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

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Abstract

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.

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References

  1. Hourani, R.; Kakkar, A. Advances in the elegance of chemistry in designing dendrimers. Macromol. Rapid Commun. 2010, 31, 947–974

    Article  CAS  PubMed  Google Scholar 

  2. Sowinska, M.; Urbanczyk-Lipkowska, Z. Advances in the chemistry of dendrimers. New J. Chem. 2014, 38, 2168–2203

    Article  CAS  Google Scholar 

  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, 139–150

    Article  Google Scholar 

  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, 362–368

    Article  CAS  PubMed  Google Scholar 

  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, 6595–605

    Article  CAS  PubMed  Google Scholar 

  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, 989–997

    Article  CAS  PubMed  Google Scholar 

  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, 9132–9139

    Article  CAS  Google Scholar 

  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, 2489–2494

    Article  CAS  Google Scholar 

  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, 717–724

    Article  CAS  Google Scholar 

  10. Kesharwani, P.; Jain, K.; Jain, N. Dendrimer as nanocarrier for drug delivery. Prog. Polym. Sci. 2014, 39, 268–307

    Article  CAS  Google Scholar 

  11. Datija, J.; Sai, V. V. R.; Mukherji, S. Dendrimers in biosensors: concept and applications. J. Mater. Chem. 2011, 21, 14367–14386

    Article  CAS  Google Scholar 

  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. 375–392

    Google Scholar 

  13. Kim, J. H.; Park, K.; Nam, H. Y., Lee, S.; Kim, K.; Kwon, I. C. Polymers for bioimaging. Prog. Polym. Sci. 2007, 32, 1031–1053

    Article  CAS  Google Scholar 

  14. Wang, Z.; Niu, G.; Chen, X. Polymeric materials for theranostic applications. Pharm. Res. 2014, 31, 1358–1376

    Article  CAS  PubMed  Google Scholar 

  15. Dufes, C.; Uchegbu, I. F.; Schätzlein, A. G. Dendrimers in gene delivery. Adv. Drug Deliver. Rev. 2005, 57, 2177–2202

    Article  CAS  Google Scholar 

  16. Eliyahu, H.; Barenholz, Y.; Domb, A. J. Polymers for DNA delivery. Molecules 2005, 10, 34–64

    Article  CAS  PubMed  Google Scholar 

  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, 581–593

    Article  CAS  PubMed  Google Scholar 

  18. Schaffert, D.; Wagner, E. Gene therapy progress and prospects: synthetic polymer-based systems. Gene Ther. 2008, 15, 1131–1138

    Article  CAS  PubMed  Google Scholar 

  19. Mintzer, M. A.; Simanek, E. E. Nonviral vectors for gene delivery. Chem. Rev. 2009, 109, 259–302

    Article  CAS  PubMed  Google Scholar 

  20. O’Rorke, S.; Keeney, M.; Pandit, A. Non-viral polyplexes: scaffold mediated delivery for gene therapy. Prog. Polym. Sci. 2010, 35, 441–458

    Article  CAS  Google Scholar 

  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, 97–108

    CAS  Google Scholar 

  22. Guo, X.; Huang, L. Recent advances in nonviral vectors for gene delivery. Acc. Chem. Res. 2012, 45, 971–979

    Article  CAS  PubMed  Google Scholar 

  23. Yue, Y.; Wu, C. Progress and perspectives in developing polymeric vectors for in vitro gene delivery. Biomater. Sci. 2013, 1, 152–170

    Article  CAS  Google Scholar 

  24. Biswas, S.; Torchilin, V. P. Dendrimers for siRNA delivery. Pharmaceuticals 2013, 6, 161–183

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Pourianazar, N. T.; Mutulu, P.; Gunduz, U. Bioapplications of poly(amidoamine) (PAMAM) dendrimers in nanomedicine. J. Nanopart. Res. 2014, 16, 2342/1-2342/38

    Article  CAS  Google Scholar 

  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, 1–173

    Article  CAS  Google Scholar 

  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, 232–245

    Article  CAS  Google Scholar 

  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, 335–341

    CAS  Google Scholar 

  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, 2156–2165

    Article  CAS  PubMed  Google Scholar 

  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, 55–63

    Article  CAS  PubMed  Google Scholar 

  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, 2557–2564

    CAS  PubMed  Google Scholar 

  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, 123–130

    Article  CAS  PubMed  Google Scholar 

  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, 2054–2060

    Article  CAS  Google Scholar 

  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, 9–38

    Article  CAS  Google Scholar 

  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, 3305–3312

    Article  CAS  PubMed  Google Scholar 

  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, 815–817

    Article  CAS  Google Scholar 

  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, 1928–1963

    Article  CAS  Google Scholar 

  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, 1204–1214

    Article  CAS  Google Scholar 

  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, 1544–1536

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Park, J. H.; Park, J. S.; Choi, J. S. Basic amino acidconjugated polyamidoamine dendrimers with enhanced gene transfection efficiency. Macromol. Res. 2014, 22, 500–508

    Article  CAS  Google Scholar 

  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, 9187–9198

    Article  CAS  PubMed  Google Scholar 

  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, 592–597

    Article  CAS  Google Scholar 

  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, 665–673

    Article  CAS  PubMed  Google Scholar 

  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, 2317–2323

    Article  CAS  Google Scholar 

  45. Eltoukhy, Q. Effect of molecular weight of amine endmodified poly(P-amino ester)s on gene delivery efficiency and toxicity. Biomaterials 2012, 33, 3594–3603

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, 6951–6957

    Article  CAS  PubMed  Google Scholar 

  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, 195–202

    Article  CAS  PubMed  Google Scholar 

  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, 8111–8121

    Article  CAS  PubMed  Google Scholar 

  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, 9187–9198

    Article  CAS  PubMed  Google Scholar 

  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, 3867–3875

    Article  CAS  PubMed  Google Scholar 

  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, 110–117

    Article  CAS  PubMed  Google Scholar 

  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, 132–139

    Article  CAS  PubMed  Google Scholar 

  53. Liu, J. Pharmacology of oleanolic acid and ursolic acid. J. Ethnopharmacol 1995, 49, 57–68

    Article  CAS  PubMed  Google Scholar 

  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, 101–107

    Article  CAS  PubMed  Google Scholar 

  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, 576–580

    Article  CAS  PubMed  Google Scholar 

  56. Gao, J. Hepatoprotective activity of terminalia catappa l. leaves and its two triterpenoids. J. Pharm. Pharmacol. 2004, 56, 1449–1455

    Article  CAS  PubMed  Google Scholar 

  57. Liu, J. The Effects of 10 triterpenoid compounds on experimental liver injury in mice. Fundam. Appl. Toxicol. 1994, 22, 34–40

    Article  CAS  PubMed  Google Scholar 

  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, 199–206

    Article  CAS  PubMed  Google Scholar 

  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, 713–718

    Article  CAS  PubMed  Google Scholar 

  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, 115–121

    Article  CAS  PubMed  Google Scholar 

  61. Ovesna, Z.; Kozics, K.; Slamenov", D. Protective effects of ursolic acid and oleanolic acid in leukemic cells. Mutation Res 2006, 600, 131–137

    Article  CAS  PubMed  Google Scholar 

  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, 4375–83

    CAS  PubMed  Google Scholar 

  63. Moon H. K.; Yang, E. S.; Park, J. W. Protection of peroxynitrite-induced DNA damage by dietary antioxidant. Arch. Pharm. Res. 2006, 29, 213–217

    Article  CAS  PubMed  Google Scholar 

  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, 2827–2833

    CAS  PubMed  Google Scholar 

  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, 2023–2031

    Article  PubMed  Google Scholar 

  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, 701–708

    CAS  PubMed  Google Scholar 

  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, 279–285

    Article  CAS  PubMed  Google Scholar 

  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, 2769–2779

    Article  CAS  PubMed  Google Scholar 

  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, 66–73

    Article  CAS  PubMed  Google Scholar 

  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, 37–46

    Article  CAS  PubMed  Google Scholar 

  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, 253–260

    Article  CAS  PubMed  Google Scholar 

  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, 1163–1177

    Article  CAS  PubMed  Google Scholar 

  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, 1268–1273

    Article  CAS  Google Scholar 

  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, 1078–1090

    Article  CAS  PubMed  Google Scholar 

  75. Saravanan, R. Pugalendi, V. Impact of ursolic acid on chronic ethanol-induced oxidative stress in the rat heart. Pharmacol. Rep. 2006, 58, 41–47

    CAS  PubMed  Google Scholar 

  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, 1663–1674

    Article  CAS  Google Scholar 

  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, 131–133

    Article  CAS  PubMed  Google Scholar 

  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, 3971–3977

    Article  CAS  PubMed  Google Scholar 

  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, 1062–1068

    Article  CAS  PubMed  Google Scholar 

  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, 443–448

    Article  CAS  PubMed  Google Scholar 

  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, 115–121

    Article  CAS  PubMed  Google Scholar 

  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, 121–129

    Article  CAS  PubMed  Google Scholar 

  83. Ikeda, Y.; Murakami, A.; Ohigashi, H. Ursolic acid: an antiand pro-inflammatory triterpenoid. Mol. Nutr. Food Res. 2008, 52, 26–42

    Article  CAS  PubMed  Google Scholar 

  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, 402–408

    Article  CAS  PubMed  Google Scholar 

  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, 914–925

    Article  CAS  PubMed  Google Scholar 

  86. Kim, M.; Han, C. H.; Lee, M. Y. Enhancement of platelet aggregation by ursolic acid and oleanolic acid. Biomol. Ther 2014, 22, 254–259

    Article  CAS  Google Scholar 

  87. Liu, J. Oleanolic acid and ursolic acid: research perspectives. J. Ethnopharmacol. 2005, 100, 92–94

    Article  CAS  PubMed  Google Scholar 

  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, 9816–9825

    Article  CAS  PubMed  Google Scholar 

  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), 1172–1186

    Article  CAS  Google Scholar 

  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, 10468–10472

    Article  CAS  PubMed  Google Scholar 

  91. Von Seel, F. in "Grundlagen der analytischen Chemie, Vol. 82", ed. By Geier, G., Verlag Chemie, Weinheim, 1970, p. 962

    Google Scholar 

  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, 201–210

    Article  CAS  PubMed  Google Scholar 

  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, 637–645

    CAS  Google Scholar 

  94. Fernandez, L. Solubilization and release properties of dendrimers evaluation as prospective drug delivery systems. J. Supramol. Chem. 2006, 18, 633–643

    Article  CAS  Google Scholar 

  95. Santo, M.; Fox, M. A. Hydrogen bonding interactions between Starburst dendrimers and several molecules of biological interest. Phys. Org. Chem. 1999, 12, 293–307

    Article  CAS  Google Scholar 

  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, 123–143

    Article  CAS  PubMed  Google Scholar 

  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, 239–241

    Article  CAS  PubMed  Google Scholar 

  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, 143–160

    Article  CAS  PubMed  Google Scholar 

  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, 1743–1746

    Article  CAS  Google Scholar 

  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, 144–177

    Article  CAS  Google Scholar 

  101. Seebacher, W.; Simic, N.; Weis, R.; Saf, R.; Kunert, O. Spectral assignments and reference data. Magn. Reson. Chem. 2003, 41, 636–638

    Article  CAS  Google Scholar 

  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, 232–245

    Article  CAS  Google Scholar 

  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, 7195–7206

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

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Acknowledgments

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

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  1. These authors contributed equally to this work.

Authors and Affiliations

  1. Dipartimento di Farmacia, Sezione di Chimica e Tecnologie Farmaceutiche e Alimentari, Università di Genova, Viale Cembrano 4, I-16148, Genova, Italy

    Silvana Alfei, Gaby Brice Taptue, Silvia Catena & Angela Bisio

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  1. Silvana Alfei
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  2. Gaby Brice Taptue
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  3. Silvia Catena
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  4. Angela Bisio
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Correspondence to Silvana Alfei.

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

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Alfei, S., Taptue, G.B., Catena, S. et al. Synthesis of Water-soluble, Polyester-based Dendrimer Prodrugs for Exploiting Therapeutic Properties of Two Triterpenoid Acids. Chin J Polym Sci 36, 999–1010 (2018). https://doi.org/10.1007/s10118-018-2124-9

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  • DOI: https://doi.org/10.1007/s10118-018-2124-9

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