Abstract
Doxorubicin (DOX) is one of the most commonly used chemotherapeutic agents for treating human cancer. However, its clinical use has been limited by DOX-induced cardiotoxicity as well as other side effects. In the present study, we designed and synthesized the fullerenol (FU)-DOX conjugates and folic acid (FA)-grafted FU-DOX conjugates for improving the selectivity and activity of DOX in cancer cells. We further characterized the physicochemical properties and examined the release kinetics, cellular uptake, and in vitro anticancer activities of FU-DOX and FA-FU-DOX. The results showed that FU-DOX and FA-FU-DOX had a mean diameter of <200 nm and a low polydispersity. Both FU-DOX and FA-FU-DOX exhibited pH sensitivity and their DOX release rates were higher at pH 5.9 vs. pH 7.4. The cellular uptake studies indicated that FU conjugation enhanced the intracellular accumulation of DOX in human hepatocellular carcinoma (HCC) cell lines (BEL-7402 and HepG2) and the immortalized normal human hepatocytes (L02). The conjugation of FA to FU-DOX further promoted the drug internalization in an FR-dependent manner and enhanced the cytotoxicity against HCC cells. In conclusion, the newly prepared FA-FU-DOX conjugates can optimize the safety and efficacy profile of DOX.
Highlights
Doxorubicin (DOX, named adriamycin), as a broad-spectrum anticancer drug, is widely used in leukemia, lymphomas, and solid tumors such as liver cancer, breast cancer, ovarian cancer, etc. (Kalyanaraman, 2020)
The nuclear magnetic resonance (NMR) spectrum of folic acid (FA)-Fullerenol-Doxorubicin Conjugates (FU-DOX) (Figure 2) showed signals at 8.64, 7.64, 6.94, 6.65, 4.48, and 4.33 ppm, representing H-carbon units of FA, and signals at 7.90, 5.47, 5.30, 4.94, 4.85, 4.57, 4.20, and 3.98 ppm, belonging to H-carbon units of DOX, which indicated that FA and DOX had been successfully linked to FU carrier
Our results have shown that the cumulative release rates of DOX from FU-DOX and FA-FUDOX are similar at both physiological and endolysosomal pH conditions, which is in line with the degradation features of the hydrazine group (Liu et al, 2014; Rezaian et al, 2018)
Summary
Doxorubicin (DOX, named adriamycin), as a broad-spectrum anticancer drug, is widely used in leukemia, lymphomas, and solid tumors such as liver cancer, breast cancer, ovarian cancer, etc. (Kalyanaraman, 2020). Fullerene is a series of cage-like, spherical nano-molecules formed by carbon atoms, which have been found to have some excellent biological activities, such as antioxidant, antiviral, anticancer, and FA-FU-DOX Conjugates for Cancer Therapy immunomodulatory effects, etc. Fullerene can act as a transporter for anticancer drugs, such as DOX (Grebinyk et al, 2019; Kazemzadeh and Mozafari, 2019). These biological properties of fullerenes and the potential ability to carry drugs make it attractive to be applied in the drug delivery system
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