Abstract 5382: A breakthrough in application of a drug delivery nanoparticle system for therapy and diagnosis of solid tumor

Abstract

Abstract Introduction: Nanoparticle systems are usually designed to deliver the incorporated molecular to tumors. However, we found an interesting breakthrough in conducting the super carbonate apatite (sCA) nanoparticles itself. So far we have introduced the sCA as an in vivo pH sensitive delivery system of doxorubicin (PLoS ONE 8(4): e60428. 2013) or siRNA, which simply consist of inorganic ions and quickly accumulate specifically in tumors yet yield no serious adverse events in mice and monkeys. Intravenously administered sCA-siRNA markedly accumulated in the tumor cells at 90 min and survivin-siRNA delivered by sCA significantly inhibited in vivo tumor growth, compared with the two other in vivo commercially available delivery reagents, Invivofectamine 2.0 and Atelocollagen. In this study, we confirmed a unique characteristic of sCA itself, not as a drug delivery system. Empty sCA alone markedly enhanced the uptake of low molecular chemicals into tumor cells in vitro and in vivo. Methods: Doxorubicin (DXR), fluorouracil (5-FU), oxaliplatin (L-OHP) and indocyanine green (ICG) are used as low molecular chemicals. Cellular uptake of doxorubicin was analyzed by flow cytometry using a BD FACS Aria II instrument (BD Biosciences). Cell viability was examined by WST-8 assay (Dojindo). As for the in vivo tumor imaging assay, sCA and ICG were simultaneously administered via the separate routes to the mice bearing colon cancer HT29; sCA was administered i.v. (intravenously) and ICG was administered i.p. (intraperitoneally). Mice were imaged under anesthesia using IVIS (PerkinElmer) for ex vivo and in vivo imaging. Results and Discussions: Empty sCA itself enhanced the uptake and cytotoxic effect of anti-cancer agents in vitro, although sCA itself was not toxic. The flow cytometric analysis showed the mean florescence index (MFI: 2186) of the cells, first treated with sCA for 24 h and then treated with DXR for another 24 h, was higher than the MFI (1684) of the cells directly treated with DXR for 24 h. The IC50 (μM; mean ± SD) of 5-FU and L-OHP in colon cancer HCT116 were 47.6 ± 10.0 and 31.3 ± 2.2, whereas the IC50 of both drugs in the sCA pre-treated cells for 24 h were 11.7 ± 2.0 and 3.70 ± 1.1, respectively. Furthermore, the empty sCA itself also improved the efficacy of in vivo tumor imaging by ICG, even when ICG and sCA were administered through the separate routes; sCA was administered i.v. and ICG was administered i.p.. We should mention that we had not been able to incorporate ICG into sCA nanoparticles before this experiment. Time course studies showed that ICG levels in tumors with treatment of sCA plus ICG were significantly higher throughout the examined time points than those treated with ICG alone (P = 0.0142 for 4 h, P = 0.0139 for 8 h, P = 0.0433 for 12 h, P = 0.0304 for 24 and 48 h). Conclusion: Our data suggest that sCA itself, while designed as an in vivo delivery device, can facilitate entrance of low molecular chemicals into tumor cells in vitro and in vivo. Citation Format: Xin Wu, Hirofumi Yamamoto, Mamoru Uemura, Taishi Hata, Junichi Nishimura, Ichiro Takemasa, Tsunekazu Mizushima, Yuichiro Doki, Masaki Mori. A breakthrough in application of a drug delivery nanoparticle system for therapy and diagnosis of solid tumor. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5382. doi:10.1158/1538-7445.AM2014-5382