Environmental Chemistry Letters

, Volume 17, Issue 3, pp 1209–1223 | Cite as

Drug delivery systems using pullulan, a biocompatible polysaccharide produced by fungal fermentation of starch

  • Anca Giorgiana GrigorasEmail author


Advanced drug delivery systems are now designed with biodegradable, biocompatible and non-toxic materials such as polysaccharides. Pullulan is a polysaccharide consisting of maltotriose units. Pullulan is produced from starch by the fungus Aureobasidium pullulans. Pullulan and derivatives are able to conjugate or complex with hydrophobic drugs. Scientists are optimizing the physical interactions and hydrophilic–hydrophobic balance to create systems with controlled loading and targeted delivery of the drugs to cancer cells or liver cell receptors. This article reviews pullulan-based systems of various therapeutic properties. Pullulan structure can be easily modified to transfer various drugs. Pullulan can form microparticles, nanoparticles, micelles, films and hydrogels. Therapeutic properties include antibacterial, antifungal, antitumor, anti-inflammatory, immunomodulatory, antioxidant, antiglycemic, antilipidemic, bone regenerator and systemic protective role. The medical suitability of pullulan-based drug carriers is confirmed by profiles of drug release and cytotoxicity tests carried out in vivo or in vitro.


Pullulan Drug delivery systems Pharmaceutical formulations Therapeutic properties Antimicrobial Antitumor 



  1. Bae YH, Park K (2011) Targeted drug delivery to tumors: myths, reality and possibility. J Control Release 153:198–205. CrossRefGoogle Scholar
  2. Bishwambhar M, Vuppu S (2012) Release study of naproxen, a modern drug from pH sensitive pullulan acetate microsphere. Int J Drug Dev Res 4:184–191Google Scholar
  3. Bowman SM, Free SJ (2006) The structure and synthesis of the fungal cell wall. Bioassays 28:799–808. CrossRefGoogle Scholar
  4. Chen L, Wang X, Ji F, Bao Y, Wang J, Wang X, Guo L, Li Y (2015) New bifunctional-pullulan-based micelles with good biocompatibility for efficient co-delivery of cancer-suppressing p53 gene and doxorubicin to cancer cells. RSC Adv 5:94719–94731. CrossRefGoogle Scholar
  5. Cheng K-C, Demirci A, Catchmark JM (2011) Pullulan: biosynthesis, production, and applications. Appl Microbiol Biotechnol 92:29–44. CrossRefGoogle Scholar
  6. Choi JM, Lee B, Jeong D, Park KH, Choi E-J, Jeon Y-J, Dindulkar SD, Cho E, Do SH, Lee K, Lee I-S, Park S, Jun B-H, Yu J-H, Jung S (2017) Characterization and regulated naproxen release of hydroxypropyl cyclosophoraose-pullulan microspheres. J Ind Eng Chem 48:108–118. CrossRefGoogle Scholar
  7. Constantin M, Bucatariu S, Stoica I, Fundueanu G (2017) Smart nanoparticles based on pullulan-g-poly(N-isopropylacrylamide) for controlled delivery of indomethacin. Int J Biol Macromol 94:698–708. CrossRefGoogle Scholar
  8. Cristescu R, Popescu C, Popescu AC, Socol G, Mihailescu I, Caraene G, Albulescu R, Buruiana T, Chrisey D (2012) Pulsed laser processing of functionalized polysaccharides for controlled release drug delivery systems: Functionalized polysaccharides processed for drug delivery. In: Vaseashta A (ed) Technological innovations in sensing and detection of chemical, biological, radiological, nuclear threats and ecological terrorism, NATO science for peace and security series a: chemistry and biology. Springer, Berlin, pp 231–236. CrossRefGoogle Scholar
  9. de Arce Velasquez A, Ferreira LM, Stangarlin MFL, da Silva Cde B, Rolim CMB, Cruz L (2014) Novel Pullulan-Eudragit S100 blend microparticles for oral delivery of risedronate: formulation, in vitro evaluation and tableting of blend microparticles. Mater Sci Eng C 38:212–217. CrossRefGoogle Scholar
  10. de Lima JA, Paines TC, Motta MH, Weber WB, Dos Santos SS, Cruz L, da Silva CDB (2017) Novel Pemulen/pullulan blended hydrogel containing clotrimazole-loaded cationic nanocapsules: evaluation of mucoadhesion and vaginal permeation. Mater Sci Eng C 79:886–893. CrossRefGoogle Scholar
  11. Di Meo C, Montanari E, Manzi L, Villani C, Coviello T, Matricardi P (2015) Highly versatile nanohydrogel platform based on riboflavin-polysaccharide derivatives useful in the development of intrinsically fluorescent and cytocompatible drug carriers. Carbohydr Polym 115:502–509. CrossRefGoogle Scholar
  12. Dickinson BC, Chang CJ (2011) Chemistry and biology of reactive oxygen species in signaling or stress responses. Nat Chem Biol 7:504–511. CrossRefGoogle Scholar
  13. El-Malah Y, Nazzal S (2013) Real-time disintegration analysis and D-optimal experimental design for the optimization of diclofenac sodium fast-dissolving films. Pharm Dev Technol 18:1355–1360. CrossRefGoogle Scholar
  14. Flores FC, Rosso RS, Cruz L, Beck RCR, Silva CB (2017) An innovative polysaccharide nanobased nail formulation for improvement of onychomycosis treatment. Eur J Pharm Sci 100:56–63. CrossRefGoogle Scholar
  15. Ganeshkumar M, Ponrasu T, Subamekala MK, Janani M, Suguna L (2016) Curcumin loaded on pullulan acetate nanoparticles protects the liver from damage induced by DEN. RSC Adv 6:5599–5610. CrossRefGoogle Scholar
  16. Garhwal R, Shady SF, Ellis EJ, Leahy CD, McCarthy SP, Crawford KS, Gaines P (2012) Sustained ocular delivery of ciprofloxacin using nanospheres and conventional contact lens materials. Invest Ophthalmol Vis Sci 53:1341–1352. CrossRefGoogle Scholar
  17. Grigoras AG (2016) A review on medical applications of poly(N-vinylcarbazole) and its derivatives. Int J Polym Mater Polym Biomater 65:888–900. CrossRefGoogle Scholar
  18. Grigoras AG (2019) Drug Delivery Systems Based on Pullulan Polysaccharides and Their Derivatives. In: Arora D, Sharma C, Jaglan S, Lichtfouse E (eds) Pharmaceuticals from Microbes, Environmental Chemistry for a Sustainable World, vol 26. Springer, Cham, pp 99–141. CrossRefGoogle Scholar
  19. Guhagarkar SA, Shah D, Patel MD, Sathaye SS, Devarajan PV (2015) Polyethylene sebacate-Silymarin nanoparticles with enhanced hepatoprotective activity. J Nanosci Nanotechnol 15:4090–4093. CrossRefGoogle Scholar
  20. Hassanzadeh F, Varshosaz J, Khodarahmi GA, Rostami M, Hassanzadeh F (2016) Biotin-encoded pullulan-retinoic acid engineered nanomicelles: preparation, optimization and in vitro cytotoxicity assessment in MCF-7 cells. Indian J Pharm Sci 78:557–565. CrossRefGoogle Scholar
  21. Hassanzadeh F, Mehdifar M, Varshosaz J, Khodarahmi GA, Rostami M (2018) Folic acid targeted polymeric micelles based on tocopherol succinate- pullulan as an effective carrier for epirubicin: preparation, characterization and in vitro cytotoxicity assessment. Curr Drug Deliv 15:235–246. CrossRefGoogle Scholar
  22. Hong G-Y, Jeong Y-I, Lee SJ, Lee E, Oh JS, Lee HC (2011) Combination of paclitaxel- and retinoic acid-incorporated nanoparticles for the treatment of CT-26 colon carcinoma. Arch Pharm Res 34:407–411. CrossRefGoogle Scholar
  23. Huo M, Zhang Y, Zhou J, Zou A, Yu D, Wu Y, Li J, Li H (2010) Synthesis and characterization of low-toxic amphiphilic chitosan derivatives and their application as micelle carrier for antitumor drug. Int J Pharm 394:162–173. CrossRefGoogle Scholar
  24. Jeong YI, Na HS, Oh JS, Choi KC, Song CE, Lee HC (2006) Adriamycin release from self-assembling nanospheres of poly(DL-lactide-co-glycolide)-grafted pullulan. Int J Pharm 322:154–160. CrossRefGoogle Scholar
  25. Jung Y-S, Park W, Na K (2013) Temperature-modulated noncovalent interaction controllable complex for the long-term delivery of etanercept to treat rheumatoid arthritis. J Controll Release 171:143–151. CrossRefGoogle Scholar
  26. Kang J-H, Tachibana Y, Obika S, Harada-Shiba M, Yamaoka T (2012) Efficient reduction of serum cholesterol by combining a liver-targeted gene delivery system with chemically modified apolipoprotein B siRNA. J Controll Release 163:119–124. CrossRefGoogle Scholar
  27. Kratz F, Warneckje K, Riebessel K, Rodrigues PCA (2002) Anticancer drug conjugates with macromolecular carriers. In: Dumitriu S (ed) Polymeric biomaterials. Marcel Dekker, Inc, New York-Basel, pp 851–895. Google Scholar
  28. Krull SM, Ma Z, Li M, Dave RN, Bilgili E (2016) Preparation and characterization of fast dissolving pullulan films containing BCS class II drug nanoparticles for bioavailability enhancement. Drug Dev Ind Pharm 42:1073–1085. CrossRefGoogle Scholar
  29. Lee SJ, Hong G-Y, Jeong Y-I, Kang MS, Oh JS, Song C-E, Lee HC (2012) Paclitaxel-incorporated nanoparticles of hydrophobized polysaccharide and their antitumor activity. Int J Pharm 433:121–128. CrossRefGoogle Scholar
  30. Lee J, Jeong D, Seo S, Na K (2013) Biodegradable nanogel based on all-trans retinoic acid/pullulan conjugate for anti-cancer drug delivery. J Pharm Investig 43:63–69. CrossRefGoogle Scholar
  31. Lee SJ, Shim Y-H, Oh J-S, Jeong Y-I, Park I-K, Lee HC (2015) Folic-acid-conjugated pullulan/poly(DL-lactide-co-glycolide) graft copolymer nanoparticles for folate-receptor-mediated drug delivery. Nanoscale Res Lett 10:1–11. CrossRefGoogle Scholar
  32. Lee IW, Li J, Chen X, Park HJ (2017) Fabrication of electrospun antioxidant nanofibers by rutin-pluronic solid dispersions for enhanced solubility. J Appl Polym Sci 134:44859. Google Scholar
  33. Li F, Zhang H, Gu C, Fan L, Qiao Y, Tao Y, Cheng C, Wu H, Yi J (2013) Self-assembled nanoparticles from folate-decorated maleilated pullulan-doxorubicin conjugate for improved drug delivery to cancer cells. Polym Int 62:165–171. CrossRefGoogle Scholar
  34. Li H, Cui Y, Liu J, Bian S, Liang J, Fan Y, Zhang X (2014) Reduction breakable cholesteryl pullulan nanoparticles for targeted hepatocellular carcinoma chemotherapy. J Mater Chem B 2:3500–3510. CrossRefGoogle Scholar
  35. Li H, Cui Y, Sui J, Liang J, Fan Y, Zhang X (2015a) Efficient delivery of DOX to nuclei of hepatic carcinoma cells in the subcutaneous tumor model using pH-sensitive pullulan-DOX conjugates. ACS Appl Mater Interfaces 7:15855–15865. CrossRefGoogle Scholar
  36. Li H, Sun Y, Liang J, Fan Y, Zhang X (2015b) pH-sensitive pullulan–DOX conjugate nanoparticles for co-loading PDTC to suppress growth and chemoresistance of hepatocellular carcinoma. J Mater Chem B 41:8070–8078. CrossRefGoogle Scholar
  37. Liu J, Jo J-I, Kawai Y, Aoki I, Tanaka C, Yamamoto M, Tabata Y (2012) Preparation of polymer-based multimodal imaging agent to visualize the process of bone regeneration. J Controll Release 157(3):398–405. CrossRefGoogle Scholar
  38. Lv Q-Y, Li X-Y, Shen B-D, Dai L, Xu H, Chen C-Y, Yuan H-L, Han J (2014) A solid phospholipid-bile salts-mixed micelles based on the fast dissolving oral films to improve the oral bioavailability of poorly water-soluble drugs. J Nanopart Res 16:2455. CrossRefGoogle Scholar
  39. Mocanu G, Nichifor M, Picton L, About-Jaudet E, Le Cerf D (2014) Preparation and characterization of anionic pullulan thermoassociative nanoparticles for drug delivery. Carbohydr Polym 111:892–900. CrossRefGoogle Scholar
  40. Mohamed Wali AR, Zhou J, Ma S, He Y, Yue D, Tang JZ, Gu Z (2017) Tailoring the supramolecular structure of amphiphilic glycopolypeptide analogue toward liver targeted drug delivery systems. Int J Pharm 525(1):191–202. CrossRefGoogle Scholar
  41. Moon S, Yang S-G, Na K (2011) An acetylated polysaccharide-PTFE membrane-covered stent for the delivery of gemcitabine for treatment of gastrointestinal cancer and related stenosis. Biomaterials 32:3603–3610. CrossRefGoogle Scholar
  42. Parejiya PB, Patel RC, Mehta DM, Shelat PK, Barot BS (2013) Quick dissolving films of nebivolol hydrochloride: formulation and optimization by a simplex lattice design. J Pharm Investig 43:343–351. CrossRefGoogle Scholar
  43. Patel V, Patel J (2012) Pullulan acetate controlled-release biodegradable microsphere containing a biologically active agent: preparation, characterization and in vitro experiments. Asian J Pharm Clin Res 5:143–147Google Scholar
  44. Prajapati VD, Jani GK, Khanda SM (2013) Pullulan: an exopolysaccharide and its various applications. Carbohydr Polym 95:540–549. CrossRefGoogle Scholar
  45. Pranatharthiharan S, Patel MD, Malshe VC, Pujari V, Gorakshakar A, Madkaikar M, Ghosh K, Devarajan PV (2017) Asialoglycoprotein receptor targeted delivery of doxorubicin nanoparticles for hepatocellular carcinoma. Drug Deliv 24:20–29. CrossRefGoogle Scholar
  46. Reddy NS, Kumar CBM, Ramesh A, Chandrashekhar MS (2011) Development and in vitro evaluation of gastro retentive matrix tablets: An approach using natural gums and polymers. Res J Pharm Biol Chem Sci 2:90–107Google Scholar
  47. Santhosh Kumar B, Ganesh Kumar M, Suguna L, Sastry TP, Mandal AB (2012) Pullulan acetate nanoparticles based delivery system for hydrophobic drug. Int J Pharma Bio Sci 3:24–32Google Scholar
  48. Sarika PR, James NR, Nishna N, Anil Kumar PR, Raj DK (2015) Galactosylated pullulan-curcumin conjugate micelles for site specific anticancer activity to hepatocarcinoma cells. Coll Surf B 133:347–355. CrossRefGoogle Scholar
  49. Scomparin A, Salmaso S, Eldar-Boock A, Ben-Shushan D, Ferber S, Tiram G, Shmeeda H, Landa-Rouben N, Leor J, Caliceti P, Gabizon A, Satchi-Fainaro R (2015) A comparative study of folate receptor-targeted doxorubicin delivery systems: dosing regimens and therapeutic index. J Controll Release 208:106–120. CrossRefGoogle Scholar
  50. Seo S, Lee C-S, Jung Y-S, Na K (2012) Thermo-sensitivity and triggered drug release of polysaccharide nanogels derived from pullulan-g-poly(L-lactide) copolymers. Carbohydr Polym 87:1105–1111. CrossRefGoogle Scholar
  51. Shen S, Li H, Yang W (2014) The preliminary evaluation on cholesterol-modified pullulan as a drug nanocarrier. Drug Deliv 21:501–508. CrossRefGoogle Scholar
  52. Singh RS, Saini GK, Kennedy JF (2008) Pullulan: microbial sources, production and applications. Carbohydr Polym 73:515–531. CrossRefGoogle Scholar
  53. Singh RS, Kaura N, Kennedy JF (2015) Pullulan and pullulan derivatives as promising biomolecules for drug and gene targeting. Carbohydr Polym 123:190–207. CrossRefGoogle Scholar
  54. Singh RS, Kaura N, Ranab V, Kennedy JF (2017) Pullulan: a novel molecule for biomedical applications. Carbohydr Polym 171:102–121. CrossRefGoogle Scholar
  55. Sushmitha S, Priyanka SR, Mohan Krishna L, Srinavasa Murthy M (2014) Formulation and evaluation of mucoadhesive fast melt-away wafers using selected polymers. Res J Pharm Technol 7:176–180Google Scholar
  56. Tang HB, Li L, Chen H, Zhou ZM, Chen HL, Li XM, Liu LR, Wang YS, Zhang QQ (2010) Stability and in vivo evaluation of pullulan acetate as a drug nanocarrier. Drug Deliv 17:552–558. CrossRefGoogle Scholar
  57. Tao X, Zhang Q, Ling K, Chen Y, Yang W, Gao F, Shi G (2012) Effect of pullulan nanoparticle surface charges on HSA complexation and drug release behavior of HSA-bound nanoparticles. PLoS ONE 7:e49304. CrossRefGoogle Scholar
  58. Tuncay Tanriverdi S, Hilmiolu Polat S, Yeşim Metin D, Kandilolu G, Ozer O (2016) Terbinafine hydrochloride loaded liposome film formulation for treatment of onychomycosis: in vitro and in vivo evaluation. J Liposome Res 26:163–173. CrossRefGoogle Scholar
  59. Vishwanath B, Shivakumar HR, Sheshappa RK, Ganesh S, Prasad P, Guru GS, Bhavya BB (2012a) In-vitro release study of metoprolol succinate from the bioadhesive films of pullulan-polyacrylamide blends. I J Polym Mater Polym Biomater 61:300–307. CrossRefGoogle Scholar
  60. Vishwanath B, Shivakumar HR, Sheshappa RK, Ganesh S, Bhavya BB (2012b) Influence of blending of chitosan and pullulan on their drug release behavior: An in vitro study. Int J Pharm Pharm Sci 4:313–317Google Scholar
  61. Wang J, Cui S, Bao Y, Xing J, Hao W (2014a) Tocopheryl pullulan-based self-assembling nanomicelles for anti-cancer drug delivery. Mater Sci Eng C 43:614–621. CrossRefGoogle Scholar
  62. Wang X, Wang J, Bao Y, Wang B, Wang X, Chen L (2014b) Novel reduction-sensitive pullulan-based micelles with good hemocompatibility for efficient intracellular doxorubicin delivery. RSC Adv 4:60064–60074. CrossRefGoogle Scholar
  63. Wang Y, Liu Y, Liu Y, Wang Y, Wu J, Li R, Yang J, Zhang N (2014c) pH-sensitive pullulan-based nanoparticles for intracellular drug delivery. Polym Chem 5:423–432. CrossRefGoogle Scholar
  64. Wang M, Huang M, Wang J, Ye M, Deng Y, Li H, Qian W, Zhu B, Zhang Y, Gong R (2016) Facile one-pot synthesis of self-assembled folate-biotin-pullulan nanoparticles for targeted intracellular anticancer drug delivery. J Nanomater. Google Scholar
  65. Yang W-Z, Chen H-L, Gao F-P, Chen M-M, Li X-M, Zhang M-M, Zhang Q-Q, Liu L-R, Jiang Q, Wang Y-S (2010) Self-aggregated nanoparticles of cholesterol-modified pullulan conjugate as a novel carrier of mitoxantronep. Current Nanosci 6:298–306. CrossRefGoogle Scholar
  66. Yang W, Wang M, Ma L, Li H, Huang L (2014) Synthesis and characterization of biotin modified cholesteryl pullulan as a novel anticancer drug carrier. Carbohydr Polym 99:720–727. CrossRefGoogle Scholar
  67. Yim H, Park S-J, Bae YH, Na K (2013) Biodegradable cationic nanoparticles loaded with an anticancer drug for deep penetration of heterogeneous tumors. Biomaterials 34:7674–7682. CrossRefGoogle Scholar
  68. Yuan R, Zheng F, Zhong S, Tao X, Zhang Y, Gao F, Yao F, Chen J, Chen Y, Shi G (2014) Self-assembled nanoparticles of glycyrrhetic acid-modified pullulan as a novel carrier of curcumin. Molecules 19:13305–13318. CrossRefGoogle Scholar
  69. Zhang H-Z, Li X-M, Gao F-P, Liu LR, Zhou Z-M, Zhang Q-Q (2010) Preparation of folate-modified pullulan acetate nanoparticles for tumor-targeted drug delivery. Drug Deliv 17:48–57. CrossRefGoogle Scholar
  70. Zhang H, Li F, Yi J, Gu C, Fan L, Qiao Y, Tao Y, Cheng C, Wu H (2011) Folate-decorated maleilated pullulan-doxorubicin conjugate for active tumor-targeted drug delivery. Eur J Pharm Sci 42:517–526. CrossRefGoogle Scholar
  71. Zhu W, Romanski FS, Meng X, Mitra S, Tomassone MS (2011) Atomistic simulation study of surfactant and polymer interactions on the surface of a fenofibrate crystal. Eur J Pharm Sci 42:452–461. CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Laboratory of Natural Polymers, Bioactive and Biocompatible Materials“Petru Poni” Institute of Macromolecular ChemistryIassyRomania

Personalised recommendations