Daunorubicin Complex Research Articles

Therapeutic potential of graphyne as a new drug-delivery system for daunorubicin to treat cancer: A DFT study

In this research, for the first time; graphyne is investigated as a carrier for delivery of anticancer drug, daunorubicin. The effectiveness of graphyne as a carrier, is explored with the help of calculations of some physiochemical properties such as band-gap, dipole-moment, and chemical-reactivity-descriptors for daunorubicin drug, graphyne carrier and daunorubicin-graphyne complex by using Density Functional Theory (DFT) method. Daunorubicin has significant antimitotic and cytotoxic activity as it can form complex with DNA by intercalation. The nature of interactions between graphyne and daunorubicin complex are clarified through noncovalent-interaction (NCI) analysis, which demonstrated that Vander-Waals force of interactions are present between the graphyne carrier molecule and daunorubicin drug. Daunorubicin drug will easily off-load at the target point as weak forces are present between drug and graphyne carrier. Frontier-molecular-orbital-analysis explained that how charge-transferred from daunorubicin to graphyne in complex formation process. The charge-transfer process is further studied by charge-decomposition-analysis (CDA). The calculations at excited-state indicated that the λmax of daunorubicin-graphyne complex show red-shift of 91 nm. PET process is also studied for excited-states of daunorubicin-graphyne complex with the help of electron-hole theory and it revealed that fluorescence-quenching process will occur in complex molecule. The process of fluorescence-detection is very useful for systematic delivery of daunorubicin drug at target site for the perfect treatment. Moreover, the effect of + 1 and −1 charge-state on graphyne molecule and its complex with daunorubicin is also investigated. Overall, the calculations suggested that graphyne could be utilized as an efficient carrier for targeted-delivery of daunorubicin.

Hydrophilic Polyhedral Oligomeric Silsesquioxane, POSS(OH)32, as a Complexing Nanocarrier for Doxorubicin and Daunorubicin.

A novel strategy, recently developed by us, to use polyhedral oligomeric silsesquioxanes (POSS) as an anti-cancer drug carrier is presented. Anthracycline:POSS complexes were prepared by simple co-addition of doxorubicin (DOX) or daunorubicin (DAU) with hydrophilic POSS(OH)32. Co-delivery of POSS and anthracyclines led to higher anti-cancer activity towards HeLa (cervical cancer endothelial) and MCF-7 (human breast adenocarcinoma) cell lines. The obtained supramolecular hybrid complexes were characterised by nuclear magnetic resonance (NMR) spectroscopy (nuclear Overhauser effect spectroscopy [NOESY] and homonuclear correlation spectroscopy [COSY]), Fourier transform infrared spectroscopy (FTIR), and dynamic light scattering (DLS). The two-dimensional (2D) NOESY spectra of the complexes showed the cross-correlation peaks for hydroxyl groups of POSS (~4.3–4.8 ppm) with OH groups of DOX and DAU. FTIR showed that hydroxyl group of POSS can interact with amine and hydroxyl groups of DOX and DAU. The viability of HeLa and MCF-7 was analysed with the MTT assay to evaluate the cytotoxicity of free DOX and DAU and the relevant complexes with POSS at different molar ratios. At a low DOX concentration (2.5 µM), for molar ratios 1:1, 1:4, and 1:8 (POSS:DOX), the complexes showed two and three times higher cytotoxicity towards HeLa and MCF-7 cells, respectively, than DOX itself after both 24- and 48-h incubation. The 1 µM concentration for a 1:4 POSS:DOX molecular ratio and the 2.5 µM concentration for all complexes were more toxic towards MCF-7 cells than free DOX after 48-h incubation. In the case of POSS:DAU complexes, there was higher toxicity than that of free drug after 48-h incubation. It can be concluded that the formation of non-covalent complexes increases toxicity of anthracycline drugs towards Hela and MCF-7 cells. The novel complexes are inexpensive to prepare and more effective than free drugs at low systemic toxicity.

Structure-Dependent Complexation of Fe3+ by Anthracyclines. 1. The Importance of Pendent Hydroxyl Functionality

We have investigated the stability of doxorubicin and daunorubicin complexes with Fe(3+) in aqueous solution. Doxorubicin and daunorubicin are anthracycline chemotherapeutic agents that differ structurally by the presence of a hydroxymethylketone functionality in doxorubicin versus a methyl ketone moiety in daunorubicin. We demonstrate that the presence of the hydroxyl group in doxorubicin enhances its 1:1 complexation with Fe(3+) relative to that seen for daunorubicin. We utilize UV-visible absorbance, circular dichroism, fluorescence and EPR spectroscopies, molecular dynamics, and semiempirical calculations to understand how the presence of an additional hydroxyl group affects the interactions of anthracyclines with Fe(3+). Our data indicate that the binding mode of iron in the complex is different for doxorubicin and daunorubicin.

Targeted delivery of daunorubicin to T-cell acute lymphoblastic leukemia by aptamer

Application of daunorubicin in treatment of leukemia has been limited for its side effects like cardiotoxicity. Specific delivery of chemotherapy drugs is an important factor in decreasing their side effects. In this study, sgc8, an aptamer for protein tyrosine kinase-7 (PTK7), was used for specific delivery of daunorubicin to Molt-4 cells (PTK7+). Flow cytometric experiments showed that aptamer–daunorubicin complex was internalized effectively to Molt-4 cells (PTK7+), but not to U266 cells (PTK7−). This fact was confirmed by less cytotoxicity of aptamer–drug complex in U266 cells in compare to daunorubicin alone. No significant change in viability between daunorubicin and aptamer–daunorubicin complex treated Molt4 cells was observed. In conclusion, sgc8-daunorubicin complex is introduced as a simple and efficient system for targeted delivery of drug to acute lymphoblastic leukemia T cells.

In vitro cytotoxicity of the LDE: daunorubicin complex in acute myelogenous leukemia blast cells.

Acute myelogenous leukemia (AML) blast cells show high-affinity degradation of low-density lipoprotein (LDL), suggesting an increased expression of cellular LDL receptors. LDE is a lipid microemulsion easily synthesized in vitro which is known to mimic the metabolic pathway of LDL. We used LDE as a carrier for daunorubicin and assayed the cytotoxicity of the complex using AML blast cells since RT-PCR analysis showed that AML cells express LDL receptor mRNA. The LDE:daunorubicin complex killed 46.7% of blast cells and 20.2% of normal bone marrow cells (P<0.001; Student t-test). Moreover, this complex destroyed AML blast cells as efficiently as free daunorubicin. Thus, LDE might be a suitable carrier of chemotherapeutic agents targeting these drugs to neoplastic cells and protecting normal tissues.

Oxyradical production results from the Fe3+–doxorubicin complex undergoing self-reduction by its α-ketol group

A variety of different measures have been used to compare the self-reduction of the Fe3+ complexes of doxorubicin and daunorubicin. The Fe3(+)-doxorubicin complex exhibited a much faster rate of (i) O2 consumption, (ii) self-reduction under Ar to the Fe2+ complex, (iii) aerobic reduction of ferricytochrome c, (iv) scavenging of Fe2+ by bipyridine, (v) hydroxyl radical production measured by electron paramagnetic resonance spin-trapping experiments, and (vi) inactivation of the cytochrome c oxidase activity of beef heart submitochondrial particles, than did the corresponding Fe3(+)-daunorubicin complex. In contrast to Fe3(+)-doxorubicin, the Fe3(+)-daunorubicin complex displayed only a fast phase of inhibition of the cytochrome c oxidase activity, indicating that the initial binding of these two Fe3(+)-drug complexes is very similar. All of these results indicate that Fe3(+)-doxorubicin undergoes a much faster self-reduction to the Fe2+ complex and hence a much greater rate of production of damaging oxyradicals when the Fe2+ is reoxidized by O2 or H2O2. The addition of the alpha-ketol acetol to Fe3(+)-daunorubicin resulted in greatly increased rates of (i) ferricytochrome c reduction, (ii) Fe2+ production, and (iii) hydroxyl radical production. These results support the hypothesis that the alpha-ketol functional group of doxorubicin (which is not present on daunorubicin and is the only structural difference between these two compounds) reduces the Fe3+ while undergoing oxidation itself.

Iron(III)-adriamycin and Iron(III)-daunorubicin complexes: physicochemical characteristics, interaction with DNA, and antitumor activity.

Fe(III) complexes of two anthracyclines, adriamycin and daunorubicin, have been studied. Using potentiometric and spectroscopic measurements, we have shown that adriamycin and daunorubicin form two well-defined species with Fe(III), which can be formulated as respectively Fe(HAd)3 and Fe(HDr)3. In these formulas, HAd and HDr stand for adriamycin and daunorubicin in which the 1,4-dihydroxy-anthraquinone moiety is half-deprotonated. Both complexes are six-membered chelates. The stability constant is beta = (2.5 +/- 0.5) X 10(28) for both complexes. Interaction with DNA has been studied showing that, despite strong coordination to Fe(III), anthracyclines are able to intercalate between DNA bases pairs, releasing the metal. These complexes display antitumor activity against P 388 leukemia that compares with that of the free drug. Fe(HAd)3, unlike adriamycin, does not catalyze the flow of electrons from NADH to molecular oxygen through NADH dehydrogenase. Moreover, it is shown that the triferric adriamycin compound so called "quelamycin" is in fact a mixture of Fe(HAd)3 and polymeric ferric hydroxide.

High-performance liquid chromatography and thin-layer chromatography of anthracycline antibiotics : Separation and identification of components of the daunorubicin complex from fermentation broth

A new solvent system composed of methanol-acidic water (pH 2.0 with phosphoric acid) has been developed for high-performance liquid chromatography of the daunorubicin complex from fermentation broth on a μBondapak C 18 column. Application of this solvent system in conjunction with thin-layer chromatography in the identification of anthracycline antibiotics from the fermentation broth is discussed.