Self-assembled 4-(1,2-diphenylbut-1-en-1-yl)aniline based nanoparticles: podophyllotoxin and aloin as building blocks

Fumagalli, Gaia; Christodoulou, Michael S.; Riva, Beatrice; Revuelta, Inigo; Marucci, Cristina; Collico, Veronica; Prosperi, Davide; Riva, Sergio; Perdicchia, Dario; Bassanini, Ivan; García-Argáez, Aída Nelly; Passarella, Daniele

doi:10.1039/c6ob02591a

Cited by 14 publications

(21 citation statements)

References 18 publications

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“…Squalenoylation is a rapidly emerging strategy to prepare innovative novel nanoconjugates from various bioactive compounds (Arias et al, 2011;Desmaele et al, 2012;Borrelli et al, 2014;Maksimenko et al, 2014;Fumagalli et al, 2017a;Fumagalli et al, 2017b;Rouquette et al, 2019), therefore our NMR results may be applicable and useful to the description and purity evaluation of a wide range of such compounds. For example, in our case, the signal ratio of ca.…”

Section: Nmr Investigationsmentioning

confidence: 99%

Squalenoylated Nanoparticle Pro-Drugs of Adjuvant Antitumor 11α-Hydroxyecdysteroid 2,3-Acetonides Act as Cytoprotective Agents Against Doxorubicin and Paclitaxel

et al. 2020

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Several ecdysteroid acetonides act as adjuvant chemo-sensitizing agents against various cancer cell lines, and they can be formulated to self-assembling nanoparticle (NP) pro-drugs through a hydrolysable conjugation with squalene. In the bloodstream such squalenoylated nanoparticles dissolve into low-density lipoprotein (LDL) that allows targeting tissues containing high levels of LDL-receptors. In this work, ajugasterone C 2,3;20,22-diacetonide (3) and 11a-hydroxypoststerone 2,3-acetonide (4) were squalenoylated to obtain two new ecdysteroid pro-drugs (6 and 7) and their nano-assemblies (6 NP and 7 NP). A complete NMR signal assignment of 6 and 7 was achieved. Interaction of compounds 3 and 4 with chemotherapeutics was studied by the Chou-Talalay method. Compound 3 showed strong synergism with doxorubicin on a multi-drug resistant lymphoma cell line. In contrast, its nanoassembly 6 NP significantly decreased the cytotoxicity of doxorubicin on these MDR cells, strongly suggesting that at least the 2,3-acetonide group was cleaved by the acidic pH of lysosomes after endocytosis of the prodrug. Further, compound 4 acted in strong antagonism with paclitaxel on MCF-7 cells and its nanoassemby 7 NP also protected MCF-7 cells from the effect of paclitaxel. Our results suggest that acid-resistant A-ring substitution would be crucial to design adjuvant antitumor squalenoylated ecdysteroid prodrugs. Additionally, our results may be considered as a serendipitous discovery of a novel way to deliver cytoprotective, adaptogen ecdysteroids to healthy tissues with upregulated LDL-R.

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Section: Nmr Investigationsmentioning

confidence: 99%

Squalenoylated Nanoparticle Pro-Drugs of Adjuvant Antitumor 11α-Hydroxyecdysteroid 2,3-Acetonides Act as Cytoprotective Agents Against Doxorubicin and Paclitaxel

et al. 2020

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“…By using self-assembling conjugates it is possible to increase the loading capacity of the NPs and eliminate the need of a carrier [ 6 ]. This overcomes important drawbacks of nanomedicines including the use of many excipients, low drug loading efficiency, and crystallization [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…Squalene is a lipidic moiety and a natural precursor of many steroids that spontaneously form self-assembling NPs in water, with an unusually high drug content. Since squalene is well tolerated, it makes it an ideal component of the drug delivery system [ 7 , 9 , 13 ]. Another attractive option commonly used as lipidic moieties is fatty acids due to their biodegradability and biosafety.…”

Section: Introductionmentioning

confidence: 99%

Self-Assembly Nanoparticles of Natural Bioactive Abietane Diterpenes

Ntungwe

Domínguez-Martín

Bangay

et al. 2021

IJMS

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Different approaches have been reported to enhance penetration of small drugs through physiological barriers; among them is the self-assembly drug conjugates preparation that shows to be a promising approach to improve activity and penetration, as well as to reduce side effects. In recent years, the use of drug-conjugates, usually obtained by covalent coupling of a drug with biocompatible lipid moieties to form nanoparticles, has gained considerable attention. Natural products isolated from plants have been a successful source of potential drug leads with unique structural diversity. In the present work three molecules derived from natural products were employed as lead molecules for the synthesis of self-assembled nanoparticles. The first molecule is the cytotoxic royleanone 7α-acetoxy-6β-hydroxyroyleanone (Roy, 1) that has been isolated from hairy coleus (Plectranthus hadiensis (Forssk.) Schweinf). ex Sprenger leaves in a large amount. This royleanone, its hemisynthetic derivative 7α-acetoxy-6β-hydroxy-12-benzoyloxyroyleanone (12BzRoy, 2) and 6,7-dehydroroyleanone (DHR, 3), isolated from the essential oil of thicket coleus (P. madagascariensis (Pers.) Benth.) were employed in this study. The royleanones were conjugated with squalene (sq), oleic acid (OA), and/or 1-bromododecane (BD) self-assembly inducers. Roy-OA, DHR-sq, and 12BzRoy-sq conjugates were successfully synthesized and characterized. The cytotoxic effect of DHR-sq was previously assessed on three human cell lines: NCI-H460 (IC50 74.0 ± 2.2 µM), NCI-H460/R (IC50 147.3 ± 3.7 µM), and MRC-5 (IC50 127.3 ± 7.3 µM), and in this work Roy-OA NPs was assayed against Vero-E6 cells at different concentrations (0.05, 0.1, and 0.2 mg/mL). The cytotoxicity of DHR-sq NPs was lower when compared with DHR alone in these cell lines: NCI-H460 (IC50 10.3 ± 0.5 µM), NCI-H460/R (IC50 10.6 ± 0.4 µM), and MRC-5 (IC5016.9 ± 0.5 µM). The same results were observed with Roy-OA NPs against Vero-E6 cells as was found to be less cytotoxic than Roy alone in all the concentrations tested. From the obtained DLS results, 12BzRoy-sq assemblies were not in the nano range, although Roy-OA NP assemblies show a promising size (509.33 nm), Pdl (0.249), zeta potential (-46.2mV), and spherical morphology from SEM. In addition, these NPs had a low release of Roy at physiological pH 7.4 after 24 h. These results suggest the nano assemblies can act as prodrugs for the release of cytotoxic lead molecules.

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“…We reported NAs composed by conjugate releasable compounds [32]; by single and dual drug fluorescent hetero-NAs [33,34], by dual drug hetero-NAs (cyclopamine/taxol [34], cyclopamine/doxorubicin [35], ecdysteroid/doxorubicin [36]), and by self-assembling conjugate dual drug NAs [37]. We prepared compounds containing a squalene [31,32,33,34,35] or a 4-(1,2-diphenylbut-1-en-1-yl)aniline tail [37,38] that leads to NAs ability to self-assemble in water. We recently reported the assembly and characterization of squalene-thiocolchicine NAs that release cytotoxic, free thiocolchicine in cancer cells through a disulfide bond or a p -hydroxybenzyl moiety [38].…”

Section: Introductionmentioning

confidence: 99%

Nanolipid-Trehalose Conjugates and Nano-Assemblies as Putative Autophagy Inducers

et al. 2019

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The disaccharide trehalose is an autophagy inducer, but its pharmacological application is severely limited by its poor pharmacokinetics properties. Thus, trehalose was coupled via suitable spacers with squalene (in 1:2 and 1:1 stoichiometry) and with betulinic acid (1:2 stoichiometry), in order to yield the corresponding nanolipid-trehalose conjugates 1-Sq-mono, 2-Sq-bis and 3-Be-mono. The conjugates were assembled to produce the corresponding nano-assemblies (NAs) Sq-NA1, Sq-NA2 and Be-NA3. The synthetic and assembly protocols are described in detail. The resulting NAs were characterized in terms of loading and structure, and tested in vitro for their capability to induce autophagy. Our results are presented and thoroughly commented upon.

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Self-assembled 4-(1,2-diphenylbut-1-en-1-yl)aniline based nanoparticles: podophyllotoxin and aloin as building blocks

Cited by 14 publications

References 18 publications

Squalenoylated Nanoparticle Pro-Drugs of Adjuvant Antitumor 11α-Hydroxyecdysteroid 2,3-Acetonides Act as Cytoprotective Agents Against Doxorubicin and Paclitaxel

Squalenoylated Nanoparticle Pro-Drugs of Adjuvant Antitumor 11α-Hydroxyecdysteroid 2,3-Acetonides Act as Cytoprotective Agents Against Doxorubicin and Paclitaxel

Self-Assembly Nanoparticles of Natural Bioactive Abietane Diterpenes

Nanolipid-Trehalose Conjugates and Nano-Assemblies as Putative Autophagy Inducers

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