Bio-Guided Isolation of Acetogenins from Annona cherimola Deciduous Leaves: Production of Nanocarriers to Boost the Bioavailability Properties

Abstract

Annonaceous acetogenins (ACGs) are lipophilic polyketides isolated exclusively from Annonaceae. They are considered to be amongst the most potent antitumor compounds. Nevertheless, their applications are limited by their poor solubility. The isolation of ACGs from Annona cherimola leaves, an agricultural waste, has not been reported to date. Molvizarin (1) cherimolin-1 (2), motrilin (3), annonacin (4) and annonisin (5) are isolated for the first time from A. cherimola deciduous leaves. Annonacin was found to be four- and two-times more potent in tumoral cells (HeLa, 23.6% live cells; IGROV-1, 40.8% live cells for 24 h) than in HEK-293 at 50 µM (24 h, 87.2% live cells). Supramolecular polymer micelles (SMPMs) were synthesized to encapsulate the major ACG isolated, annonacin, in order to improve its solubility in aqueous media. The bioavailability of this compound was increased by a factor of 13 in a simulated human digestive system when compared with free annonacin and an encapsulation efficiency of 35% was achieved. In addition, the cytotoxic activity of SMPMs that hosted annonacin (100 µM, 24 h, 5.8% live cells) was increased compared with free annonacin in water (100 µM, 24 h, 92% live cells). These results highlight the use of by-products of A. cherimola, and their pure compounds, as a promising source of anticancer agents. The use of SMPMs as nanocarriers of ACGs could be an alternative for their application in food field as nutraceutical to enhance the administration and efficacy.

An Overview of the Chemical Characteristics, Bioactivity and Achievements Regarding the Therapeutic Usage of Acetogenins from Annona cherimola Mill.

“…Gutiérrez et al employed SMPMs based on α-CD and urea to encapsulate annonacin. In line with other studies, cytotoxicity to liver cells was the main objective, and it was proven that annonacin is selective to tumor cells, with over 87% of cell survival when the acetogenin is applied to non-tumoral liver cells (HEK-293) [ 20 ]. In this case, although both the encapsulation percentage and the drug delivery time provided the lowest values, it should be highlighted that annonacin is completely different from other previously encapsulated and tested acetogenins, since it presents a mono-THF structure instead of the bis-THF structure of bullatacin.…”

“…ACGs have recently generated considerable interest because of the wide range of biological activities that they have exhibited, such as anti-inflammatory, pesticidal, antimicrobial and particularly cytotoxic activities. Several studies have already demonstrated that these compounds present either none or minimal toxicity to normal cells but are highly toxic to cancerous cells [ 20 , 40 , 41 ].…”

“…From the moment acetogenins were discovered, many researchers have tried to synthesize mimics or analogous structures with a similar bioactivity profile but with a less complicated production process at laboratory scale. Attending to isolation yields, most authors reported values between 0.00019% and 0.003% [ 20 , 26 ], which poses a limit on the prospective practical usage of the acetogenins found in Annona cherimola . Naturally, different methods have been implemented to try and increase the yields obtained from the synthesis of acetogenins.…”

“…[15]. ACGs are currently considered to be amongst the most potent antitumoral compounds [20]. Both in vitro and in vivo cytotoxic activity against a large number of tumoral cell lines-some of them resistant to regular therapies-have been studied [18,21,22].…”

“…One lactone ring, at one of the ends of the molecule, completes the structure up to C37 (Figure 1) [16][17][18][19]. ACGs are currently considered to be amongst the most potent antitumoral compounds [20]. Both in vitro and in vivo cytotoxic activity against a large number of tumoral cell lines-some of them resistant to regular therapies-have been studied [18,21,22].…”