Innovative Delivery of siRNA to Solid Tumors by Super Carbonate Apatite

Abstract

RNA interference (RNAi) technology is currently being tested in clinical trials for a limited number of diseases. However, systemic delivery of small interfering RNA (siRNA) to solid tumors has not yet been achieved in clinics. Here, we introduce an in vivo pH-sensitive delivery system for siRNA using super carbonate apatite (sCA) nanoparticles, which is the smallest class of nanocarrier. These carriers consist simply of inorganic ions and accumulate specifically in tumors, yet they cause no serious adverse events in mice and monkeys. Intravenously administered sCA-siRNA abundantly accumulated in the cytoplasm of tumor cells at 4 h, indicating quick achievement of endosomal escape. sCA-survivin-siRNA induced apoptosis in HT29 tumors and significantly inhibited in vivo tumor growth of HCT116, to a greater extent than two other in vivo delivery reagents. With innovative in vivo delivery efficiency, sCA could be a useful nanoparticle for the therapy of solid tumors.

Photodynamic Therapy Using Indocyanine Green Loaded on Super Carbonate Apatite as Minimally Invasive Cancer Treatment

“…With this system, we previously reported that the nucleic acid medicine accumulated in tumor cells within 2 to 4 hours after injection via the tail vein. Because of its sensitivity to acidic environments, siRNA can easily escape from endosomes to the cytoplasm (29,30). In this study, we made sCA particles incorporating ICG via a quite simple procedure (Fig.…”

“…Free ICG binds to serum albumin and lipoproteins and constitutes high molecular compound in the blood stream. We also use 0.5% albumin for coating sCA to maintain the nanoparticle dispersal (29). Carbonate apatite particles are likely to bind to albumin because the zeta potential shifts to further negative when mixed with albumin (40).…”

“…S4), this result is encouraging because the preliminary data suggest that sCA-ICG should have the potential for dual therapy. As sCA exhibits the best affinity for nucleic acids (29,(31)(32)(33)(34), it is likely that sCA-ICG combined with certain molecular targeting may further enhance the effects of PDT. Studies of multidisciplinary PDT are currently underway in our laboratory using sCA-ICG plus siRNA targeting the stress gene NRF2 or immune checkpoint molecules PD-L1/PD-1.…”

“…The carbonate apatite consisting of biocompatible inorganic ions (CO 3 2À , Ca 2þ , and PO 4 3À ) is a superior vehicle carrying siRNA into tumor cells (28). A super carbonate apatite (sCA) is a nanoparticle for in vivo delivery and the advantages of sCA are easy production, safe constituents, and rapid uptake by the tumor (29). We previously reported the in vivo safety and potent anti-tumor effects of sCA for delivery of doxorubicin, micro-RNAs, and siRNAs (29)(30)(31)(32)(33)(34).…”

“…A super carbonate apatite (sCA) is a nanoparticle for in vivo delivery and the advantages of sCA are easy production, safe constituents, and rapid uptake by the tumor (29). We previously reported the in vivo safety and potent anti-tumor effects of sCA for delivery of doxorubicin, micro-RNAs, and siRNAs (29)(30)(31)(32)(33)(34). In the present study, we evaluated the utility of ICG loaded on sCA (sCA-ICG) for delivery to the tumor and retention of ICG in normal organs.…”