Tunneling Nanotubular Expressways for Ultrafast and Accurate M1 Macrophage Delivery of Anticancer Drugs to Metastatic Ovarian Carcinoma

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.