Synthesis of an amphiphilic bi-prodrug based on gossypol and cytarabine for drug self-delivery

Abstract

Drug-drug conjugates have become a research hotspot in nanomedicine. An amphiphilic assembled drug-drug conjugate can achieve drug self-delivery without any carriers and change the distribution of free drugs. Herein, we synthesized a pH-responsive bi-prodrug of gossypol (GP) and cytarabine (Ara-C) for cancer therapy. FT-IR, UV-vis, TLC and MS confirmed that GP-Ara-C was successfully synthesized. The nanoparticle size of GP-Ara-C is approximately 100 nm, and the stability of GP-Ara-C is maintained for 6 days in pH 7.4 phosphate-buffered saline (PBS). HeLa cell viability results showed that GP-Ara-C exhibited anticancer ability similar to that of free GP. Cellular uptake demonstrated that GP-Ara-C could be distributed in cell nuclei at 7 h. Altogether, this amphiphilic GP-Ara-C could be assembled into nanomedicine in an aqueous environment and could be a candidate for cancer therapy in clinics.

Fig. 1. (A) Structure of GP-Ara-C, (B) UV-vis curves of GP, Ara-C and GP-Ara-C in acetone, and (C) TLC and mass spectrum of GP-Ara-C.

Fig. 2. IR spectra of Ara-C, GP and GP-Ara-C.

Fig. 3. Nanoparticle sizes of GP-Ara-C measured through (A) TEM and (B) DLS, (C) their stability in pH 7.4 PBS for 6 days and (D) their pH-responsive disruption in pH 6.0 PBS in 6 hours.

Fig. 4. HeLa cell viabilities of acetate GP and GP-Ara-C with different concentrations of GP at 24 h.

Fig. 5. Morphology of HeLa cells treated with different concentrations of acetate GP and GP-Ara-C (GP's concentration) from the 96-well plate in CCK-8 assays at 24 h.

Fig. 6. Distribution of DID@GP-Ara-C in HeLa cells for 1 h, 3 h and 7 h monitored by CLSM (scale: 20×).