Heparin-Coated Liposomes Improve Antiplasmodial Activity and Reduce the Toxicity of Poupartone B

Abstract

Poupartone B is an alkyl cyclohexenone derivative isolated from Poupartia borbonica. This compound demonstrated promising antimalarial activity (IC₅₀ < 1 µg/mL), however, it was not devoid of toxicity. Thus, to reduce the adverse side effects of this natural bioactive molecule, a delivery strategy involving a nanostructure was formulated. Additionally, poupartone B-loaded liposomes were coated with heparin, a glycosaminoglycan that is known to target proteins on the surface of Plasmodium falciparum-infected red blood cells. The quantification of the compound in the formulation was performed by HPLC-DAD, while heparin was quantitated by ¹H NMR spectroscopy. The liposomes’ antiplasmodial activity was tested on artemisinin-resistant P. falciparum isolate, and toxicity was evaluated on human HeLa cells and zebrafish embryos. Throughout this research, the formulation demonstrated higher antiplasmodial activities against both P. falciparum strains and a significant decrease of in vitro toxicity. The formulation improved the selectivity index 2 times in vitro and proved to be 3 times less toxic than the compound alone in the zebrafish embryo acute toxicity test. Hence, the use of this strategy to deliver natural products in Plasmodium-infected cells, particularly those with a narrow therapeutic margin, is proposed.

Key words

poupartone - liposome - malaria - artemisinin resistance - Poupartia borbonica - anacardiaceae

Publikationsverlauf

Eingereicht: 04. November 2019
Eingereicht: 01. April 2020

Angenommen: 13. April 2020

Artikel online veröffentlicht:
18. Mai 2020

• References

• 1 D’Alessandro U, Buttiens H. History and importance of antimalarial drug resistance. Trop Med Int Heal 2001; 6: 845-848
• 2 World Health Organization. World malaria report 2016. WHO, 186. Available at: http://www.who.int/malaria/publications/world-malaria-report-2016/report/en/,
• 3 Tilley L, Straimer J, Gnädig NF, Ralph SA, Fidock DA. Artemisinin action and resistance in Plasmodium falciparum . Trends Parasitol 2016; 32: 682-696
• 4 Witkowski B, Lelièvre J, Barragán MJL, Laurent V, Su XZ, Berry A, Benoit-Vical F. Increased tolerance to artemisinin in Plasmodium falciparum is mediated by a quiescence mechanism. Antimicrob Agents Chemother 2010; 54: 1872-1877
• 5 Newman DJ, Cragg GM. Natural products as sources of new drugs from 1981 to 2014. J Nat Prod 2016; 79: 629-661
• 6 Bordignon A, Frédérich M, Ledoux A, Campos PE, Clerc P, Hermann T, Quetin-Leclercq J, Cieckiewicz E. In vitro antiplasmodial and cytotoxic activities of sesquiterpene lactones from Vernonia fimbrillifera Less. (Asteraceae). Nat Prod Res 2017; 32: 1463-1466
• 7 Helms G, Dasanna AK, Schwarz US, Lanzer M. Modeling cytoadhesion of Plasmodium falciparum-infected erythrocytes and leukocytes-common principles and distinctive features. FEBS Lett 2016; 590: 1955-1971
• 8 Juillerat A, Igonet S, Vigan-Womas I, Guillotte M, Gangnard S, Faure G, Baron B, Raynal B, Mercereau-Puijalon O, Bentley GA. Biochemical and biophysical characterisation of DBL1α1-varO, the rosetting domain of PfEMP1 from the VarO line of Plasmodium falciparum . Mol Biochem Parasitol 2010; 170: 84-92
• 9 Regev-Rudzki N, Wilson DW, Carvalho TG, Sisquella X, Coleman BM, Rug M, Bursac D, Angrisano F, Gee M, Hill AF, Baum J, Cowman AF. Cell-cell communication between malaria-infected red blood cells via exosome-like vesicles. Cell 2013; 153: 1120-1133
• 10 Marques J, Moles E, Urbán P, Prohens R, Busquets MA, Sevrin C, Grandfils C, Fernández-Busquets X. Application of heparin as a dual agent with antimalarial and liposome targeting activities toward Plasmodium-infected red blood cells. Nanomedicine 2014; 10: 1719-1728
• 11 Rathore D, McCutchan TF. Heparin can regulate the binding of Plasmodium falciparum circumsporozoite protein. Mol Biochem Parasitol 2000; 108: 253-256
• 12 Ismail M, Ling L, Du Y, Yao C, Li X. Liposomes of dimeric artesunate phospholipid: A combination of dimerization and self-assembly to combat malaria. Biomaterials 2018; 163: 76-87
• 13 Isacchi B, Arrigucci S, La Marca G, Bergonzi MC, Vannucchi MG, Novelli A, Bilia AR. Conventional and long-circulating liposomes of artemisinin: preparation, characterization, and pharmacokinetic profile in mice. J Liposome Res 2011; 21: 237-244
• 14 Aditya NP, Vathsala PG, Vieira V, Murthy RSR, Souto EB. Advances in nanomedicines for malaria treatment. Adv Colloid Interface Sci 2013; 201-202: 1-17
• 15 Ledoux A, St-Gelais A, Cieckiewicz E, Jansen O, Bordignon A, Illien B, Di Giovanni N, Marvilliers A, Hoareau F, Pendeville H, Quetin-Leclercq J, Frédérich M. Antimalarial activities of alkyl cyclohexenone derivatives isolated from the leaves of Poupartia borbonica . J Nat Prod 2017; 80: 1750-1757
• 16 Otto A, Porzel A, Schmidt J, Brandt W, Wessjohann L, Arnold N. Structure and absolute configuration of pseudohygrophorones A¹² and B¹², alkyl cyclohexenone derivatives from Hygrophorus abieticola (Basidiomycetes). J Nat Prod 2016; 79: 74-80
• 17 Roumy V, Fabre N, Portet B, Bourdy G, Acebey L, Vigor C, Valentin A, Moulis C. Four anti-protozoal and anti-bacterial compounds from Tapirira guianensis . Phytochemistry 2009; 70: 305-311
• 18 David JM, Chavez JP, Chai HB, Pezzuto JM, Cordell GA. New cytotoxic compounds from Tapirira guianensis . J Nat Prod 1998; 61: 287-289
• 19 Correia SDJ, David JM, David JP, Chai HB, Pezzuto JM, Cordell GA. Alkyl phenols and derivatives from Tapirira obtusa . Phytochemistry 2001; 56: 781-784
• 20 Bozzuto G, Molinari A. Liposomes as nanomedical devices. Int J Nanomedicine 2015; 10: 975-999
• 21 Kang JH, Jang WY, Ko YT. The effect of surface charges on the cellular uptake of liposomes investigated by live cell imaging. Pharm Res 2017; 34: 704-717
• 22 Naveen P, Lingaraju HB, Deepak M, Medhini B, Prasad KS. Method development and validation for the determination of caffeine: An alkaloid from Coffea arabica by high-performance liquid chromatography method. Pharmacognosy Res 2018; 10: 88-91
• 23 Whiteman P. The quantitative measurement of Alcian Blue-glycosaminoglycan complexes. Biochem J 1973; 131: 343-350
• 24 Baumgärtner F, Jourdan J, Scheurer C, Blasco B, Campo B, Mäser P, Wittlin S. In vitro activity of anti-malarial ozonides against an artemisinin-resistant isolate. Malar J 2017; 16: 45
• 25 Witkowski B, Khim N, Chim P, Kim S, Ke S, Kloeung N, Chy S, Duong S, Leang R, Ringwald P, Dondorp AM, Tripura R, Benoit-Vical F, Berry A, Gorgette O, Ariey F, Barale JC, Mercereau-Puijalon O, Menard D. Reduced artemisinin susceptibility of Plasmodium falciparum ring stages in western Cambodia. Antimicrob Agents Chemother 2013; 57: 914-923
• 26 Yaouba S, Koch A, Guantai EM, Derese S, Irungu B, Heydenreich M, Yenesew A. Alkenyl cyclohexanone derivatives from Lannea rivae and Lannea schweinfurthii . Phytochem Lett 2017; 23: 141-148
• 27 Okoth DA, Akala HM, Johnson JD, Koorbanally NA. Alkyl phenols, alkenyl cyclohexenones and other phytochemical constituents from Lannea rivae (chiov) Sacleux (Anacardiaceae) and their bioactivity. Med Chem Res 2016; 25: 690-703
• 28 MacDonald RC, MacDonald RI, Menco BP, Takeshita K, Subbarao NK, Hu LR. Small-volume extrusion apparatus for preparation of large, unilamellar vesicles. Biochim Biophys Acta 1991; 1061: 297-303
• 29 BEI Resources, BEI Reagent Search. Available at https://www.beiresources.org/Catalog/BEIParasiticProtozoa/MRA-102.aspx
• 30 BEI Resources, BEI Reagent Search. Available from https://www.beiresources.org/Catalog/BEIParasiticProtozoa/MRA-1236.aspx,
• 31 Trager W, Jensen JB. Human malaria parasites in continuous culture. Science 1976; 193: 673-675
• 32 Jansen O, Angenot L, Tits M, Nicolas JP, De Mol P, Nikiéma JB, Frédérich M. Evaluation of 13 selected medicinal plants from Burkina Faso for their antiplasmodial properties. J Ethnopharmacol 2010; 130: 143-150
• 33 Makler MT, Ries JM, Williams JA, Bancroft JE, Piper RC, Gibbins BL, Hinrichs DJ. Parasite lactate dehydrogenase as an assay for Plasmodium falciparum drug sensitivity. Am J Trop Med Hyg 1993; 48: 739-741
• 34 Ali S, Mil HGJVan, Richardson MK. Large-scale assessment of the zebrafish embryo as a possible predictive model in toxicity testing. PLoS One 2011; 6: e21076