Abstract
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces cancer cell-specific apoptosis and has garnered intense interest as a promising agent for cancer treatment. However, the development of TRAIL has been hampered in part because most human cancer cells are resistant to TRAIL. A few small molecules including natural compounds such as piperlongumine (PL) have been reported to sensitize cancer cells to TRAIL. We prepared a novel type of nanomaterial, micelle-in-liposomes (MILs) for solubilization and delivery of PL. PL-loaded MILs were used to sensitize cancer cells to TRAIL. As visualized by cryo-TEM, micelles were successfully loaded inside the aqueous core of liposomes. The MILs increased the water solubility of PL by ~20 fold. A sustained PL release from MILs in physiologically relevant buffer over 7 days was achieved, indicating that the liposomes prevented premature drug release from the micelles in the MILs. Also demonstrated is a potent synergistic apoptotic effect in cancer cells by PL MILs in conjunction with liposomal TRAIL. MILs provide a new formulation and delivery vehicle for hydrophobic anticancer agents, which can be used alone or in combination with TRAIL to promote cancer cell death.
Highlights
Selective killing of cancer cells has been long pursued in the development of effective cancer treatment, while achieving little to no side effects
To increase the therapeutic effectiveness of the protein against resistant cancer cells, a few small molecules including some chemotherapy drugs such as paclitaxel and bortezomib, and natural compounds such as piperlongumine (PL) and curcumin were reported for the sensitization of cancer cells to TRAIL [11,12,13,14,15]
PL was identified in a high throughput screening as a drug candidate that induces apoptosis selectively in cancer cells but has little apoptotic effect on normal cells [16]
Summary
Selective killing of cancer cells has been long pursued in the development of effective cancer treatment, while achieving little to no side effects. The cancer-specific apoptotic potential of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has attracted great attention among biologists and oncologists, with some studies using recombinant human TRAIL (rhTRAIL) reaching clinical trials [1]. TRAIL belongs to the TNF cytokine superfamily that induces apoptosis in a broad spectrum of human cancer cell lines while sparing most healthy cells [2]. Despite the potent tumor-specific properties of TRAIL against a broad range of cancer cells, some cell lines have been found to be resistant to the effects of TRAIL [10]. PL was identified in a high throughput screening as a drug candidate that induces apoptosis selectively in cancer cells but has little apoptotic effect on normal cells [16].
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