Novel CD44 receptor targeting multifunctional “nano-eggs” based on double pH-sensitive nanoparticles for co-delivery of curcumin and paclitaxel to cancer cells and cancer stem cells

Most anticancer drugs cannot kill cancer stem cells (CSCs) effectively, which lead to the failure of anticancer chemotherapy, such as relapse and metastasis. In this study, we prepared a multifunctional oligosaccharides of hyaluronan (oHA) conjugates, oHA-histidine-menthone 1,2-glycerol ketal (oHM). The oHM conjugates possess pH-sensitive menthone 1,2-glycerol ketal (MGK) as hydrophobic moieties and oHA as the target of CD44 receptor. Anticancer drugs, curcumin(Cur) and paclitaxel(PTX), were loaded into oHM micelles via self-assembly. Then, oHM micelles were mineralized through controlled deposition of inorganic calcium and phosphate ions on the nanoparticular shell via a sequential addition method to fabricate the “nano-eggs.” The formed nano-eggs had a smaller size (120.6 ± 4.5 nm) than oHM micelles (158.6 ± 6.4 nm), indicating that mineralization made the appearance of compact nanoparticles. Interestingly, when the nano-eggs were put into the acidic conditions (pH 6.5), their outer shell(inorganic minerals) will be destroyed with the larger size, while the “nano-eggs” were stable under pH 7.4. For both nano-eggs and oHM micelles, the Cur and PTX were released in a sustained manner depending on the pH of the solution. However, the nano-eggs showed much lower released than the oHM micelles due to the dissolution of the inorganic minerals and pH-sensitive ketal at mildly acidic environments (pH 6.5). In vivo study, the nano-eggs could get to the tumor site more effectively than oHM micelles. CSCs were sorted by a side population assay from MDA-MB-231 breast cancer cell lines over-expressing CD44 receptors. Antitumor activity was also evaluated on MDA-MB-231 xenografts in nude mice. The antitumor efficacy indicated that nano-eggs with co-delivery of Cur and PTX produced the strongest antitumor efficacy, and nano-eggs showed strong activity against cancer stem cells. These double pH-sensitive nano-eggs may provide a promising strategy for drug delivery to both cancer cells and cancer stem cells.