Cancer-Cell-Specific Mitochondria-Targeted Drug Delivery by Dual-Ligand-Functionalized Nanodiamonds Circumvent Drug Resistance

Abstract

We demonstrate a nanotechnology approach for the development of cancer-cell-specific subcellular organelle-targeted drug nanocarriers based on photostable nanodiamonds (ND) functionalized with folic acid and mitochondrial localizing sequence (MLS) peptides. We showed that these multifunctional NDs not only distinguish between cancer cells and normal cells, and transport the loaded drugs across the plasma membrane of cancer cells, but also selectively deliver them to mitochondria and induce significant cytotoxicity and cell death compared with free Dox localized in lysosomes. Importantly, the cellular uptake of Dox was dramatically increased in a resistant model of MCF-7 cells, which contributed to the significant circumvention of P-glycoprotein-mediated drug resistance. Our work provides a novel method of designing nanodiamond-based carriers for targeted delivery and for circumventing drug resistance in doxorubicin-resistant human breast adenocarcinoma cancer cells.

The Response of HeLa Cells to Fluorescent NanoDiamond Uptake

“…Chu et al showed that nanodiamonds escape to the cytoplasm [ 16 ] but did not give an indication to which organelle the diamonds are ultimately localized. Lake and Bouchard very thoroughly demonstrated that they were able to target nanodiamonds toward the nuclear pore complex [ 45 ] and Chan et al directed the diamonds towards the mitochondria [ 46 ]. During our confocal analysis, we found that diamonds seem to localize near the nucleus.…”

Graphitic and oxidised high pressure high temperature (HPHT) nanodiamonds induce differential biological responses in breast cancer cell lines

“… 23 Oxidized nanodiamonds also appear to enhance uptake of various pharmaceuticals and their corresponding efficacy. 24 The rate at which graphitic and oxidized nanodiamonds are expelled from cells has been reported to be slow, with only about 15% oxidized nanodiamonds expelled after six days in HeLa cells. 21 , 25 …”

Multifunctional nanodiamonds in regenerative medicine: Recent advances and future directions

“…Chan et al . demonstrated this concept with ND-Dox to facilitate both active cell targeting of chemoresistant breast cancer cells as well as subcellular targeting after internalization to sequester Dox to the mitochondria and bypass Pgp-mediated efflux [119]. Dually-targeted ND-Dox complexes were formed by chemical conjugation of NDs with folic acid (FA) in addition to mitochondrial localizing sequence (MLS) peptides.…”