Loading...
Please wait, while we are loading the content...
Similar Documents
Enhanced intracellular drug delivery of pH-sensitive doxorubicin /poly(ethylene glycol)- block -poly(4-vinylbenzylphosphonate) nanoparticles in multi- drug resistant human epidermoid KB carcinoma cells
| Content Provider | Semantic Scholar |
|---|---|
| Author | Kamimura, Masao Furukawa, Tatsuhiko Akiyama, Shin-Ichi Nagasaki, Yukio |
| Copyright Year | 2013 |
| Abstract | A pH-sensitive nanoparticle was prepared using our original amphiphilic block copolymer, poly(ethylene glycol)-b-poly(4-vinylbenzylphosphonate) (PEG-b-PVBP), which possesses phosphate groups as a side chain of its hydrophobic segment (termed here, phosphate nanoparticle (PNP)). The cationic anticancer drug, doxorubicin (DOX) was incorporated into a PNP (DOX@PNP), and its loading capacity was 320 mg g−1-PNP. Electrostatic and hydrophobic interactions in the core of the PNP might act synergistically to significantly improve its loading capacity. The cytotoxicity of the DOX@PNP was examined using the drug-sensitive human epidermoid KB carcinoma cell line (KB-3-1) and two different multi-drug resistance (MDR) KB cell lines (P-glycoprotein (P-gp) overexpressed (KB-C-2) and multidrug resistance protein 1 (MRP1) overexpressed (KB/MRP) cell lines). The DOX@PNP displayed a lower cytotoxic activity than free DOX against KB-3-1 cells. In contrast, the DOX@PNP showed a higher cytotoxic activity than free DOX against MDR cells. Of particular note, the cytotoxicity of the DOX@PNP against KB-C-2 cells was much higher than that against KB/MRP cells, suggesting that different mechanisms of drug reflux via the ATP binding cassette (ABC) transporting system play an important role in nanoparticle-assisted chemotherapy. Observation with confocal laser scanning microscopy (CLSM) indicated that the DOX@PNP was taken up by cells via the endocytosis pathway. The DOX@PNP was initially localized in the late endosome and lysosome, with the subsequent release of DOX from the DOX@PNP in response to the acidic pH of the late endosome and lysosome. Quantitative analysis using flow cytometry confirmed that the uptake of the DOX@PNP into KB-C-2 cells was much higher than that into KB/MRP cells, which was one of the reasons for the enhanced toxicity of the DOX@PNP against KB-C-2 cells compared to that against KB/MRP cells. Reflux of the liberated free DOX in the cytosol, via an endosomal membrane transporter, is considered one of the reasons for the low efficiency of DOX@PNP chemotherapy against KB/MRP cells. However, compared to the free DOX dose, a high dose of the DOX@PNP was effectively delivered to the nuclei of the KB/MRP cells. On the basis of these results, the pH-sensitive DOX@PNP is anticipated as one of the effective chemotherapeutic drugs with enhanced cytotoxicity for multiple types of MDR cancer cells. |
| Starting Page | 361 |
| Ending Page | 367 |
| Page Count | 7 |
| File Format | PDF HTM / HTML |
| DOI | 10.1039/C2BM00156J |
| Volume Number | 1 |
| Alternate Webpage(s) | http://www.rsc.org/suppdata/bm/c2/c2bm00156j/c2bm00156j.pdf |
| Alternate Webpage(s) | https://doi.org/10.1039/C2BM00156J |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
