Chinese Journal of Polymer Science

, Volume 36, Issue 9, pp 999–1010 | Cite as

Synthesis of Water-soluble, Polyester-based Dendrimer Prodrugs for Exploiting Therapeutic Properties of Two Triterpenoid Acids

  • Silvana Alfei
  • Gaby Brice Taptue
  • Silvia Catena
  • Angela Bisio


Dendrimers are macromolecules characterized by high controlled size, shape and architecture, presence of inner cavities able to accommodate small molecules and many peripheral functional groups to bind target entities. They are of eminent interest for biomedical applications, including gene transfection, tissue engineering, imaging, and drug delivery. The well-known pharmacological activities of ursolic and oleanolic acids are limited by their small water solubility, non-specific cell distribution, low bioavailability, poor pharmacokinetics, and their direct administration could result in the release of thrombi. To overcome such problems, in this paper we described their physical incorporation inside amino acids-modified polyester-based dendrimers which made them highly water-soluble. IR, NMR, zeta potential, mean size of particles, buffer capacity and drug release profiles of prepared materials were reported. The achieved water-soluble complexes harmonize a polycationic character and a buffer capacity which presuppose efficient cell penetration and increased residence time with a biodegradable cell respectful scaffold, thus appearing as a promising team of not toxic prodrugs for safe administration of ursolic and oleanolic acids.


Polyester-based amino acids-modified dendrimers Physical encapsulation Water-soluble dendriplexes Buffer capacity NMR investigations 


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The authors are very thankful to Mr Gagliardo Osvaldo for Elemental Analysis and to University of Genova.

Supplementary material

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Synthesis of Water-soluble, Polyester-based Dendrimer Prodrugs for Exploiting Therapeutic Properties of Two Triterpenoid Acids


  1. 1.
    Hourani, R.; Kakkar, A. Advances in the elegance of chemistry in designing dendrimers. Macromol. Rapid Commun. 2010, 31, 947–974Google Scholar
  2. 2.
    Sowinska, M.; Urbanczyk-Lipkowska, Z. Advances in the chemistry of dendrimers. New J. Chem. 2014, 38, 2168–2203Google Scholar
  3. 3.
    Madaan, K.; Kumar, S.; Poonia, N.; Lather, V.; Pandita, D. Dendrimers in drug delivery and targeting: Drug-dendrimer interactions and toxicity issues. J. Pharm. Bioall. Sci. 2014, 6, 139–150Google Scholar
  4. 4.
    Hu, X. L.; Liu, G. H.; Li, Y.; Wang, X. R.; Liu, S. Y. Cellpenetrating hyperbranched polyprodrug amphiphiles for synergistic reductive milieu-triggered drug release and enhanced magnetic resonance signals. J. Am. Chem. Soc. 2015, 137, 362–368Google Scholar
  5. 5.
    Li, X.; Qian, Y.; Liu, T.; Hu, X.; Zhang, G.; You, Y.; Liu, S. Amphiphilic multiarm star block copolymer-based multifunctional unimolecular micelles for cancer targeted drug delivery and MR imaging. Biomaterials 2011, 32, 6595–605Google Scholar
  6. 6.
    Xu, J.; Luo, S. Z.; Shi, W. F.; Liu, S. Y. Two-stage collapse of unimolecular micelles with double thermoresponsive coronas. Langmuir 2006, 22, 989–997Google Scholar
  7. 7.
    Luo, S. Z.; Xu, J.; Zhu, Z. Y.; Wu, C.; Liu, S. Y. Phase transition behavior of unimolecular micelles with thermoresponsive poly(N-isopropylacrylamide) coronas. J. Physic. Chem. 2006, 110, 9132–9139Google Scholar
  8. 8.
    Xu, H. X.; Xu, J.; Jiang, X. Z.; Zhu, Z. Y.; Rao, J. Y.; Yin, J.; Wu, T.; Liu, H. W.; Liu, S. Y. Thermosensitive unimolecular micelles surface-decorated with gold nanoparticles of tunable spatial distribution. Chem. Mater. 2007, 19, 2489–2494Google Scholar
  9. 9.
    Luo, S.; Hu, X.; Ling, C.; Liu, X.; Chen, S.; Han, M. Multiarm star-like unimolecular micelles with a dendritic core and a dual thermosensitive shell. Polym. Int. 2011, 60, 717–724Google Scholar
  10. 10.
    Kesharwani, P.; Jain, K.; Jain, N. Dendrimer as nanocarrier for drug delivery. Prog. Polym. Sci. 2014, 39, 268–307Google Scholar
  11. 11.
    Datija, J.; Sai, V. V. R.; Mukherji, S. Dendrimers in biosensors: concept and applications. J. Mater. Chem. 2011, 21, 14367–14386Google Scholar
  12. 12.
    Caminade, A M. in "Dendrimers: towards catalytic, material and biomedical uses, Chapter 15", ed. By Caminade, A. M.; Turrin, C. O.; Laurent, R.; Ouali, A.; Delavaux-Nicot, B. John Wiley & Sons, Chichester, UK., 2011, p. 375–392Google Scholar
  13. 13.
    Kim, J. H.; Park, K.; Nam, H. Y., Lee, S.; Kim, K.; Kwon, I. C. Polymers for bioimaging. Prog. Polym. Sci. 2007, 32, 1031–1053Google Scholar
  14. 14.
    Wang, Z.; Niu, G.; Chen, X. Polymeric materials for theranostic applications. Pharm. Res. 2014, 31, 1358–1376Google Scholar
  15. 15.
    Dufes, C.; Uchegbu, I. F.; Schätzlein, A. G. Dendrimers in gene delivery. Adv. Drug Deliver. Rev. 2005, 57, 2177–2202Google Scholar
  16. 16.
    Eliyahu, H.; Barenholz, Y.; Domb, A. J. Polymers for DNA delivery. Molecules 2005, 10, 34–64Google Scholar
  17. 17.
    Pack, D. W.; Hoffman, A. S.; Pun, S.; Stayton, P. S. Design and development of polymers for gene delivery. Nat. Rev. Drug Discov. 2005, 4, 581–593Google Scholar
  18. 18.
    Schaffert, D.; Wagner, E. Gene therapy progress and prospects: synthetic polymer-based systems. Gene Ther. 2008, 15, 1131–1138Google Scholar
  19. 19.
    Mintzer, M. A.; Simanek, E. E. Nonviral vectors for gene delivery. Chem. Rev. 2009, 109, 259–302Google Scholar
  20. 20.
    O’Rorke, S.; Keeney, M.; Pandit, A. Non-viral polyplexes: scaffold mediated delivery for gene therapy. Prog. Polym. Sci. 2010, 35, 441–458Google Scholar
  21. 21.
    Marvaniya, H. M.; Parikh, P. K.; Patel, V. R.; Modi, K. N.; Sen, D. J. Dendrimer nanocarriers as versatile vectors in gene delivery. J. Chem. Pharm. Res. 2010, 2, 97–108Google Scholar
  22. 22.
    Guo, X.; Huang, L. Recent advances in nonviral vectors for gene delivery. Acc. Chem. Res. 2012, 45, 971–979Google Scholar
  23. 23.
    Yue, Y.; Wu, C. Progress and perspectives in developing polymeric vectors for in vitro gene delivery. Biomater. Sci. 2013, 1, 152–170Google Scholar
  24. 24.
    Biswas, S.; Torchilin, V. P. Dendrimers for siRNA delivery. Pharmaceuticals 2013, 6, 161–183Google Scholar
  25. 25.
    Pourianazar, N. T.; Mutulu, P.; Gunduz, U. Bioapplications of poly(amidoamine) (PAMAM) dendrimers in nanomedicine. J. Nanopart. Res. 2014, 16, 2342/1-2342/38Google Scholar
  26. 26.
    Newkome, G. R.; Shreiner, C. D. Poly(amidoamine), polypropylenimine, and related dendrimers and dendrons possessing different 1 - 2 branching motifs: An overview of the divergent procedures. Polymer 2008, 49, 1–173Google Scholar
  27. 27.
    Eichman, J. D.; Bielinska, A. U.; Kukowska-Latallo, J. F.; Baker Jr, J. R. The use of PAMAM dendrimers in the efficient transfer of genetic material into cells. Sci. Technol. Today 2000, 3, 232–245Google Scholar
  28. 28.
    Zong, H.; Shah, D.; Selwa, K.; Tsuchida, R. E.; Rattan, R.; Mohan, J.; Stein, A. B.; Otis, J. B.; Goonewardena, S. N. Design and evaluation of tumor-specific dendrimer epigenetic therapeutics chemistryopen. Chem. Open 2015, 4, 335–341Google Scholar
  29. 29.
    Han, L.; Huang, R.; Liu, S.; Huang, S.; Jiang, C. Peptideconjugated PAMAM for targeted doxorubicin delivery to transferrin receptor overexpressed tumors. Mol. Pharm. 2010, 7, 2156–2165Google Scholar
  30. 30.
    Gao, Y.; Li, Z.; Xie, X.; Wang, C.; You, J.; Mo, F.; Jin, B.; Chen, J.; Shao, J.; Chen, H.; Jia, L. Dendrimeric anticancer prodrugs for targeted delivery of ursolic acid to folate receptor-expressing cancer cells: synthesis and biological evaluation. Eur. J. Pharm. Sci. 2015, 70, 55–63Google Scholar
  31. 31.
    Zhang, Y.; Thomas, T. P.; Lee, K. H.; Li, M.; Zong, H.; Desai, A. M.; Kotlyar, A.; Huang, B.; Banaszak H. M. M.; Baker, J. R. Jr. Polyvalent saccharide-functionalized generation 3 poly(amidoamine) dendrimer-methotrexate conjugate as a potential anticancer agent. Bioorg. Med. Chem. 2011, 19, 2557–2564Google Scholar
  32. 32.
    Mekuria, S. L.; Debele, T. A.; Chou, H Y.; Tsai, H C. IL-6 antibody and RGD peptide conjugated poly(amidoamine) dendrimer for targeted drug delivery of HeLa cells. J. Phys. Chem. B 2016, 120, 123–130Google Scholar
  33. 33.
    Kolhatkar, R. B.; Kitchens, K. M.; Swaan, P. W.; Ghandehari, H. Surface acetylation of polyamidoamine (PAMAM) dendrimers decreases cytotoxicity while maintaining membrane permeability. Bioconj. Chem. 2007, 18, 2054–2060Google Scholar
  34. 34.
    Waite, C. L.; Sparks, S. M.; Uhrich, K. E.; Roth, C. M. Acetylation of PAMAM dendrimers for cellular delivery of siRNA. BMC Biotechnol. 2009, 9, 9–38Google Scholar
  35. 35.
    Liu, J. F.; Liu, J. J.; Chu, L. P.; Tong, L. L.; Gao, H. J.; Yang, C. H.; Wang, D. Z.; Shi, L. Q.; Kung, D. L.; Li, Z. J. Synthesis, biodistribution, and imaging of PEGylatedacetylated polyamidoamine dendrimers. J. Nanosci. Nanotechnol. 2014, 14, 3305–3312Google Scholar
  36. 36.
    Ciolkowski, M.; Petersen, J. F.; Ficker, M.; Janaszewska, A.; Christensen, J. B.; Klajnert, B.; Bryszewska, M. Surface modifi-cation of PAMAM dendrimer improves its biocompatibility. Nanomed. Nanotechnol. 2012, 8, 815–817Google Scholar
  37. 37.
    Ghilardi, A.; Pezzoli, D.; Bellucci, M. C.; Malloggi, C.; Negri, A.; Sgnappa, A.; Tedeschi, G.; Candiani, G.; Volonterio, A. Synthesis of multifunctional PAMAM-aminoglycoside conjugates with enhanced transfection efficiency. Bioconj. Chem. 2013, 24, 1928–1963Google Scholar
  38. 38.
    Arima, H.; Motoyama, K.; Higashi, T. Sugar-appended polyamidoamine dendrimer conjugates with cyclodextrins as cell-specific non-viral vectors. Adv. Drug Deliver. Rev. 2013, 65, 1204–1214Google Scholar
  39. 39.
    Navath, R. S. Menjoge, A. R.; Wang, B.; Romero, R.; Kannan, S.; Kannan, R. M. Amino acid-functionalized dendrimers with heterobifunctional chemoselective peripheral groups for drug delivery applications. Biomacromolecules 2010, 11, 1544–1536Google Scholar
  40. 40.
    Park, J. H.; Park, J. S.; Choi, J. S. Basic amino acidconjugated polyamidoamine dendrimers with enhanced gene transfection efficiency. Macromol. Res. 2014, 22, 500–508Google Scholar
  41. 41.
    Wang, F.; Wang, Y.; Wang, H.; Shao, N.; Chen, Y.; Cheng, Y. Synergistic effect of amino acids modified on dendrimer surface in gene delivery. Biomaterials 2014, 35, 9187–9198Google Scholar
  42. 42.
    Lam, S. J.; Sulistio, A.; Ladewig, K.; Wong, E. H. H.; Blencowe, A.; Qiao, G. G. Peptide-based star polymers as potential siRNA carriers. Austr. J. Chem. 2014, 67, 592–597Google Scholar
  43. 43.
    Nam, H. Y.; Nam, K.; Hahn, H. J.; Kim, B. H.; Lim, H. J.; Kim, H. J.; Choi, J. S.; Park, J. S. Biodegradable PAMAM ester for enhanced transfection efficiency with low cytotoxicity. Biomaterials 2009, 30, 665–673Google Scholar
  44. 44.
    Liu, M.; Chen, J.; Xue, Y. N.; Liu, W. M.; Zhuo, R. X.; Huang, S. W. Poly(beta-aminoester)s with pendant primary amines for efficient gene delivery. Bioconj. Chem 2009, 20, 2317–2323Google Scholar
  45. 45.
    Eltoukhy, Q. Effect of molecular weight of amine endmodified poly(P-amino ester)s on gene delivery efficiency and toxicity. Biomaterials 2012, 33, 3594–3603Google Scholar
  46. 46.
    Bishop, C. J.; Ketola, T M.; Tzeng, S. Y.; Sunshine, J. C.; Urttio, A.; Lemmetyinen, H., Vuorimaa-Laukkanen, E., Yliperttula, M.; Green, J. J. The effect and role of carbon atoms in poly(beta-amino ester)s for DNA Binding and Gene Delivery. J. Am. Chem. Soc. 2013, 135, 6951–6957Google Scholar
  47. 47.
    Chang, K. L.; Higuchi, Y.; Kawakami, S.; Yamashita, F.; Hashida, M. Development of lysine-histidine dendron modified chitosan for improving transfection efficiency in HEK293 cells. J. Control. Release 2011, 156, 195–202Google Scholar
  48. 48.
    Wen, Y.; Guo, Z.; Du, Z.; Fang, R.; Wu, H.; Zeng, X.; Wang, C.; Feng, M.; Pan, S. Serum tolerance and endosomal escape capacity of histidine-modified pDNA-loaded complexes based on polyamidoamine dendrimer derivatives. Biomaterials 2012, 33, 8111–8121Google Scholar
  49. 49.
    Wang, F.; Wang, Y.; Wang, H.; Shao, N.; Chen, Y.; Cheng, Y. Synergistic effect of amino acids modified on dendrimer surface in gene delivery. Biomaterials 2014, 35, 9187–9198Google Scholar
  50. 50.
    Liu, X.; Liu, C.; Zhou, J.; Chen, C.; Qu, F.; Rossi, J. J.; Rocchi, P.; Peng, L. Promoting siRNA delivery via enhanced cellular uptake using an arginine-decorated amphiphilic dendrimer. Nanoscale 2015, 7, 3867–3875Google Scholar
  51. 51.
    Kim, J. B.; Choi, J. S.; Nam, K.; Lee, M.; Park, J. S.; Lee, J. K. Enhanced transfection of primary cortical cultures using arginine-grafted PAMAM dendrimer, PAMAM-Arg. J. Control. Release 2006, 114, 110–117Google Scholar
  52. 52.
    Kim, T.; Bai, C. Z.; Nam, K.; Park, J. Comparison between arginine conjugated PAMAM dendrimers with structural diversity for gene delivery systems. J. Control. Release 2009, 136, 132–139Google Scholar
  53. 53.
    Liu, J. Pharmacology of oleanolic acid and ursolic acid. J. Ethnopharmacol 1995, 49, 57–68Google Scholar
  54. 54.
    Andersson, D.; Cheng, Y.; Duan, R. D. Ursolic acid inhibits the formation of aberrant crypt foci and affects colonic sphingomyelin hydrolyzing enzymes in azoxymethane-treated rats. J. Cancer Res. Clin. Oncol 2008, 134, 101–107Google Scholar
  55. 55.
    Furtado, R. A.; Rodrigues, E. P.; Araujo, F. R. R.; Oliveira, W. L.; Furtado, M. A.; Castro, M. B.; Cunha, W. R.; Tavares, D. C. Ursolic acid and oleanolic acid suppress preneoplastic lesions induced by 1,2-dimethylhydrazine in rat colon. Toxicol. Pathol. 2008, 36, 576–580Google Scholar
  56. 56.
    Gao, J. Hepatoprotective activity of terminalia catappa l. leaves and its two triterpenoids. J. Pharm. Pharmacol. 2004, 56, 1449–1455Google Scholar
  57. 57.
    Liu, J. The Effects of 10 triterpenoid compounds on experimental liver injury in mice. Fundam. Appl. Toxicol. 1994, 22, 34–40Google Scholar
  58. 58.
    Martin-Aragon, S.; de Las Heras, B.; Sanchez-Reus, M. I.; Benedi, J. Pharmacological modification of endogenous antioxidant enzymes by ursolic acid on tetrachloride-induced liver damage in rats and primary cultures of rat hepatocytes. Exp. Toxicol. Pathol. 2001, 53, 199–206Google Scholar
  59. 59.
    Saravanan, R.; Viswanathan, P.; Pugalendi, K. V. Protective effect of ursolic acid on ethanol-mediated experimental liver damage in rats. Life Sci. 2006, 78, 713–718Google Scholar
  60. 60.
    Somova, L. O.; Nadar, A.; Rammanan, P.; Shode, F. O. Cardiovascular, antihyperlipidemic and antioxidant effects of oleanolic and ursolic acids in experimental hypertension. Phytomedicine 2003, 10, 115–121Google Scholar
  61. 61.
    Ovesna, Z.; Kozics, K.; Slamenov", D. Protective effects of ursolic acid and oleanolic acid in leukemic cells. Mutation Res 2006, 600, 131–137Google Scholar
  62. 62.
    Shishodia, S.; Majumdar, S.; Banerjee, S.; Aggarwal, B. B. Ursolic acid inhibits nuclear factor-kappaB activation induced by carcinogenic agents through suppression of IkappaBalpha kinase and p65 phosphorylation: correlation with downregulation of cyclooxygenase 2, matrix metalloproteinase 9, and cyclin D1. Cancer Res. 2003, 63, 4375–83Google Scholar
  63. 63.
    Moon H. K.; Yang, E. S.; Park, J. W. Protection of peroxynitrite-induced DNA damage by dietary antioxidant. Arch. Pharm. Res. 2006, 29, 213–217Google Scholar
  64. 64.
    Lee, I.; Lee, J.; Lee, Y. H.; Leonard, J. Ursolic acid-induced changes in tumor growth, O2 consumption, and tumor interstitial fluid pressure. Anticancer Res. 2001, 21, 2827–2833Google Scholar
  65. 65.
    Yim, E. K.; Lee, M. J.; Lee, K. H., Um, S. J.; Park, J. S. Antiproliferative and antiviral mechanisms of ursolic acid and dexamethasone in cervical carcinoma cell lines. Int. J. Gynecol. Cancer. 2006, 16, 2023–2031Google Scholar
  66. 66.
    Huang, M. T.; Ho, C. T.; Wang, Z. Y.; Ferraro, T.; Lou, Y. R.; Stauber, K.; Ma, W.; Georgiadis, C.; Laskin, J. D.; Conney, A. K. Inhibition of skin tumorigenesis by rosemary and its constituents carnosol and ursolic acid. Cancer. Res. 1994, 54, 701–708Google Scholar
  67. 67.
    Tokuda, H.; Ohigashi, H.; Koshimizu, K.; Ito, Y. Inhibitory effects of ursolic and oleanolic acid on skin tumor promotion by 12-0-tetradecanoylphorbol-13-acetate. Cancer Lett. 1986, 33, 279–285Google Scholar
  68. 68.
    Kim, K. A.; Lee, J. S.; Park, H. J.; Kim, J. W.; Kim, C. J.; Shim, I. S.; Kim, N. J.; Han, S. M.; Lim, S. Inhibition of cytochrome P450 activities by oleano-lic acid and ursolic acid in human liver microsomes. Life Sci. 2004, 74, 2769–2779Google Scholar
  69. 69.
    Ramos, A. A.; Lima, C. F.; Pereira, M. L.; Fernandes-Ferreira, M.; Pereira-Wilson, C. Antigenotoxic effects of quercetin, rutin and ursolic acid on HepG2 cells: evaluation by the comet assay. Toxicol. Lett. 2008, 177, 66–73Google Scholar
  70. 70.
    Chiang, L. C.; Chiang, W.; Chang, M. Y.; Ng, L. T.; Lin, C. C. Antileukemic activity of selected natural products in Taiwan. Am. J. Chin. Med. 2003, 31, 37–46Google Scholar
  71. 71.
    Fan, Y. M.; Xu, L. Z.; Gao, J.; Wang, Y.; Tang, X. H. Zhao, X. N.; Zhang, Z. X. Phytochemical and antiinflammatory studies on Terminalia catappa. Fitoterapia 2004, 75, 253–260Google Scholar
  72. 72.
    Peng, Q.; Zhu, J.; Yu, Y.; Hoffman, L.; Yang, X. Hyperbranched lysine-arginine copolymer for gene delivery. J. Biomater. Sci. Polym. Ed. 2015, 26, 1163–1177Google Scholar
  73. 73.
    Resende, F. A.; Mattos de Andrade Barcala, C. A.; da Silva Faria, M. C.; Kato, F. H.; Cunha, W. R.; Tavares, D. C. Antimutagenicity of ursolic acid and oleanolic acid against doxorubicin-induced clastogenesis in Balb/c mice. Life Sci. 2006, 79, 1268–1273Google Scholar
  74. 74.
    Lu, J.; Zheng, Y. L.; Wu, D. M.; Luo, L.; Sun, D. X.; Shan, Q. Ursolic acid ameliorates cognition deficits and attenuates oxidative damage in the brain of senescent mice induced by D-galactose. Biochem. Pharmacol. 2007, 74, 1078–1090Google Scholar
  75. 75.
    Saravanan, R. Pugalendi, V. Impact of ursolic acid on chronic ethanol-induced oxidative stress in the rat heart. Pharmacol. Rep. 2006, 58, 41–47Google Scholar
  76. 76.
    Wang, Y.; He, Z.; Deng, S. Ursolic acid reduces the metalloprotease/anti-metalloprotease imbalance in cerebral ischemia and reperfusion injury. Drug Des., Devel. Ther. 2016, 10, 1663–1674Google Scholar
  77. 77.
    Senthil, S.; Chandramohan, G.; Pugalendi, K. V. Isomers (oleanolic and ursolic acids) differ in their protective effect against isoproterenol-induced myocardial ischemia in rats. Int. J. Cardiol. 2007, 119, 131–133Google Scholar
  78. 78.
    Radhiga, T.; Rajamanickam, C.; Senthil, S.; Pugalendi, K. V. Effect of ursolic acid on cardiac marker enzymes, lipid profile and macroscopic enzyme mapping assay in isoproterenolinduced myocardial ischemic rats. Food Chem. Toxicol. 2012, 50, 3971–3977Google Scholar
  79. 79.
    Aguirre-Crespo, F.; Vergara-Galicia, J.; Villalobos-Molina, R.; Lopez-Guerrero, J. J.; Navarrete-Vazquez, G.; Estrada-Soto, S. Ursolic acid mediates the vasorelaxant activity of Lepechinia caulescens via NO release in isolated rat thoracic aorta. Life Sci. 2006, 79, 1062–1068Google Scholar
  80. 80.
    Martinez-Gonzalez, J.; Rodriguez-Rodriguez, R.; Gonzalez-Diez, M.; Rodriguez, C.; Herrera, M. D.; Ruiz-Gutierrez, V.; Badimon, L. Oleanolic acid induces prostacyclin release in human vascular smooth muscle cells through a cyclooxygenase-2-dependent mechanism. J. Nutr. 2008, 138, 443–448Google Scholar
  81. 81.
    Somova, L. O.; Nadar, A.; Rammanan, P.; Shode, F. O. Cardiovascular, antihyperlipidemic and antioxidant effects of oleanolic and ursolic acids in experimental hypertension. Phytomedicine 2003, 10, 115–121Google Scholar
  82. 82.
    Somova, L. I.; Shode, F. O.; Mipando, M. Cardiotonic and antidysrhythmic effects of oleanolic and ursolic acids, methyl maslinate and uvaol. Phytomedicine 2004, 11, 121–129Google Scholar
  83. 83.
    Ikeda, Y.; Murakami, A.; Ohigashi, H. Ursolic acid: an antiand pro-inflammatory triterpenoid. Mol. Nutr. Food Res. 2008, 52, 26–42Google Scholar
  84. 84.
    Messner, B. Ursolic acid causes DNA damage, p53-mediated, mitochondria-and caspase-dependent human endothelial cell apoptosis, and accelerates atherosclerotic plaque formation in vivo. Atherosclerosis 2011, 219, 402–408Google Scholar
  85. 85.
    Liu, Y.; Oh, S. J.; Chang, K. H.; Kim, Y. G.; Lee, M. Y. Antiplatelet effect of AMP-activated protein kinase activator and its potentiation by the phosphodiesterase inhibitor dipyridamole. Biochem. Pharmacol. 2013, 86, 914–925Google Scholar
  86. 86.
    Kim, M.; Han, C. H.; Lee, M. Y. Enhancement of platelet aggregation by ursolic acid and oleanolic acid. Biomol. Ther 2014, 22, 254–259Google Scholar
  87. 87.
    Liu, J. Oleanolic acid and ursolic acid: research perspectives. J. Ethnopharmacol. 2005, 100, 92–94Google Scholar
  88. 88.
    Nahak, P.; Karmakar, G.; Chettri, P.; Roy, B.; Guha, P.; Besra, S. E.; Soren, A.; Bykov, A. G.; Akentiev, A. V.; Noskov, B. A.; Panda, A. K. Influence of lipid core material on physicochemical characteristics of an ursolic acid-loaded nanostructured lipid carrier: an attempt to enhance anticancer activity. Langmuir 2016, 32, 9816–9825Google Scholar
  89. 89.
    Alfei, S.; Castellaro, S. Synthesis and characterization of polyester-based dendrimers containing peripheral arginine or mixed amino acids as potential vectors for gene and drug delivery. Macromol. Res. 2017, 25(12), 1172–1186Google Scholar
  90. 90.
    Bisio, A.; Romussi, G.; Russo, E.; Cafaggi, S.; Schito, A. M.; Repetto, B.; De Tommasi, N. Antimicrobial activity of the ornamental species salvia corrugata, a potential new crop for extractive purposes. J. Agric. Food Chem. 2008, 56, 10468–10472Google Scholar
  91. 91.
    Von Seel, F. in "Grundlagen der analytischen Chemie, Vol. 82", ed. By Geier, G., Verlag Chemie, Weinheim, 1970, p. 962Google Scholar
  92. 92.
    Aravindan, L.; Bicknell, K. A.; Brooks, G.; Khutoryanskiya, V. V.; Williams, A. C. Effect of acyl chain length on transfection efficiency and toxicity of polyethylenimine. Int. J. Pharm. 2009, 378, 201–210Google Scholar
  93. 93.
    Benns, J. M.; Choi, J. S.; Mahato, R. I.; Park, J. S.; Kim, S. W. pH-sensitive cationic polymer gene delivery vehicle: N-Acpoly( L-histidine)-graft-poly(L-lysine) comb shaped polymer. Bioconj. Chem. 2000, 11, 637–645Google Scholar
  94. 94.
    Fernandez, L. Solubilization and release properties of dendrimers evaluation as prospective drug delivery systems. J. Supramol. Chem. 2006, 18, 633–643Google Scholar
  95. 95.
    Santo, M.; Fox, M. A. Hydrogen bonding interactions between Starburst dendrimers and several molecules of biological interest. Phys. Org. Chem. 1999, 12, 293–307Google Scholar
  96. 96.
    Cheng, Y.; Xu, Z.; Ma, M.; Xu, T. Dendrimers as drug carriers: applications in different routes of drug administration. J. Pharm. Sci. 2008, 97, 123–143Google Scholar
  97. 97.
    Milhem, O. M.; Myles, C.; McKeown, N. B.; Attwood, D.; D’Emanuele, A. Polyamidoamine Starburst dendrimers as solubility enhancers. Int. J. Pharm. 2000, 197, 239–241Google Scholar
  98. 98.
    Kolhe, P.; Misra, E.; Kannan, R. M.; Kannan, S.; Lieh-Lai, M. Drug complexation, in vitro release and cellular entry of dendrimers and hyperbranched polymers. Int. J. Pharm. 2003, 259, 143–160Google Scholar
  99. 99.
    Twyman, L. J.; Beezer, A. E.; Esfand, R.; Hardy, M. J.; Mitchell, J. C. The synthesis of water soluble dendrimers, and their application as possible drug delivery systems. Tetrahedron Lett. 1999, 40, 1743–1746Google Scholar
  100. 100.
    Alfei, S.; Castellaro, S.; Taptue, G. B. Synthesis and NMR characterization of dendrimers based on 2, 2-bis-(hydroxymethyl)-propanoic acid (bis-HMPA) containing peripheral amino acid residues for gene transfection. Org. Commun. 2017, 10, 144–177Google Scholar
  101. 101.
    Seebacher, W.; Simic, N.; Weis, R.; Saf, R.; Kunert, O. Spectral assignments and reference data. Magn. Reson. Chem. 2003, 41, 636–638Google Scholar
  102. 102.
    Eichman, J. D.; Bielinska, A. S. U.; Kukowska-Latallo, J. F.; Baker J. R. Jr. The use of PA-MAM dendrimers in the efficient transfer of genetic material into cells. Sci. Technol. Today 2000, 3, 232–245Google Scholar
  103. 103.
    Wang, J. Q.; Mao, W. W.; Lock, L. L.; Tang, J. B.; Sui, M. H.; Sun, W. L.; Cui, H. G.; Xu, D.; Shen, Y. Q. The role of micelle size in tumor accumulation, penetration, and treatment. ACS Nano 2015, 9, 7195–7206Google Scholar
  104. 104.
    Yu, H.; Cui, Z.; Yu, P.; Guo, C.; Feng, B.; Jiang, T.; Wang, S.; Yin, Q.; Zhong, D.; Yang, X.; Zhang, Z.; Li, Y. pH-and NIR light-responsive micelles with hyperthermia-triggered tumor penetration and cytoplasm drug release to reverse doxorubicin resistance in breast cancer. Adv. Funct. Mater. 2015, 25, 2489–2500.Google Scholar

Copyright information

© Chinese Chemical Society, Institute of Chemistry, Chinese Academy of Sciences and Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Silvana Alfei
    • 1
  • Gaby Brice Taptue
    • 1
  • Silvia Catena
    • 1
  • Angela Bisio
    • 1
  1. 1.Dipartimento di Farmacia, Sezione di Chimica e Tecnologie Farmaceutiche e AlimentariUniversità di GenovaGenovaItaly

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