Abstract
Lipoic acid derivative of cyclodextrin, βCDLip, was used as the drug carrier for doxorubicin (DOX) and the stability constants of the DOX–βCDLip were determined in the environment of the cell medium. The experiments were performed in neutral (pH 7.6) and acidified (pH 6.3) cell media containing more than forty interferences including: amino acids, vitamins, lipids and proteins. We proved that the pH of the medium has a noticeable impact on the affinity of the drug towards the carrier. At neutral pH, the formation constants of the complex are higher than at pH 6.3, what is characteristic for the cancer cells microenvironment. Furthermore, the values obtained in both cell media are twice smaller than the values obtained previously for the same complex but in the absence of common cell media components indicating that there is a competition between DOX and some hydrophobic medium components for the complex formation with βCDLip. On the other hand at pH 7.6, the amount of free DOX is highly limited due to the fact that most of DOX is still in the complexed form, while at pH 6.3 the cell media ingredients become strong interferences in the formation of the complex between DOX and the drug carrier. The observed behaviour is due to partial protonation of DOX and to competition between the drug and the lipoic side arm of cyclodextrin for the cyclodextrin cavity. The stability constants of the DOX–βCDLip complex in acidic pH are similar to the values for DOX with native β-cyclodextrin, demonstrating that the strengthening effect of DOX–CD complex resulting from the presence of cyclodextrin’s aromatic substituent (Lip) occurs only in the case of neutral pH. The high value of the stability constant of the DOX–βCDLip complex in cell medium at pH 7.6 indicates high selectivity of βCDLip ligand which would be of importance both for the effective drug delivery and for its application in DOX sensing devices.
Highlights
Cyclodextrins (CDs) are cyclic organic compounds obtained by the enzymatic transformation of starch
In this study we examined the influence of cell medium on the stability constants of DOX complex with a potential drug carrier-the lipoic acid derivative of βCD
The lipoic acid derivative of βCD was chosen since it was shown to increase the stability of the complex compared with that of pristine CD in synthetic solutions
Summary
Cyclodextrins (CDs) are cyclic organic compounds obtained by the enzymatic transformation of starch They possess a hydrophilic exterior and a hydrophobic cavity able to host various guest compounds bound via noncovalent bonds to form inclusion complexes [1,2,3]. DOX molecule contains a weakly basic amino sugar, daunosamine, linked via a glycosidic bond to the red-pigmented tetracyclic moiety, adriamycinone. It is used for the treatment of several types of cancers, such as lung [6], breast [7], cervix [8], ovarian [9], prostate [10] and brain cancers [11]. The specific toxicity of the drug is due to reactive oxygen species (ROS) produced by redox reactions of anthracyclines creating radical
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