Polymer Bulletin

, Volume 76, Issue 6, pp 2945–2963 | Cite as

Guar gum–poly(N-isopropylacrylamide) smart hydrogels for sustained delivery of 5-fluorouracil

  • Subhraseema Das
  • Usharani SubuddhiEmail author
Original Paper


Smart hydrogels comprising guar gum (GG) and poly(N-isopropylacrylamide) (PNIPAAm) cross-linked using a non-toxic cross-linker, tetraethyl orthosilicate, have been designed to explore the sustained release of an anticancer drug, 5-fluorouracil (5FU). Hydrogels containing preformed solid inclusion complexes (IC) of 5FU in β-cyclodextrin (β-CD) were designed to regulate the drug delivery. The formation of true 5FU/β-CD ICs was affirmed from different spectroscopic techniques. The DSC studies of the hydrogels revealed that the thermosensitivity of PNIPAAm is retained in the resultant hydrogels, also corroborated from the swelling measurements. The rate of 5FU release from the hydrogels containing the IC was significantly prolonged in comparison with those containing the free drug. Higher amounts of GG in the matrix led to slower release of drug. The preliminary kinetics of drug release indicated the collective influence of β-CD and GG content on the polymer relaxation process which was key in sustaining the drug delivery. Release studies in simulated gastric (SGF) and intestinal (SIF) fluids showed less than 10% of 5FU release during the initial 2 h in SGF and an increased release in SIF. Thus, the developed smart hydrogels can be utilized as potential candidates for sustained oral delivery of 5FU to the intestine.


Guar gum PNIPAAm Cyclodextrin 5-Fluorouracil Controlled drug delivery 



The authors thank the Department of Science and Technology, India, through the DST Fast Track Young Scientist Scheme (SR/FT/CS-76/2010) for the financial assistance.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

289_2018_2526_MOESM1_ESM.docx (568 kb)
Supplementary material 1 (DOCX 568 kb)


  1. 1.
    Qiu Y, Park K (2001) Environment-sensitive hydrogels in drug delivery. Adv Drug Deliv Rev 53:321–339CrossRefGoogle Scholar
  2. 2.
    Muniz EC, Geuskens G (2001) Compressive elastic modulus of polyacrylamide hydrogels and semi-IPNs with poly (N-isopropylacrylamide). Macromolecules 43:4480–4484CrossRefGoogle Scholar
  3. 3.
    Xiao F, Chen L, Xing RF, Zhao YP, Dong J, Guo G, Zhang R (2009) In vitro cytocompatibility and cell detachment of temperature-sensitive dextran hydrogel. Colloid Surf B Biointerface 71:13–18CrossRefGoogle Scholar
  4. 4.
    Sinha VR, Kumria R (2008) Polysaccharides in colon-specific drug delivery. Int J Pharm 224:19–38CrossRefGoogle Scholar
  5. 5.
    Shukla RK, Tiwari A (2012) Carbohydrate polymers: applications and recent advances in delivering drugs to the colon. Carbohydr Polym 88:399–416CrossRefGoogle Scholar
  6. 6.
    Sharma K, Kaith BS, Kalia S, Kumar V, Swart HC (2015) Gum-ghatti based biodegradable and conductive carriers for colon-specific drug delivery. Colloid Polym Sci 293:1181–1190CrossRefGoogle Scholar
  7. 7.
    Prabaharan M (2011) Prospective of guar gum and its derivatives as controlled drug delivery systems. Int J Biol Macromol 49:117–124CrossRefGoogle Scholar
  8. 8.
    Aminabhavi TM, Nadagouda MN, Joshi SD, More UA (2014) Guar gum as platform for the oral controlled release of therapeutics. Expert Opin Drug Deliv 11:753–766CrossRefGoogle Scholar
  9. 9.
    Mudgil D, Barak S, Khatkar BS (2014) Guar gum: processing, properties and food applications—a review. J Food Sci Technol 51:409–418CrossRefGoogle Scholar
  10. 10.
    Sen G, Mishra S, Jha U, Pal S (2010) Microwave initiated synthesis of polyacrylamide grafted guar gum—characterizations and applications as matrix for controlled release of 5-amino salicylic acid. Int J Biol Macromol 47:164–170CrossRefGoogle Scholar
  11. 11.
    Sharma S, Kaur J, Sharma G, Thakur KK, Chauhan GS, Chauhan K (2013) Preparation and characterization of pH-responsive guar gum microspheres. Int J Biol Macromol 62:636–641CrossRefGoogle Scholar
  12. 12.
    Li X, Wu W, Liu W (2008) Synthesis and properties of thermo-responsive guar gum/poly (N-isopropylacrylamide) interpenetrating polymer network hydrogels. Carbohydr Polym 71:394–402CrossRefGoogle Scholar
  13. 13.
    Lang YY, Li SM, Pan WS, Zheng LY (2006) Thermo- and pH-sensitive drug delivery from hydrogels constructed using block copolymers of poly (N-isopropylacrylamide) and guar gum. J Drug Deliv Sci Technol 16:65–69CrossRefGoogle Scholar
  14. 14.
    Bahaddi Y, Lelievre F, Gareil P, Maignan J, Galons H (1997) Preparation and complexation ability of zwitterionic derivatives of cyclodextrins. Carbohydr Res 303:229–232CrossRefGoogle Scholar
  15. 15.
    Syed TA, Qureshi ZA, Ahman SA, Ali SM (2000) Management of intravaginal warts in women with 5-fluorouracil (1%) in vaginal hydrophilic gel: a placebo-controlled double-blind study. Int J STD AIDS 11:371–374CrossRefGoogle Scholar
  16. 16.
    Jin L, Liu Q, Sun Z, Ni X, Wei M (2010) Preparation of 5-fluorouracil/β-cyclodextrin complex intercalated in layered double hydroxide and the controlled drug release properties. Ind Eng Chem Res 49:11176–11181CrossRefGoogle Scholar
  17. 17.
    Diasio RB, Harris BE (1989) Clinical pharmacology of 5-fluorouracil. Clin Pharm 16:215–237CrossRefGoogle Scholar
  18. 18.
    Bilensoy E, Cirpanli Y, Sen M, Dogan AL, Calis S (2007) Thermosensitive mucoadhesive gel formulation loaded with 5-Fu: cyclodextrin complex for HPV-induced cervical cancer. J Incl Phenom Macrocycl Chem 57:363–370CrossRefGoogle Scholar
  19. 19.
    Bilensoy E, Moroy P, Cirpanli Y, Bilensoy T, Dogan AL, Calis S, Mollamahmutoglu LA (2011) A double-blind placebo-controlled study of 5-fluorouracil: cyclodextrin complex loaded thermosensitive gel for the treatment of HPV induced condyloma. J Incl Phenom Macrocycl Chem 69:309–313CrossRefGoogle Scholar
  20. 20.
    Watson C, Vine KL, Locke JM, Bezos A, Parish CR, Ranso M (2013) The antiangiogenic properties of sulfated β-cyclodextrins in anticancer formulations incorporating 5-fluorouracil. Anticancer Drugs 24:704–714CrossRefGoogle Scholar
  21. 21.
    Bibby DC, Davies NM, Tucker IG (2000) Mechanisms by which cyclodextrins modify drug release from polymeric drug delivery systems. Int J Pharm 197:1–11CrossRefGoogle Scholar
  22. 22.
    Das S, Subuddhi U (2013) Cyclodextrin mediated controlled release of naproxen from pH-sensitive chitosan/poly (vinyl alcohol) hydrogels for colon targeted delivery. Ind Eng Chem Res 52:14192–14200CrossRefGoogle Scholar
  23. 23.
    Das S, Subuddhi U (2014) Exploring poly(vinyl alcohol) hydrogels containing drug–cyclodextrin complexes as controlled drug delivery systems. J Appl Polym Sci 131:40318 (1-13)Google Scholar
  24. 24.
    Das S, Subuddhi U (2014) Controlled delivery of dexamethasone to the intestine from poly (vinyl alcohol)–poly (acrylic acid) microspheres containing drug-cyclodextrin complexes: influence of method of preparation of inclusion complex. RSC Adv 4:24222–24231CrossRefGoogle Scholar
  25. 25.
    Huang WJ, Lee WF (2009) Effects of silane couplings agents on swelling behaviours and mechanical properties of thermo-sensitive hybrid gels. J Appl Polym Sci 111:2025–2034CrossRefGoogle Scholar
  26. 26.
    Huang WJ, Lee WF (2010) Effects of TEOS contents on swelling behaviours and mechanical properties of thermo-sensitive hybrid gels. Polym Compos 31:887–896CrossRefGoogle Scholar
  27. 27.
    Rasool N, Yasin T, Heng JYY, Akhter Z (2010) Synthesis and characterization of novel pH-, ionic strength and temperature-sensitive hydrogel for insulin delivery. Polymer 51:1687–1693CrossRefGoogle Scholar
  28. 28.
    Jumel K, Harding SE, Mitchell JR (1996) Effect of gamma irradiation on the macromolecular integrity of guar gum. Carbohydr Res 282:223–236CrossRefGoogle Scholar
  29. 29.
    Saurabh CK, Gupta S, Bahadur J, Mazumdar S, Variyar PS, Sharma A (2013) Mechanical and barrier properties of guar gum based nano-composite films. Carbohydr Polym 98:1610–1617CrossRefGoogle Scholar
  30. 30.
    Eid EEM, Abdul AB, Suliman FEO, Sukari MA, Rasedee A, Fatah SS (2011) Characterization of the inclusion complex of zerumbone with hydroxypropyl-β-cyclodextrin. Carbohydr Polym 83:1707–1714CrossRefGoogle Scholar
  31. 31.
    Kim JW, Suh KD (1998) Amphiphilic urethane acrylate hydrogels having heterophasic gel structure: swelling behaviours and mechanical properties. Colloid Polym Sci 276:342–348CrossRefGoogle Scholar
  32. 32.
    Serra L, Domenech J, Peppas NA (2006) Drug transport mechanisms and release kinetics from molecularly designed poly (acrylic acid-g-ethylene glycol) hydrogels. Biomaterials 27:5440–5451CrossRefGoogle Scholar
  33. 33.
    Higuchi T (1963) Mechanism of sustained action medication. Theoretical analysis of rate of release of solid drugs dispersed in solid matrices. J Pharm Sci 52:1145–1149CrossRefGoogle Scholar
  34. 34.
    Ritger PL, Peppas NA (1987) A simple equation for description of solute release. II. Fickian and anomalous release from swellable devices. J Controll Release 5:37–42CrossRefGoogle Scholar
  35. 35.
    Peppas NA, Sahlin JJ (1989) A simple equation for description of solute release. III. Coupling of diffusion and relaxation. Int J Pharm 57:169–172CrossRefGoogle Scholar
  36. 36.
    Cascone S (2017) Modelling and comparison of release profiles: effect of the dissolution method. Eur J Pharm Sci 106:352–361CrossRefGoogle Scholar
  37. 37.
    Yamaoka K, Nakagawa T, Uno T (1978) Application of Akaike Information Criterion (AIC) in the evaluation of linear pharmacokinetic equations. J Pharmacokinet Biopharm 6:165–175CrossRefGoogle Scholar
  38. 38.
    Cheddadi M, Lopez-Cabarcos E, Slowing K, Barcia E, Fernandez-Carballido A (2011) Cytotoxicity and biocompatibility evaluation of a poly (magnesium acrylate) hydrogel synthesized for drug delivery. Int J Pharm 413:126–133CrossRefGoogle Scholar
  39. 39.
    Islam A, Yasin T, Bano I, Riaz M (2012) Controlled release of aspirin from pH-sensitive chitosan/poly (vinyl alcohol) hydrogel. J Appl Polym Sci 124:4184–4192CrossRefGoogle Scholar
  40. 40.
    Han J, Wang K, Yang D, Nie J (2009) Photopolymerization of methacrylated chitosan/PNIPAAm hybrid dual-sensitive hydrogels as carrier for drug delivery. Int J Biol Macromol 44:229–235CrossRefGoogle Scholar
  41. 41.
    Zhang X, Zheng S, Lin Z, Tan S (2012) Preparation of guar gum bonded with β-cyclodextrin microspheres and the absorption on basic fuchsine. J Appl Polym Sci 123:2250–2256CrossRefGoogle Scholar
  42. 42.
    Kajjari PB, Manjeshwar LS, Aminabhavi TM (2012) Novel pH- and temperature-responsive blend hydrogel microspheres of sodium alginate and PNIPAAm-g-GG for controlled release of isoniazid. AAPS PharmSciTech 13:1147–1157CrossRefGoogle Scholar
  43. 43.
    Otake K, Inomata H, Konno M, Saito S (1990) Thermal analysis of the volume phase transition with N-isopropylacrylamide gels. Macromolecules 23:283–289CrossRefGoogle Scholar
  44. 44.
    Wenceslau AC, dos Santos FG, Ramos ERF, Nakamura CV, Rubira AF, Muniz EC (2012) Thermo- and pH-sensitive IPN hydrogels based on PNIPAM and PVA-Ma networks with LCST tailored close to human body temperature. Mater Sci Eng C 32:1259–1265CrossRefGoogle Scholar
  45. 45.
    Reddy KM, Babu VR, Rao KSVK, Subha MCS, Rao KC, Sairam M, Aminabhavi TM (2008) Temperature sensitive semi-IPN microspheres from sodium alginate and N-isopropylacrylamide for controlled release of 5-Fluorouracil. J Appl Polym Sci 107:2820–2829CrossRefGoogle Scholar
  46. 46.
    Varaprasad K, Ravindra S, Reddy NN, Vimala K, Raju KM (2010) Design and development of temperature-sensitive porous poly(NIPAAm-AMPS) hydrogels for drug release of doxorubicin—a cancer chemotherapy drug. J Appl Polym Sci 116:3593–3602Google Scholar
  47. 47.
    Mundargi RC, Shelke NB, Babu VR, Patel P, Rangaswamy V, Aminbhavi TM (2010) Novel thermo-responsive semi-interpenetrating network microspheres of gellan gum-PNIPAAm for controlled release of atenolol. J Appl Polym Sci 116:1832–1841Google Scholar
  48. 48.
    Zeitoun AA, Dib JG, Mroueh M (2003) A comparative single-dose bioequivalence study of two enteric coated aspirin brands among healthy volunteers. J Appl Res 3(3):242–248Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of ChemistryNational Institute of TechnologyRourkelaIndia

Personalised recommendations