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A Glutamine-Rich Carrier Efficiently Delivers Anti-CD47 siRNA Driven by a “Glutamine Trap” To Inhibit Lung Cancer Cell Growth
It is not efficient enough using
the current approaches for tumor-selective
drug delivery based on the EPR effect and ligand–receptor interactions,
and they have largely failed to translate into the clinic. Therefore,
it is urgent to explore an enhanced strategy for effective delivery
of anticancer agents. Clinically, many cancers require large amounts
of glutamine for their continued growth and survival, resulting in
circulating glutamine extraction by the tumor being much greater than
that for any organs, behaving as a “glutamine trap”.
In the present study, we sought to elucidate whether the glutamine-trap
effect could be exploited to deliver therapeutic agents to selectively
kill cancer cells. Here, a macromolecular glutamine analogue, glutamine-functionalized
branched polyethylenimine (GPI), was constructed as the carrier to
deliver anti-CD47 siRNA for the blockage of CD47 “don’t
eat me” signals on cancer cells. The GPI/siRNA glutamine-rich
polyplexes exhibited remarkably high levels of cellular uptake by
glutamine-dependent lung cancer cells, wild-type A549 cells (A549<sup>WT</sup>), and its cisplatin-resistant cells (A549<sup>DDP</sup>),
specifically under glutamine-depleted conditions. It was noted that
the glutamine transporter ASCT2 was highly expressed both on A549<sup>WT</sup> and A549<sup>DDP</sup> but with almost no expression in
normal human lung fibroblasts cells. Inhibition of ASCT2 significantly
prevented the internalization of GPI polyplexes. These findings raised
the intriguing possibility that the glutamine-rich GPI polyplexes
utilize the ASCT2 pathway to selectively facilitate their cellular
uptake by cancer cells. GPI further delivered anti-CD47 siRNA efficiently
both in vitro and in vivo to downregulate the intratumoral mRNA and
protein expression levels of CD47. CD47 functions as a “don’t
eat me” signal and binds to the immunoreceptor SIRPα
inducing evasion of phagocytic clearance. GPI/anti-CD47 siRNA polyplexes
achieved significant antitumor activities both on A549<sup>WT</sup> and A549<sup>DDP</sup> tumor-bearing nude mice. Notably, it had
no adverse effect on CD47-expressing red blood cells and platelets,
likely because of selective delivery. Therefore, the glutamine-rich
carrier GPI driven by the glutamine-trap effect provides a promising
new strategy for designing anticancer drug delivery systems