Complexation and enhancement of temozolomide solubility with cyclodextrins

Abstract

Temozolomide is a poorly soluble anti-cancer drug used in the treatment of some brain cancers. Following literature reports about the enhancement of solubility and stability for these kinds of drugs upon complexation with cyclodextrins, we aimed to form an inclusion complex between temozolomide and the different types of cyclodextrins (CDs) to enhance its solubility. In this study, three different cyclodextrins (β-CD, hydroxyl-β-CD and γ-CD) were used, and changes in solubility was measured by UV-Vis Spectroscopy and HPLC. Morphological changes upon complexation were shown by the Scanning Electron Microscope (SEM), and weight loss profiles with respect to temperatures which were unique to the compounds were shown by Thermogravimetric Analysis. Changes in heat release profiles were shown by Differential Scanning Calorimeter (DSC). Drug solubility was measured to be increased to around 25% for 1:1 molar ratio for all used CD complexations. Changes of morphology, heat release and weight loss profiles are consistent with the formation of an inclusion complex between CDs and temozolomide. In this study, success was shown in the enhancement of temozolomide solubility upon complexation with different types of CDs. It has been demonstrated that cyclodextrins can be used as complexing agents for poorly soluble anti-cancer drugs, increasing their solubility and hence drug availability.

Co-Loading of Temozolomide and Curcumin into a Calix[4]arene-Based Nanocontainer for Potential Combined Chemotherapy: Binding Features, Enhanced Drug Solubility and Stability in Aqueous Medium

“…UV-vis spectrophotometric quantitative analyses (λ 330 nm) showed that the micellar SC4OC6 enhanced the intrinsic TMZ solubility (3.5 mg/mL) with an enhancement solubility factor (δ) of 21% (Figure S8). A similar enhancement was reported for the inclusion complex of the TMZ and cyclodextrins [14]. In the colloidal solution, the amount of soluble TMZ was calculated to be 0.11 mg per mg of SC4OC6.…”

“…However, prolonged therapy leads to TMZ resistance and poor responsiveness to subsequent treatments. The entrapment of TMZ in the cavity of macrocycles, such as cyclodextrin [14,15], cucurbituril [16], or p-sulfonato-calix [4]arene [17], and in nanostructured systems, including liposome [18], lactoferrin nanoparticle [19], and lipidic nanocarriers [20], has enhanced the chemotherapeutic efficacy of TMZ by increasing its half-life and consequently the amount of drug gaining in the target cells.…”

Thermodynamic Solubility Profile of Temozolomide in Different Commonly Used Pharmaceutical Solvents

“…A fusion enthalpy (∆H fus ) of −107.05 kJ mol −1 and a ∆H fus value of −110.85 kJ mol −1 were observed for the pure and equilibrated TMZ samples, respectively (Figure 2A,B). The Tfus and ∆Hfus for both pure TMZ and the equilibrated sample corresponded with each other, reflecting that TMZ was in the pure crystalline form [8] without any alteration to the amorphous or polymorphic form after equilibrium. The Tfus of 474.8 K for pure TMZ detected in the current study is consistent with the previously reported value of 482.2 K [8,21].…”

“…Solubility data were further utilized for apparent thermodynamic calculation using the equations described by Van't Hoff and Krug et al [13][14][15]. Many approaches for the delivery of TMZ, including complexation [8], niosomes [6], solid lipid nanoparticles [9] lipid-based nanoparticles [1], nanomicelles [10], and chitosan engineered PAMAM dendrimers, [11] have previously been described for the augmentation of drug dissolution and bioavailability. The solubility of TMZ in H2O (2-4 mg/mL) and ethanol (EtOH, 0.4-0.6 mg/mL) is reported elsewhere [12]; however, the solubility of TMZ in solvents such as Transcutol ® (TC), propylene glycol (PG), isopropyl alcohol (IPA), ethylene glycol (EG), polyethylene glycol-400 (PEG-400), 1-butanol (1-BuOH), dimethyl sulfoxide (DMSO), and ethyl acetate (EA) has not been described thus far.…”

Cyclodextrin Monomers and Polymers for Drug Activity Enhancement

“…Several biological studies in vitro and in vivo were carried out to express the anticancer activity of complexes containing anticancer compounds [ 17 ]. The anticancer drugs, among plenty of others, such as camptothecin [ 108 ], curcumin [ 109 ], paclitaxel [ 110 ], tamoxifen [ 111 ], resveratrol [ 112 , 113 ], quercetin [ 114 ], temozolomide [ 115 ], doxorubicin [ 116 ], oxaliplatin [ 117 ], β-lapachone [ 118 ], N-biphenylnicotinamides (PTA34 and PTA73) [ 119 ], 13-cis-retinoic acid (13-cis-RA) [ 120 ], oxaliplatin [ 117 ], epothilone A [ 121 ], paclitaxel (PCX) [ 122 ], difluorinated curcumin (CDF) [ 123 ], niclosamide [ 124 ], are complexed with CDs and their derivatives to improve their efficacy, stability, solubility, and bioavailability; reduce their toxicity; and modify their physicochemical peculiarities [ 125 ], in comparison to their uncomplexed forms. After the identification of these new therapeutic anticancer strategies, of particular interest was also the noninclusion complex between CDs and riboflavin (RF) [ 126 ].…”