Stepwise Glucoheptoamidation of Poly(Amidoamine) Dendrimer G3 to Tune Physicochemical Properties of the Potential Drug Carrier: In Vitro Tests for Cytisine Conjugates

Czerniecka‐Kubicka, Anna; Tutka, Piotr; Pyda, M.; Walczak, Małgorzata; Uram, Łukasz; Misiorek, Maria; Chmiel, Ewelina; Wołowiec, Stanisław

doi:10.3390/pharmaceutics12050473

Cited by 10 publications

(13 citation statements)

References 42 publications

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“…Tsypysheva et al also investigated the cytotoxic properties of cytisine derivatives against cell lines НЕК293, Jurkat, A549, MCF-7, and SH-SY5Y [10]. Cytisine was nontoxic against normal human fibroblasts (BJ), human squamous cell carcinoma (SCC-15), and U-118 human glioma cells up to 500 µM after 24 h incubation [11].…”

Section: Introductionmentioning

confidence: 99%

Determination of Cytisine and N-Methylcytisine from Selected Plant Extracts by High-Performance Liquid Chromatography and Comparison of Their Cytotoxic Activity

Petruczynik

Wróblewski

Misiurek

et al. 2020

Toxins

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Quinolizidine alkaloids exhibit various forms of biological activity. A lot of them were found in the Leguminosae family, including Laburnum and Genista. The aim of the study was the optimization of a chromatographic system for the analysis of cytisine and N-methylcytisine in various plant extracts as well as an investigation of the cytotoxic activities of selected alkaloids and plant extracts obtained from Laburnum anagyroides, Laburnum anagyroides L. quercifolium, Laburnum alpinum, Laburnum watereri, Genista germanica, and Genista tinctoria against various cancer cell lines. The determination of investigated compounds was performed by High Performance Liquid Chromatography with Diode Array Detection (HPLC-DAD), while High Performance Liquid Chromatography coupled with Quadrupole Time-of-Flight–Mass Spectrometry (HPLC-QTOF-MS) was applied for the qualitative analysis of plant extracts. The retention, separation selectivity, peaks shape, and systems efficiency obtained for cytisine and N-methylcytisine in different chromatographic systems were compared. The application of columns with alkylbonded and phenyl stationary phases led to a very weak retention of cytisine and N-methylcytisine, even when the mobile phases containing only 5% of organic modifiers were used. The strongest retention was observed when hydrophilic interaction chromatography (HILIC) or especially when ion exchange chromatography (IEC) were applied. The most optimal system in terms of alkaloid retention, peak shape, and system efficiency containing an strong cation exchange (SCX) stationary phase and a mobile phase consisted of 25% acetonitrile and formic buffer at pH 4.0 was applied for investigating alkaloids analysis in plant extracts. Cytotoxic properties of the investigated plant extracts as well as cytisine and N-methylcytisine were examined using human tongue squamous carcinoma cells (SCC-25), human pharyngeal squamous carcinoma cells (FaDu), human triple-negative breast adenocarcinoma cell line (MDA-MB-231), and human breast adenocarcinoma cell line (MCF-7). The highest cytotoxic activity against FaDu, MCF-7, and MDA-MB cancer cell lines was observed after applying the Genista germanica leaves extract. In contrast, the highest cytotoxic activity against SCC-25 cell line was obtained after treating with the seed extract of Laburnum watereri. The investigated plant extracts exhibit significant cytotoxicity against the tested human cancer cell lines and seem to be promising for further research on its anticancer activity.

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Section: Introductionmentioning

confidence: 99%

Determination of Cytisine and N-Methylcytisine from Selected Plant Extracts by High-Performance Liquid Chromatography and Comparison of Their Cytotoxic Activity

Petruczynik

Wróblewski

Misiurek

et al. 2020

Toxins

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“…The encapsulation of ALA by conjugates was accompanied by an increase of molecular size of conjugates, comparable to those observed for protonation. Thus, the number-average size determined by dynamic light scattering (DLS) of G3 32gh in water was 1.8 (±0.2) nm, while the molecule expanded into 4.0 (±0.2) nm at pH 5 [ 31 ]. The molecules of G3 32gh , G3 2B27gh , and G3 6B21gh expanded from 2.0 (±0.2) nm in water into 5.0, 5.3, and 5.4 (±0.3) nm upon addition of 5 equivalents of ALAxHCl and further for solution containing 16 equivalents of ALA.…”

Section: Resultsmentioning

confidence: 99%

“…The chitosan was further equipped with folic acid for targeting cell membrane and enhancing nanoparticle endocytosis via the folate receptor [ 36 ]. Generally, a dendrimer-based PSDS can be constructed either as encapsulates of PS in dendrimer [ 37 , 38 , 39 , 40 ] or conjugates of the dendrimer with the PS molecule attached covalently [ 31 ]. In both strategies, the dendrimeric carrier can be designed to enter the cell; in the latter, the active molecule of PS needs to be cleaved from the conjugate [ 41 ].…”

Section: Resultsmentioning

confidence: 99%

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Biotin-Containing Third Generation Glucoheptoamidated Polyamidoamine Dendrimer for 5-Aminolevulinic Acid Delivery System

Kaczorowska

Malinga-Drozd

Kałas

et al. 2021

IJMS

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Polyamidoamine PAMAM dendrimer generation 3 (G3) was modified by attachment of biotin via amide bond and glucoheptoamidated by addition of α-D-glucoheptono-1,4-lacton to obtain a series of conjugates with a variable number of biotin residues. The composition of conjugates was determined by detailed 1-D and 2-D NMR spectroscopy to reveal the number of biotin residues, which were 1, 2, 4, 6, or 8, while the number of glucoheptoamide residues substituted most of the remaining primary amine groups of PAMAM G3. The conjugates were then used as host molecules to encapsulate the 5-aminolevulinic acid. The solubility of 5-aminolevulinic acid increased twice in the presence of the 5-mM guest in water. The interaction between host and guest was accompanied by deprotonation of the carboxylic group of 5-aminolevulinic acid and proton transfer into internal ternary nitrogen atoms of the guest as evidenced by a characteristic chemical shift of resonances in the 1H NMR spectrum of associates. The guest molecules were most likely encapsulated inside inner shell voids of the host. The number of guest molecules depended on the number of biotin residues of the host, which was 15 for non-biotin-containing glucoheptoamidated G3 down to 6 for glucoheptoamidated G3 with 8 biotin residues on the host surface. The encapsulates were not cytotoxic against Caco-2 cells up to 200-µM concentration in the dark. All encapsulates were able to deliver 5-aminolevulinic acid to cells but aqueous encapsulates were more active in this regard. Simultaneously, the reactive oxygen species were detected by staining with H2DCFDA in Caco-2 cells incubated with encapsulates. The amount of PpIX was sufficient for induction of reactive oxygen species upon 30-s illumination with a 655-nm laser beam.

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“…Therefore, PAMAM G3, G4, and G5 dendrimers with 32, 64, and 128 amine groups, respectively, were used to covalently bind anticancer drug molecules such as methotrexate [ 6 ], daunorubicin [ 7 ], or paclitaxel [ 8 ] to obtain highly drug-loaded conjugates. Additionally, the hydrophilic properties of these macromolecular drug carriers can be tuned by terminal amine group acylation or polyhydroxylation with glycidol [ 7 , 8 , 9 ] or carbohydrate lactones [ 6 , 10 , 11 ]. Thus, PAMAM chiral dendrimers can be obtained that are surface-modified with various substituents, derived from D-gluconolactone [ 10 ], D-glucoheptono-1,4-lactone [ 6 , 12 ], amino acids [ 13 ], and by polyethylene glycol (PEG)ylation [ 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

Chiral Recognition of Homochiral Poly (amidoamine) Dendrimers Substituted with R- and S-Glycidol by Keratinocyte (HaCaT) and Squamous Carcinoma (SCC-15) Cells In Vitro

et al. 2021

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The generation 2 and 3 poly(amidoamine) dendrimers (PAMAM G2 and G3) were converted into N-(2,3-dihydroxy)propyl derivatives by the addition of enantiomerically pure S- and R-glycidol. The homochiral dendrimers bind to HaCaT and SCC-15 cell membranes with an R/S glycidol enantioselectivity ratio of 1.5:1, as was quantitatively determined by fluorescence microscopy and visualized by confocal microscopy. Fully substituted G2 and G3 dendrimers were equipped with 32 and 64 N-(2,3-dihydroxy)propyl residues and showed effectively radial symmetry for homochiral derivatives in 13C NMR spectrum in contrary to analogs obtained by reaction with rac-glycidol. The sub-stoichiometric derivatives of G2 and G3 were also obtained in order to characterize them spectroscopically. The homochiral dendrimers were labeled with two different fluorescent labels, fluorescein, and rhodamine B, using their isothiocyanates to react with G2 and G3 followed by the addition of S- and R-glycidol. Obtained fluorescent derivatives were deficiently filled with N-(2,3-dihydroxy)propyl substituents due to steric hindrance imposed by the attached label. Nevertheless, these derivatives were used to determine their ability to bind to the cell membrane of human keratinocytes (HaCaT) and squamous carcinoma cells (SCC-15). Confocal microscopy images obtained from cells treated with variously labeled conjugates and fluorescence analysis with fluorescence reader allowed us to conclude that R-glycidol derivatives were bound and entered the cells preferentially, with higher accumulation in cancer cells. The G3 polyamidoamine (PAMAM)-based dendrimers were taken up more efficiently than G2 derivatives. Moreover, S- and R-glycidol furnished dendrimers were highly biocompatible with no toxicity up to 300 µM concentrations, in contrast to the amine-terminated PAMAM analogs.

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Stepwise Glucoheptoamidation of Poly(Amidoamine) Dendrimer G3 to Tune Physicochemical Properties of the Potential Drug Carrier: In Vitro Tests for Cytisine Conjugates

Cited by 10 publications

References 42 publications

Determination of Cytisine and N-Methylcytisine from Selected Plant Extracts by High-Performance Liquid Chromatography and Comparison of Their Cytotoxic Activity

Determination of Cytisine and N-Methylcytisine from Selected Plant Extracts by High-Performance Liquid Chromatography and Comparison of Their Cytotoxic Activity

Biotin-Containing Third Generation Glucoheptoamidated Polyamidoamine Dendrimer for 5-Aminolevulinic Acid Delivery System

Chiral Recognition of Homochiral Poly (amidoamine) Dendrimers Substituted with R- and S-Glycidol by Keratinocyte (HaCaT) and Squamous Carcinoma (SCC-15) Cells In Vitro

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