Generation of natural killer cell-mimic nanoparticles to target tumour cells
Alizadeh Zeinabad, Hojjat
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Natural killer (NK) cells are effector immune cells in the innate immune system. It is increasingly recognised that NK cells play a crucial role eliminating emerging tumour cells. Some tumour cells however can escape and evolve by developing strategies to inactivate or hide from NK cells. Here, we engineered a nanoparticle (NP) able to identify and kill specific cancer cells using mechanisms NK cells utilise. The first part of the thesis presents my work on developing liposomes functionalised with the NK-expressed death ligand, TNF-related apoptosis-inducing ligand (TRAIL) enabling tumour-specific cytotoxicity. The cytotoxic potential of the TRAIL-conjugated liposomes (LP/TRAIL) was confirmed using a panel of cancer cell lines. Our results showed that LP/TRAIL had significantly higher pro-apoptotic potential than the soluble form of TRAIL (sTRAIL) showing that LPs enable delivery of TRAIL in its native-like, biologically active conformation. The second part of the thesis presents the work on improving the bioactivity of LP/TRAIL by functionalisation with tumour-targeting antibodies thus generating NK cell-mimic NPs. The anticancer efficiency of the NK cell-mimic NPs was evaluated in vitro, ex vivo and in vivo. In vitro, NK cell-mimic LPs showed slightly increased cytotoxicity than LP/TRAIL against acute myeloid leukaemia (AML) cell lines. Ex vivo studies, using primary, patient-derived AML cells corroborated the in vitro findings, where the NK cell-mimic LPs had superior cytotoxicity over sTRAIL and LP/TRAIL. Furthermore, NK cell-mimic NPs could kill patient-derived leukemic stem cells substantially more than sTRAIL or LP/TRAIL. The efficacy of the NK cell-mimic LPs was finally assessed in vivo, using a disseminated (bone marrow-localised) AML mouse model. In this study, while LP/TRAIL reduced tumour burden, NK cell-mimic NPs were markedly more effective, underlining that features of NK cells can be replicated in nanomedicine to achieve active tumour targeting linked with potent and selective killing of cancer cells.