Host-guest inclusion systems of two bioactive natural products derivantives and three polyamine-modified β-cyclodextrins: Preparation, characterization, biological activity

Two bioactive natural products derivatives including hydroxycamptothecin (HCPT) and etoposide (EPEG), which are one of the most common classes of first-line anticancer drugs used for the treatment of cancer. Of note, their application is still limited by poor water solubility and bioavailability. Therefore, it is very important to develop a new means to solve these shortcomings. In this work, the molecular binding behavior of three polyamine-modified β-cyclodextrins (H1-3) with HCPT and EPEG was investigated. The six novel H1-3/HCPT (EPEG) inclusion complexes were prepared and characterized by Fourier transform infrared spectrometry (FTIR), 2D nuclear magnetic resonance (2D ROESY), 1H nuclear magnetic resonance (NMR), X-ray powder diffraction (XRD) and scanning electron microscopy (SEM). The phase solubility diagrams indicated that the stability constants (K1:1) of host H1-3 to the free drugs decrease sequentially as follows: H3>H2>H1. After forming inclusion complexes with H1-3, the water solubility of HCPT (EPEG) were obviously increased from the initial value of 0.0011 mg/mL (0.373 mg/mL) to 0.90 mg/mL (32.55 mg/mL), 2.01 mg/mL (38.73 mg/mL), and 2.39 mg/mL (47.42 mg/mL), enhanced by 84.9–225.5 times compared with the free drug, respectively. The in vitro release tests confirmed that the cumulative release of drug from H1-3/EPEG (HCPT) complexes was significantly higher than that from free drug solution in 50 h. The cytotoxicity assay showed that the H1/HCPT exhibited higher cytotoxicity towards MCF-7 cell in comparison to the free drug HCPT. Meanwhile, the toxicity of HCPT is obviously reduced after the formation of H2/HCPT. Apoptosis experiments revealed that the percentage of apoptotic cells was increased by H3/HCPT (65.80%), which close to increasing by free drugs HCPT (74.00%) when the concentrations of H3/HCPT and HCPT reached to a certain level (5.0 μg/mL). The satisfactory water solubility, high activity, and low toxicity of H1-3/HCPT (EPEG) inclusion complexes contributes to research with new applications of the HCPT and EPEG as anticancer drug formulations.