Fabrication and intracellular delivery of doxorubicin/carbonate apatite nanocomposites: effect on growth retardation of established colon tumor

• Published in: PloS one 2013-04, Vol.8 (4), p.e60428
• Main Authors: Hossain, Sharif, Yamamoto, Hirofumi, Chowdhury, Ezharul Hoque, Wu, Xin, Hirose, Hajime, Haque, Amranul, Doki, Yuichiro, Mori, Masaki, Akaike, Toshihiro
• Format: Article
• Language: English
• Subjects: Analysis; Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - therapeutic use; Apatite; Apatites - chemistry; Biology; Cancer; Cancer therapies; Cancer treatment; Carbonates; Cell Line, Tumor; Cell surface; Chemotherapy; Colon; Colon cancer; Colonic Neoplasms - drug therapy; Colorectal cancer; Cytometry; Cytotoxicity; Doxorubicin; Doxorubicin - administration & dosage; Doxorubicin - therapeutic use; Drug delivery systems; Drug resistance; Drug Resistance, Neoplasm; Drugs; Electron microscopy; Endosomes; Fabrication; Female; Flow cytometry; Growth rate; Halides; Health aspects; Humans; Hydrogen ions; Intracellular; Materials Science; Medicine; Mice; Mice, Inbred BALB C; Mice, Nude; Microbial drug resistance; Microclimate; Microclimates; Multidrug resistance; Nanocomposites; Nanocomposites - analysis; Nanocomposites - chemistry; Nanoparticles; Ovarian cancer; Penicillin; Permeability; pH effects; Phosphate minerals; Retention; Scanning electron microscopy; Solid tumors; Surgery; Toxicity; Tumor cell lines; Tumor cells; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0060428

In continuing search for effective treatments of cancer, the emerging model aims at efficient intracellular delivery of therapeutics into tumor cells in order to increase the drug concentration. However, the implementation of this strategy suffers from inefficient cellular uptake and drug resistance. Therefore, pH-sensitive nanosystems have recently been developed to target slightly acidic extracellular pH environment of solid tumors. The pH targeting approach is regarded as a more general strategy than conventional specific tumor cell surface targeting approaches, because the acidic tumor microclimate is most common in solid tumors. When nanosystems are combined with triggered release mechanisms in endosomal or lysosomal acidic pH along with endosomolytic capability, the nanocarriers demonstrated to overcome multidrug resistance of various tumors. Here, novel pH sensitive carbonate apatite has been fabricated to efficiently deliver anticancer drug Doxorubicin (DOX) to cancer cells, by virtue of its pH sensitivity being quite unstable under an acidic condition in endosomes and the desirable size of the resulting apatite-DOX for efficient cellular uptake as revealed by scanning electron microscopy. Florescence microscopy and flow cytometry analyses demonstrated significant uptake of drug (92%) when complexed with apatite nanoparticles. In vitro chemosensitivity assay revealed that apatite-DOX nanoparticles executed high cytotoxicity in several human cancer cell lines compared to free drugs and consequently apatite-DOX-facilitated enhanced tumor inhibitory effect was observed in colorectal tumor model within BALB/cA nude mice, thereby shedding light on their potential applications in cancer therapy.