environments were assessed to determine the pH-dependent release mechanism. Mechanical properties, swell-ability and degradation rate of these matrices were studied. The cross-linking density of the hydrogel as well as pH changes played an important role in the characteristic of these hydrogels. The hydrogels degraded faster in lower pH, while the hydrogel with lower cross-linking density showed longer gelation time and faster degradation rate compared to the gel with higher cross-linking density. In vitro cytotoxicity assessment of these hydrogels in 48 h indicated the non-toxic effect of these hydrogels toward mesenchymal stem cells (MSCs) in the test period.

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
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Hussain A, Ahsan F. The vagina as a route for systemic drug delivery. J Control Release. 2005;103:301–13.

    Article  CAS  Google Scholar 

  2. Alexander NJ, Baker E, Kaptein M, Karck U, Miller L, Zampaglione E. Why consider vaginal drug administration? Fertil Steril. 2004;82:1–12.

    Article  Google Scholar 

  3. Machado RM, Palmeira-De-Oliveira A, Martinez-De-Oliveira J, Palmeira-De-Oliveira R. Vaginal films for drug delivery. J Pharm Sci. 2013;102:2069–81.

    Article  CAS  Google Scholar 

  4. Ensign LM, Tang BC, Wang Y-Y, Tse TA, Hoen T, Cone R, et al. Mucus-penetrating nanoparticles for vaginal drug delivery protect against herpes simplex virus. Sci. Transl. Med. 2012;4. https://doi.org/10.1126/scitranslmed.3003453.

    Article  Google Scholar 

  5. Yohe ST, Herrera VLM, Colson YL, Grinstaff MW. 3D superhydrophobic electrospun meshes as reinforcement materials for sustained local drug delivery against colorectal cancer cells. J Control Release. 2012;162:92–101.

    Article  CAS  Google Scholar 

  6. Wolinsky JB, Colson YL, Grinstaff MW. Local drug delivery strategies for cancer treatment: gels, nanoparticles, polymeric films, rods, and wafers. J Control Release. 2012;159:14–26.

    Article  CAS  Google Scholar 

  7. Harwood B, Mishell DR Jr. Contraceptive vaginal rings. Semin Reprod Med. 2001;19:381–90.

    Article  CAS  Google Scholar 

  8. Thurman AR, Clark MR, Hurlburt JA, Doncel GF. Intravaginal rings as delivery systems for microbicides and multipurpose prevention technologies. Int J Womens Health. 2013;5:695–708.

    Article  Google Scholar 

  9. Loxley A, Mitchnick M, Okoh O, McConnell J, Goldman L, Morgan C, et al. Ethylene vinyl acetate intravaginal rings for the simultaneous delivery of the antiretroviral UC781 and contraceptive levonorgestrel. Drug Deliv Transl Res. 2011;1:247–55.

    Article  CAS  Google Scholar 

  10. Malcolm RK, Forbes CJ, Geer L, Veazey RS, Goldman L, Klasse PJ, et al. Pharmacokinetics and efficacy of a vaginally administered maraviroc gel in rhesus macaques. J Antimicrob Chemother. 2013;68:678–83.

    Article  CAS  Google Scholar 

  11. Johnson TJ, Srinivasan P, Albright TH, Watson-Buckheit K, Rabe L, Martin A, et al. Safe and sustained vaginal delivery of pyrimidinedione HIV-1 inhibitors from polyurethane intravaginal rings. J Antimicrob Chemother. 2012;56:1291–9.

    Article  CAS  Google Scholar 

  12. Sitruk-Ware R, Nath A, Mishell DR. Contraception technology: past, present and future. Contraception. 2013;87:319–30.

    Article  Google Scholar 

  13. Clifford GM, Smith JS, Plummer M, Muñoz N, Franceschi S. Human papillomavirus types in invasive cervical cancer worldwide: a meta-analysis. Br J Cancer. 2003;88:63.

    Article  CAS  Google Scholar 

  14. Gupta S, Gupta MK. Possible role of nanocarriers in drug delivery against cervical cancer. Nano Rev Exp. 2017;8:1335567.

    Article  Google Scholar 

  15. Ghaemmaghami F, Behtash N, Yarandi F, Moosavi A, Modares M, Toogeh G, et al. First-line chemotherapy with 5-FU and platinum for advanced and recurrent cancer of the cervix: a phase II study. J Obstet Gynaecol. 2003;23:422–5.

    Article  CAS  Google Scholar 

  16. Robati M, Holtz D, Dunton CJ. A review of topotecan in combination chemotherapy for advanced cervical cancer. Ther Clin Risk Manag. 2008;4:213–8.

    Article  CAS  Google Scholar 

  17. Zeng X, Tao W, Mei L, Huang L, Tan C, Feng S-S. Cholic acid-functionalized nanoparticles of star-shaped PLGA-vitamin E TPGS copolymer for docetaxel delivery to cervical cancer. Biomaterials. 2013;34:6058–67.

    Article  CAS  Google Scholar 

  18. Miyamoto T, Takabe Y, Watanabe M, Terasima T. Effectiveness of a sequential combination of bleomycin and mitomycin‐C on an advanced cervical cancer. Cancer. 1978;41:403–14.

    Article  CAS  Google Scholar 

  19. Valet P, Senard JM, Devedjian JC, Planat V, Salomon R, Voisin T, et al. Characterization and distribution of alpha 2-adrenergic receptors in the human intestinal mucosa. J Clin Investig. 1993;91:2049–57.

    Article  CAS  Google Scholar 

  20. Omura GA, Hubbard J, Hatch K. Chemotherapy of cervix cancer with doxorubicin and cisplatin. A phase I pilot study of the Gynecologic Oncology Group. Am J Clin Oncol. 1985;8:347–9.

    Article  CAS  Google Scholar 

  21. Petrou I. Hormonal therapies offer females a targeted acne TX. Dermatol Times. 2007;28:2–S10, S3.

    Google Scholar 

  22. Welling LL. Psychobehavioral effects of hormonal contraceptive use. Evol Psychol. 2013;11:718–42.

    Article  Google Scholar 

  23. Smith JS, Green J, Berrington de Gonzalez A, Appleby P, Peto J, Plummer M, et al. Cervical cancer and use of hormonal contraceptives: a systematic review. Lancet. 2003;361:1159–67.

    Article  Google Scholar 

  24. Moreno V, Bosch FX, Muñoz N, Meijer CJLM, Shah KV, Walboomers JMM, et al. Effect of oral contraceptives on risk of cervical cancer in women with human papillomavirus infection: the IARC multicentric case-control study. Lancet. 2002;359:1085–92.

    Article  CAS  Google Scholar 

  25. Han YA, Singh M, Saxena BB. Development of vaginal rings for sustained release of nonhormonal contraceptives and anti-HIV agents. Contraception. 2007;76:132–8.

    Article  CAS  Google Scholar 

  26. Saxena BB, Singh M, Gospin RM, Chu CC, Ledger WJ. Efficacy of nonhormonal vaginal contraceptives from a hydrogel delivery system. Contraception. 2004;70:213–9.

    Article  CAS  Google Scholar 

  27. Jalalvandi E, Hanton LR, Moratti SC. Schiff-base based hydrogels as degradable platforms for hydrophobic drug delivery. Eur Polym J. 2017;90:13–24.

    Article  CAS  Google Scholar 

  28. Liu L, Yao W, Rao Y, Lu X, Gao J. pH-responsive carriers for oral drug delivery: challenges and opportunities of current platforms. Drug Deliv. 2017;24:569–81.

    Article  CAS  Google Scholar 

  29. Grassi G, Farra R, Caliceti P, Guarnieri G, Salmaso S, Carenza M, et al. Temperature-sensitive hydrogels. Am J Drug Deliv. 2005;3:239–51.

    Article  CAS  Google Scholar 

  30. Anseth KS, Metters AT, Bryant SJ, Martens PJ, Elisseeff JH, Bowman CN. In situ forming degradable networks and their application in tissue engineering and drug delivery. J Control Release. 2002;78:199–209.

    Article  CAS  Google Scholar 

  31. Casettari L, Vllasaliu D, Castagnino E, Stolnik S, Howdle S, Illum L. PEGylated chitosan derivatives: synthesis, characterizations and pharmaceutical applications. Progress Polym Sci. 2012;37:659–85.

    Article  CAS  Google Scholar 

  32. Deacon MP, Davis SS, White RJ, Nordman H, Carlstedt I, Errington N, et al. Are chitosan–mucin interactions specific to different regions of the stomach? Velocity ultracentrifugation offers a clue. Carbohydr Polym. 1999;38:235–8.

    Article  CAS  Google Scholar 

  33. Acarturk F. Mucoadhesive vaginal drug delivery systems. Recent Pat Drug Deliv Formul. 2009;3:193–205.

    Article  CAS  Google Scholar 

  34. Rençber S, Karavana SY, Şenyiğit ZA, Eraç B, Limoncu MH, Baloğlu E. Mucoadhesive in situ gel formulation for vaginal delivery of clotrimazole: formulation, preparation, and in vitro/in vivo evaluation. Pharm Dev Technol. 2017;22:551–61.

    Article  Google Scholar 

  35. Clarke MA, Rodriguez AC, Gage JC, Herrero R, Hildesheim A, Wacholder S, et al. A large, population-based study of age-related associations between vaginal pH and human papillomavirus infection. BMC Infect Dis. 2012;12:33.

  36. Krauss-Silva L, Almada-Horta A, Alves MB, Camacho KG, Moreira MEL, Braga A. Basic vaginal pH, bacterial vaginosis and aerobic vaginitis: prevalence in early pregnancy and risk of spontaneous preterm delivery, a prospective study in a low socioeconomic and multiethnic South American population. BMC Pregnancy Childbirth. 2014;14:107.

  37. Kato Y, Onishi H, Machida Y. N-succinyl-chitosan as a drug carrier: water-insoluble and water-soluble conjugates. Biomaterials. 2004;25:907–15.

    Article  CAS  Google Scholar 

  38. Aiping Z, Tian C, Lanhua Y, Hao W, Ping L. Synthesis and characterization of N-succinyl-chitosan and its self-assembly of nanospheres. Carbohydr Polym. 2006;66:274–9.

    Article  Google Scholar 

  39. Jalalvandi E, Hanton LR, Moratti SC. Preparation of a pH sensitive hydrogel based on dextran and polyhydrazide for release of 5-flurouracil, an anticancer drug. J Drug Deliv Sci Technol. 2018;44:146–52.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  41. Xu W, He X, Zhong M, Hu X, Xiao Y. A novel pH-responsive hydrogel based on natural polysaccharides for controlled release of protein drugs. RSC Adv. 2015;5:3157–67.

    Article  CAS  Google Scholar 

  42. Jalalvandi E, Cabral J, Hanton LR, Moratti SC. Cyclodextrin-polyhydrazine degradable gels for hydrophobic drug delivery. Mater Sci Eng C. 2016;69:144–53.

    Article  CAS  Google Scholar 

  43. Kamoun EA. N-succinyl chitosan–dialdehyde starch hybrid hydrogels for biomedical applications. J Adv Res. 2016;7:69–77.

    Article  CAS  Google Scholar 

  44. Horkay F, Han M-H, Han IS, Bang I-S, Magda JJ. Separation of the effects of pH and polymer concentration on the swelling pressure and elastic modulus of a pH-responsive hydrogel. Polymer. 2006;47:7335–8.

    Article  CAS  Google Scholar 

  45. Yang B, Li X, Shi S, Kong X, Guo G, Huang M, et al. Preparation and characterization of a novel chitosan scaffold. Carbohydr Polym. 2010;80:860–5.

    Article  CAS  Google Scholar 

  46. Yan C, Chen D, Gu J, Hu H, Zhao X, Qiao M. Preparation of N-succinyl-chitosan and their physical-chemical properties as a novel excipient. Yakugaku Zasshi. 2006;126:789–93.

    Article  CAS  Google Scholar 

  47. Bashir S, Teo YY, Naeem S, Ramesh S, Ramesh K. pH responsive N-succinyl chitosan/poly(acrylamide-co-acrylic acid) hydrogels and in vitro release of 5-fluorouracil. PLoS ONE. 2017;12:e0179250.

    Article  Google Scholar 

  48. Gipson IK. Mucins of the human endocervix. Front Biosci. 2001;6:D1245–55.

    Article  CAS  Google Scholar 

  49. Xiao N, Liang H, Lu J. Degradable and biocompatible aldehyde-functionalized glycopolymer conjugated with doxorubicinvia acid-labile Schiff base linkage for pH-triggered drug release. Soft Matter. 2011;7:10834–40.

    Article  CAS  Google Scholar 

  50. Ball C, Krogstad E, Chaowanachan T, Woodrow KA. Drug-eluting fibers for HIV-1 inhibition and contraception. PLoS ONE. 7:e49792.

    Article  CAS  Google Scholar 

  51. Hong CY, Lee MF, Lai LJ, Wang CP. Effect of lipid peroxidation on beating frequency of human sperm tail. Andrologia. 1994;26:61–5.

    Article  CAS  Google Scholar 

  52. Jones R, Mann T. Lipid peroxides in spermatozoa; formation, role of plasmalogen, and physiological significance. Proc R Soc Lond Ser B Biol Sci. 1976;193:317–33.

    Article  CAS  Google Scholar 

  53. Calamera JC, Giovenco P, Quiros MC, Brugo S, Dondero F, Nicholson RF. Effect of lipid peroxidation upon human spermatic adenosinetriphosphate (ATP). Relationship with motility, velocity and linearity of the spermatozoa. Andrologia. 1989;21:48–54.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Bailey Howe library at UVM and OCEM at Otago University for their resources.

Author information

Authors and Affiliations

  1. Department of Mechanical Engineering, College of Engineering and Mathematical Sciences, University of Vermont, Burlington, VT, 05405, USA

    Esmat Jalalvandi

  2. Department of Food Science, Centre for Bioengineering and Nanomedicine, University of Otago, Dunedin, 9054, New Zealand

    Amin Shavandi

Authors
  1. Esmat Jalalvandi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Amin Shavandi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Esmat Jalalvandi.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jalalvandi, E., Shavandi, A. In situ-forming and pH-responsive hydrogel based on chitosan for vaginal delivery of therapeutic agents. J Mater Sci: Mater Med 29, 158 (2018). https://doi.org/10.1007/s10856-018-6166-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s10856-018-6166-x

Search

Navigation