Adjusting the Structure of ß-Cyclodextrin to Improve Complexation of Anthraquinone-Derived Drugs.

ß-Cyclodextrin (CD) derivatives containing an aromatic triazole ring were studied as potential carriers of the following drugs containing an anthraquinone moiety: anthraquinone-2-sulfonic acid (AQ2S); anthraquinone-2-carboxylic acid (AQ2CA); and a common anthracycline, daunorubicin (DNR). UV-Vis and voltammetry measurements were carried out to determine the solubilities and association constants of the complexes formed, and the results revealed the unique properties of the chosen CDs as effective pH-dependent drug complexing agents. The association constants of the drug complexes with the CDs containing a triazole and lipoic acid (ßCDLip) or galactosamine (ßCDGAL), were significantly larger than that of the native ßCD. The AQ2CA and AQ2S drugs were poorly soluble, and their solubilities increased as a result of complex formation with ßCDLip and ßCDGAL ligands. AQ2CA and AQ2S are negatively charged at pH 7.4. Therefore, they were less prone to form an inclusion complex with the hydrophobic CD cavity than at pH 3 (characteristic of gastric juices) when protonated. The ßCDTriazole and ßCDGAL ligands were found to form weaker inclusion complexes with the positively charged drug DNR at an acidic pH (pH 5.5) than in a neutral medium (pH 7.4) in which the drug dissociates to its neutral, uncharged form. This pH dependence is favorable for antitumor applications.

Incorporation of simvastatin into lipid membranes: Why deliver a statin in form of inclusion complex with hydrophilic cyclodextrin.

In this work, the effects of simvastatin (SIM), (2-hydroxypropyl)-ß-cyclodextrin (HPßCD) and their complex (SIM:HPßCD) on the structure and properties of lipid membranes were investigated for the first time by Langmuir technique combined with PM-IRRAS spectroscopy. An improved understanding of the differences of the interactions between free SIM, and SIM in the form of an inclusion complex with HPßCD with the lipid membrane will improve the development of preparation methods for in vivo applications. Monolayers of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), cholesterol (Chol) and their mixture DMPC:Chol (7:3) served as simple models of one leaflet of the cell membrane. The penetration of well-organized lipid layers by simvastatin lead to their fluidization but the extent of this unwanted effect was smaller when the drug was delivered in the form of the SIM:HPßCD complex. Surface pressure vs. time dependencies showed that the drug encapsulated with cyclodextrin dissociated from the complex upon contact with the lipid layer and the weak interactions between the exterior polar part of the HPßCD and the polar headgroups of the lipid layer facilitated smooth incorporation of the released lipophilic drug into the membrane. At a longer time-scale, the HPßCD ligand released from the complex removed some cholesterol, but not DMPC, from the lipid layer, hence, similarly to the enzyme inhibiting action of statins - it lead to the decrease of the amount of cholesterol in the membrane. Delivery of simvastatin in the form of an inclusion complex with HPßCD is proposed as an approach improving its bioavailability in the cholesterol-lowering therapies.

Water-soluble galactosamine derivative of ß-cyclodextrin as protective ligand and targeted carrier for delivery of toxic anthracycline drug.

ß-cyclodextrin modified with an electron-rich aromatic triazole linker and targeting moiety (galactosamine) was synthesized and studied as a carrier for the anticancer drug, doxorubicin (DOX), with the aim of targeting the pathological cells, reducing the cardiotoxic side effects and increasing the binding of the drug to DNA. The ß-cyclodextrins modified with galactosamine (ßCDGAL) are non-toxic and highly soluble in aqueous medium compared to the native ßCD and ßCD modified only with aromatic moiety, such as triazole linker. Molecular modelling and NMR study gave a deeper insight into the ligand structure, providing an explanation for its increased solubility, and the drug-ligand interactions. The triazole linker strengthened the drug binding and introduced pH dependence of the complex stability constants for ßCDGAL derivative, as confirmed by the voltammetry measurements. Spectroscopic studies have shown that entrapment of the DOX in ßCDGAL cavity reduces the stability constant of the DOX:Fe(III) complex responsible for the production of cardiotoxic reactive oxygen species and additionally supports the binding of the drug to the double strand DNA. The MTT assay and confocal microscopy results showed that despite encapsulation of the drug in the cyclodextrin molecule, its cytotoxic effect on the liver cancer cell line (HepG2) is comparable to that of the free, non-protected drug.

Voltammetric/UV-Vis study of temozolomide inclusion complexes with cyclodextrin derivatives.

Temozolomide (TMZ) - a chemotherapeutic agent possessing cytotoxic activity is used in single or combined therapies of human glioma. Difficulties in these applications, connected with low solubility and stability of temozolomide lead us to study the inclusion complexes between TMZ, and three cyclodextrins: ß-cyclodextrin (ßCD), monodeoxy-6-monoamino-ß-cyclodextrin hydrochloride (ßCDamine), and ß-cyclodextrin containing galactosamine and triazole ring in the side group (ßCDgal). The voltammetric and spectroscopy studies showed the improvement of the drug solubility and formation of stable complexes. Higuchi and Connors method was used to determine the solubilities of the drug in the presence of the selected cyclodextrins. Phase solubility diagrams showed increase of TMZ solubility and 1:1 stoichiometry of the complexes formed. The stability constant of TMZ- ßCDgal complex was pH - dependent, larger at pH 7.4 (corresponding to the pH of the body fluids), than at pH 5.5, characteristic for the cancer cells environment. ßCDgal ligand was an effective complexing agent for TMZ due to additional strong proton-acceptor π-π interactions between the triazole ring of the cyclodextrin and the ring of TMZ. The increased solubility and sustainability of TMZ complexes with ßCDgal allow to propose this cyclodextrin as a promising TMZ carrier for further studies in the biological cell environment.

Competition between self-inclusion and drug binding explains the pH dependence of the cyclodextrin drug carrier - molecular modelling and electrochemistry studies.

A non-toxic lipoic acid derivative of ß cyclodextrin (ßCDLip) with an electron-rich aromatic linker was studied as a carrier for the drug doxorubicin with the aim of decreasing the toxic side effects of this drug. The modified cyclodextrin strengthened the drug binding and differentiated the complex-forming ability with dependence on pH. The stability constants of the complexes were evaluated by voltammetry and spectrofluorometry. Molecular modelling provided deeper insight into the nature of the ligand structure itself and the drug-ligand interactions, showing the different contributions of the self-inclusion of the ligand substituent at different pH values. As a result, the modes of interaction of ßCDLip with the drug and factors affecting the stabilities of the complex under the pH conditions of healthy and tumour cells could be discovered and explained.