79P - Co-delivered crizotinib and gefitinib based on nanoparticle for synergically overcoming resistance lung adenocarcinoma treatment

Background

Gefitinib has been employed as a first-line treatment for patients with NSCLC with EGFR mutation, but rapid drug resistance in tumors induces disease progression. Overactivation of PI3K/AKT is associated with gefitinib resistance (GR) in lung adenocarcinoma. Clinically, crizotinib inhibits AKT and extracellular regulated protein kinases (ERK) signal activation in various tumor cells.

Methods

Gefitinib and crizotinib were loaded into a hydrophobic core, which was formed by the amphiphilic block poly (ethylene glycol)–poly (hexyl ethylene phosphate) (GC@NP) through nano self-assembly method. And the anti-tumor effect and mechanism of GC@NP were verified in vivo and in vitro.

Results

According to particle characterization results, GC@NP had a homogeneous and stable nanoscale, which was 40.1±1.1 nm. Especially, GC@NP had a good drug loading efficiency, the values are 6.52 ± 0.21% and 7.09 ± 0.39% for gefitinib and crizotinib respectively. At the cellular level, GC@NP can be effectively ingested by PC9GR cells within 2 hours. When the concentration of gefitinib was set to 2 μM, the cell viability of the free gefitinib group was 90%, while GC@NP group was only about 50%. At the same time, GC@NP exhibited higher proliferative inhibition and apoptotic induction effects compared to free gefitinib group, the apoptosis rates were 25% and 5% respectively. At the animal level, GC@NP significantly inhibited the growth and metastasis of PC9GR tumors, and also inhibited the brain metastasis associated with GR. Meanwhile, we validated GC@NP has good biosafety in the transgenic zebrafish model. In the nude mouse tumor model, our results indicate that GC@NP can significantly inhibit the growth of PC9GR tumors, while the combination of free gefitinib and crizotinib didn't show significant therapeutic effects. Mechanistically and importantly, GC@NP synergism promoted the dephosphorylation of the overactivated AKT signal and inhibited the feedback activation of ERK signal, which inducing apoptosis in PC9GR cells.

Conclusions

The co-delivery nanoparticle GC@NP we have constructed provides a potential therapeutic approach for advanced lung adenocarcinoma patients with targeting-drug resistance and brain metastasis.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Haiyu Zhou.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.