Polysaccharide-based self-assembling nanohydrogels: An overview on 25-years research on pullulan

The aim of this overview is to review the evolution of the studies carried out, during more than 25 years, on nanohydrogels obtained by self-assembling of pullulan (PUL) using several hydrophobization strategies. After the first publications, mainly devoted to the preparation and characterization of PUL nanogels, a remarkable number of studies demonstrated how wide can be the field of applications within the main topic of biopharmaceutics. Numerous hydrophilic and lipophilic drugs were entrapped in the nanogel networks, consequently PUL nanogels have been proposed as delivery systems for single drugs and for combination therapies which allowed improvements of pharmacological activities and patient compliance. Furthermore, the large amount of water content allowed loading also proteins which could maintain their native structure and properties. Stimuli-sensitive and stealth PUL nanogel formulations allowed improving the performances of antitumor drugs. These nanohydrogels have also been studied for imaging techniques and for vaccines to be administered by injection and by mucosal application. The studies on PUL nanogels are still in progress and the perspectives for future researches are also addressed

Pursuing intracellular pathogens with hyaluronan. From a 'pro-infection' polymer to a biomaterial for 'trojan horse' systems

© 2018 by the authors. Licensee MDPI, Basel, Switzerland. Hyaluronan (HA) is among the most important bioactive polymers in mammals, playing a key role in a number of biological functions. In the last decades, it has been increasingly studied as a biomaterial for drug delivery systems, thanks to its physico-chemical features and ability to target and enter certain cells. The most important receptor of HA is 'Cluster of Differentiation 44' (CD44), a cell surface glycoprotein over-expressed by a number of cancers and heavily involved in HA endocytosis. Moreover, CD44 is highly expressed by keratinocytes, activated macrophages and fibroblasts, all of which can act as 'reservoirs' for intracellular pathogens. Interestingly, both CD44 and HA appear to play a key role for the invasion and persistence of such microorganisms within the cells. As such, HA is increasingly recognised as a potential target for nano-carriers development, to pursuit and target intracellular pathogens, acting as a 'Trojan Horse'. This review describes the biological relationship between HA, CD44 and the entry and survival of a number of pathogens within the cells and the subsequent development of HA-based nano-carriers for enhancing the intracellular activity of antimicrobials

Long-Circulating Hyaluronan-Based Nanohydrogels as Carriers of Hydrophobic Drugs

[EN] Nanohydrogels based on natural polymers, such as polysaccharides, are gaining interest as vehicles for therapeutic agents, as they can modify the pharmacokinetics and pharmacodynamics of the carried drugs. In this work, hyaluronan-riboflavin nanohydrogels were tested in vivo in healthy rats highlighting their lack of toxicity, even at high doses, and their different biodistribution with respect to that of native hyaluronan. They were also exploited as carriers of a hydrophobic model drug, the anti-inflammatory piroxicam, that was physically embedded within the nanohydrogels by an autoclave treatment. The nanoformulation was tested by intravenous administration showing an improvement of the pharmacokinetic parameters of the molecule. The obtained results indicate that hyaluronan-based self-assembled nanohydrogels are suitable systems for low-soluble drug administration, by increasing the dose as well as the circulation time of poorly available therapeutic agents.Financial support from University Sapienza Progetti di Ricerca: grant RP116154C2EF9AC8 and grant RM11715C1743EE89 are acknowledged. Isabel Gonzalez-Alvarez, Marta Gonzalez-Alvarez and Marival Bermejo acknowledge partial financial support to project SAF2016-78756 from MINECO (Spanish Ministry of economy, industry and competitivity). Mayte Martinez-Martínez received a grant from the Ministry of Education and Science of Spain (FPU13-01105).Di Meo, C.; Martínez Martínez, M.; Coviello, T.; Bermejo, M.; Merino Sanjuán, V.; Gonzalez-Alvarez, I.; Gonzalez-Alvarez, M.... (2018). Long-Circulating Hyaluronan-Based Nanohydrogels as Carriers of Hydrophobic Drugs. Pharmaceutics. 10(4):1-15. https://doi.org/10.3390/pharmaceutics10040213S115104Allison, D. D., & Grande-Allen, K. J. (2006). Review. Hyaluronan: A Powerful Tissue Engineering Tool. Tissue Engineering, 12(8), 2131-2140. doi:10.1089/ten.2006.12.2131Prestwich, G. D. (2008). Engineering a clinically-useful matrix for cell therapy. Organogenesis, 4(1), 42-47. doi:10.4161/org.6152Ossipov, D. A. (2010). Nanostructured hyaluronic acid-based materials for active delivery to cancer. Expert Opinion on Drug Delivery, 7(6), 681-703. doi:10.1517/17425241003730399Rao, N. V., Yoon, H. Y., Han, H. S., Ko, H., Son, S., Lee, M., … Park, J. H. (2015). Recent developments in hyaluronic acid-based nanomedicine for targeted cancer treatment. Expert Opinion on Drug Delivery, 13(2), 239-252. doi:10.1517/17425247.2016.1112374Dosio, F., Arpicco, S., Stella, B., & Fattal, E. (2016). Hyaluronic acid for anticancer drug and nucleic acid delivery. Advanced Drug Delivery Reviews, 97, 204-236. doi:10.1016/j.addr.2015.11.011Montanari, E., D’Arrigo, G., Di Meo, C., Virga, A., Coviello, T., Passariello, C., & Matricardi, P. (2014). Chasing bacteria within the cells using levofloxacin-loaded hyaluronic acid nanohydrogels. European Journal of Pharmaceutics and Biopharmaceutics, 87(3), 518-523. doi:10.1016/j.ejpb.2014.03.003Svanovsky, E., Velebny, V., Laznickova, A., & Laznicek, M. (2008). The effect of molecular weight on the biodistribution of hyaluronic acid radiolabeled with111In after intravenous administration to rats. European Journal of Drug Metabolism and Pharmacokinetics, 33(3), 149-157. doi:10.1007/bf03191112Harris, E. N., Kyosseva, S. V., Weigel, J. A., & Weigel, P. H. (2006). Expression, Processing, and Glycosaminoglycan Binding Activity of the Recombinant Human 315-kDa Hyaluronic Acid Receptor for Endocytosis (HARE). Journal of Biological Chemistry, 282(5), 2785-2797. doi:10.1074/jbc.m607787200Choi, K. Y., Min, K. H., Na, J. H., Choi, K., Kim, K., Park, J. H., … Jeong, S. Y. (2009). Self-assembled hyaluronic acid nanoparticles as a potential drug carrier for cancer therapy: synthesis, characterization, and in vivo biodistribution. Journal of Materials Chemistry, 19(24), 4102. doi:10.1039/b900456dPedrosa, S. S., Pereira, P., Correia, A., & Gama, F. M. (2017). Targetability of hyaluronic acid nanogel to cancer cells : In vitro and in vivo studies. European Journal of Pharmaceutical Sciences, 104, 102-113. doi:10.1016/j.ejps.2017.03.045Yang, C., Li, C., Zhang, P., Wu, W., & Jiang, X. (2017). Redox Responsive Hyaluronic Acid Nanogels for Treating RHAMM (CD168) Over-expressive Cancer, both Primary and Metastatic Tumors. Theranostics, 7(6), 1719-1734. doi:10.7150/thno.18340Rosso, F., Quagliariello, V., Tortora, C., Di Lazzaro, A., Barbarisi, A., & Iaffaioli, R. V. (2013). Cross-linked hyaluronic acid sub-micron particles: in vitro and in vivo biodistribution study in cancer xenograft model. Journal of Materials Science: Materials in Medicine, 24(6), 1473-1481. doi:10.1007/s10856-013-4895-4Nakai, T., Hirakura, T., Sakurai, Y., Shimoboji, T., Ishigai, M., & Akiyoshi, K. (2012). Injectable Hydrogel for Sustained Protein Release by Salt-Induced Association of Hyaluronic Acid Nanogel. Macromolecular Bioscience, 12(4), 475-483. doi:10.1002/mabi.201100352Montanari, E., Capece, S., Di Meo, C., Meringolo, M., Coviello, T., Agostinelli, E., & Matricardi, P. (2013). Hyaluronic Acid Nanohydrogels as a Useful Tool for BSAO Immobilization in the Treatment of Melanoma Cancer Cells. Macromolecular Bioscience, 13(9), 1185-1194. doi:10.1002/mabi.201300114Montanari, E., Di Meo, C., Sennato, S., Francioso, A., Marinelli, A. L., Ranzo, F., … Matricardi, P. (2017). Hyaluronan-cholesterol nanohydrogels: Characterisation and effectiveness in carrying alginate lyase. New Biotechnology, 37, 80-89. doi:10.1016/j.nbt.2016.08.004Montanari, E., De Rugeriis, M. C., Di Meo, C., Censi, R., Coviello, T., Alhaique, F., & Matricardi, P. (2015). One-step formation and sterilization of gellan and hyaluronan nanohydrogels using autoclave. Journal of Materials Science: Materials in Medicine, 26(1). doi:10.1007/s10856-014-5362-6Di 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. Carbohydrate Polymers, 115, 502-509. doi:10.1016/j.carbpol.2014.08.107Manzi, G., Zoratto, N., Matano, S., Sabia, R., Villani, C., Coviello, T., … Di Meo, C. (2017). «Click» hyaluronan based nanohydrogels as multifunctionalizable carriers for hydrophobic drugs. Carbohydrate Polymers, 174, 706-715. doi:10.1016/j.carbpol.2017.07.003Lozoya-Agullo, I., Araújo, F., González-Álvarez, I., Merino-Sanjuán, M., González-Álvarez, M., Bermejo, M., & Sarmento, B. (2018). PLGA nanoparticles are effective to control the colonic release and absorption on ibuprofen. European Journal of Pharmaceutical Sciences, 115, 119-125. doi:10.1016/j.ejps.2017.12.009Samiei, N., Mangas-Sanjuan, V., González-Álvarez, I., Foroutan, M., Shafaati, A., Zarghi, A., & Bermejo, M. (2013). Ion-pair strategy for enabling amifostine oral absorption: Rat in situ and in vivo experiments. European Journal of Pharmaceutical Sciences, 49(4), 499-504. doi:10.1016/j.ejps.2013.04.025Wei, X., Senanayake, T. H., Bohling, A., & Vinogradov, S. V. (2014). Targeted Nanogel Conjugate for Improved Stability and Cellular Permeability of Curcumin: Synthesis, Pharmacokinetics, and Tumor Growth Inhibition. Molecular Pharmaceutics, 11(9), 3112-3122. doi:10.1021/mp500290