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

Abstract

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.

Intercellular transfer of HLA‐G: its potential in cancer immunology

“…Data revealed that the HLA‐G‐targeted mAb released from the NBs could kill the residual JEG‐3 cells and inhibit the reoccurrence of tumors . Moreover, a recent study by Guo et al . reported that, using M1 macrophages as live‐cell carriers, doxorubicin‐loaded M1 macrophages (M1‐Dox) had a natural tropism to the ovarian cancer SKOV3 cells and delivered the drug doxorubicin very fast and accurately to the target cells through a tunnelling nanotube pathway.…”

“…Data revealed that the HLA-G-targeted mAb released from the NBs could kill the residual JEG-3 cells and inhibit the reoccurrence of tumors. 78 Moreover, a recent study by Guo et al 79 reported that, using M1 macrophages as live-cell carriers, doxorubicinloaded M1 macrophages (M1-Dox) had a natural tropism to the ovarian cancer SKOV3 cells and delivered the drug doxorubicin very fast and accurately to the target cells through a tunnelling nanotube pathway. The authors also found that multiple organ metastases (liver, kidneys, spleen, gastrointestinal tract, diaphragm and uterine appendages) in the BALB/c (nu/nu) nude mice established with SKOV3 cells were reduced to nearly undetectable levels in the M1-Dox-treated group.…”

Direct Transfer of Mesoporous Silica Nanoparticles between Macrophages and Cancer Cells

“…To the right, macrophages with DAPI labeled nuclei (blue) are seen surrounded by a ring of fluorescent MSN (red), while the larger CellTracker Violet labeled 4T1 cells lacked detectable MSN and TNT connections, supporting a lack of MSN transfer between RAW macrophages and syngeneic 4T1 cancer cells. While the data did not support MSN transfer among 4T1 murine breast cancer cells or from RAW macrophages to syngeneic 4T1 cancer cells, Guo et al [ 51 ] reported that doxorubicin-loaded M1 RAW macrophages transfer drug cargoes into human SKOV8 and mice ID8 ovarian cancer cells. However, while RAW macrophages and 4T1 cells are derived from BALB/c mice, ID8 cells are derived from C57BL/6 mice.…”

“…As stated previously, rapid internalization of nanoparticles by macrophages and trafficking to sites of inflammation has led to reports of macrophages functioning as cell-based drug carriers [ 49 , 50 , 51 ]. Zhang et al reported that silica-based nano capsules loaded with doxorubicin can be loaded into macrophages with minimal drug release in the first hours after uptake and minimal effect on in vivo cell migration to tumors [ 52 ].…”

Targeted Delivery of Cisplatin-Derived Nanoprecursors via a Biomimetic Yeast Microcapsule for Tumor Therapy by the Oral Route

“…These results indicated that PreCDDP/YC not only had higher oral bioavailability than CDDP and PreCDDP, but also could be stably stored in monocytes for site-specific delivery to tumors. Upon arrival at the tumor site, the active forms of Pt would be delivered to tumor cells by gradual release of PreCDDP or by transportation via tunneling nanotubes between macrophages and tumor cells 75, 76.…”