It
is extremely difficult for cancer chemotherapy to control the
peritoneal metastasis of advanced ovarian carcinoma given its inability
to target disseminated tumors and the severe toxic side effects on
healthy organs. Here, we report antitumor M1 macrophages developed
as live-cell carriers that deliver anticancer drugs for the treatment
of the metastatic ovarian carcinoma. Engineered doxorubicin-loaded
M1 macrophages (M1-Dox) significantly enhanced tumor tropism by upregulation
of CCR2 and CCR4 compared with their parent cells. Meanwhile, M1-Dox
inhibited doxorubicin-induced tumor invasion, whereas commercial Lipo-Dox
did not limit these side effects. Importantly, our data uncovered
a drug delivery mechanism by which M1-Dox transferred drug cargoes
into tumor cells via a tunneling nanotube pathway.
The tunneling nanotube network acted as a transportation expressway
for ultrafast drug delivery of M1-Dox, leading to efficient ovarian
carcinoma cell death. Furthermore, genetic, pharmacological, and physical
perturbations of these tunneling nanotubes obviously decreased drug
transfer of M1-Dox, which further validated the evident correlation
between drug delivery of M1-Dox and tunneling nanotubes. Finally,
in peritoneal metastatic ovarian carcinoma-burdened mice, M1-Dox specifically
penetrated into and accumulated deep within disseminated neoplastic
lesions compared with commercial Lipo-Dox, resulting in reducing metastatic
tumors to a nearly undetectable level and significantly increasing
overall survival. Overall, the strategy of engineered macrophages
for ultrafast and accurate drug delivery via the
tunneling nanotubular expressway potentially revolutionizes the treatment
of metastatic ovarian carcinoma.
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), and its cisplatin-resistant cells (A549), specifically under glutamine-depleted conditions. It was noted that the glutamine transporter ASCT2 was highly expressed both on A549 and A549 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 and A549 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.
YABBY gene family plays an important role in the polarity development of lateral organs. We isolated the BraYAB1-702 gene, a member of the YABBY gene family, from young leaves of Chinese cabbage line 06J45. The full-length gene has a 937 bp CDNA sequence and contains an open reading frame (ORF) of 702 bp. The subcellular localization analysis showed that the expression product of the gene was localized in the nucleus. Ectopic expression of BraYAB1-702 in Arabidopsis thaliana caused leaf curling from the adaxial epidermises to abaxial epidermises; the partial abaxialization of the adaxial epidermises of leaves; leaf trichomes and stomata numbers being significantly increased; the plants being severely stunted; the flowering stage being remarkably delayed and inhibiting the development of shoot apical meristem (SAM) with the down-regulation of the expression of SHOOT MERISTEMLESS (STM), Brevipedicellus (BP) and KNAT2 which were related to the development of shoot apical meristem. These results from the present research help to reveal the molecular mechanism of BraYAB1-702 gene in the establishment of adaxial–abaxial polarity of the lateral organs in Chinese cabbage.
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