CaCO nanoparticles pH-sensitively induce blood coagulation as a potential strategy for starving tumor therapy.

Based on the concept of starving tumor therapy, in this study we put forward a new idea that the pH-sensitive Ca delivery of calcium carbonate nanoparticles (CaCO NPs) induced blood coagulation of tumor vessels, and first explored the effect of CaCO NPs on the in vitro and in vivo blood coagulation by acid stimulus. CaCO NPs with a size of about 100 nm and a porous structure of several nanometers were synthesized in an emulsion system, which showed a high loading capacity (49%) of doxorubicin hydrochloride (DOX) with an encapsulation efficiency of 98% and a pH-sensitive drug delivery. The hemolysis test showed that CaCO NPs were blood compatible. The in vitro Ca delivery and blood clotting tests indicated that CaCO NPs pH-sensitively released Ca, and caused rapid blood coagulation at pH 5.0 but no thrombus at pH 7.4. Confocal laser scanning microscopy showed that after uptake by MCF-7 or MDA-MB-231 breast cancer cells, CaCO NPs mainly distributed in endosomes/lysosomes within the initial 2 h and then decomposed by acid stimulus, leading to the intracellular delivery of Ca that subsequently migrated outside the cells. CaCO NPs were nontoxic to NIH3T3 mouse fibroblasts, but highly toxic to both MCF-7 and MDA-MB-231 cells after loading DOX. After topical administration into the breast tumors of mice, CaCO NPs evoked significant thrombosis and hemorrhage of tumor vasculature by hematoxylin-eosin and Masson's trichrome staining. These results indicated that CaCO NPs could induce blood coagulation via acid stimulus, showing potential applications in blocking tumor vessels for starving tumor therapy.