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Abstract
Neuroendocrine (NE) cancers arise from cells within the neuroendocrine system. Chemotherapies and endoradiotherapy have been developed, but their clinical efficacy is limited. The objective of this study was to develop a dual-targeted extracellular vesicles (EV)-delivered combined therapies to treat NE cancer. Specifically, we produced EV in stirred-tank bioreactors and surface tagged both anti-somatostatin receptor 2 (SSTR 2) monoclonal antibody (mAb) and anti-C-X-C motif chemokine receptor 4 (CXCR4) mAb to generate mAbs-EV. Both live-cell confocal microscopy imaging and In Vivo Imaging System (IVIS) imaging confirmed that mAbs-EV specifically targeted and accumulated in NE cancer cells and NE tumor xenografts. Then the highly potent natural cytotoxic marine compound verrucarin A (Ver-A) with IC50 of 2.2–2.8 nM and microtubule polymerization inhibitor mertansine (DM1) with IC50 of 3.1–4.2 nM were packed into mAbs-EV. The in vivo maximum tolerated dose study performed in non-tumor-bearing mice indicated minimal systemic toxicity of mAbs-EV-Ver-A/DM1. Finally, the in vivo anticancer efficacy study demonstrated that the SSTR2/CXCR4 dual-targeted EV-Ver-A/DM1 is more effective to inhibit NE tumor growth than the single targeting and single drug. The results from this study could expand the application of EV to targeting deliver the combined potent chemotherapies for cancer treatment.
Highlights
Neuroendocrine (NE) cancers arising from cells within the neuroendocrine system are often metastatic at the time of initial diagnosis [1], and patients with untreated, isolated NE tumor (NET) liver metastases have a
We have found that both verrucarin A (Ver-A) and DM1 are potent growth inhibitors of NET cells at low nanomolar concentrations
This study demonstrated the feasibility to use Extracellular vesicles (EV) for dual receptors targeting and combined therapies delivery, which would expand the application of EV in cancer treatment
Summary
Neuroendocrine (NE) cancers arising from cells within the neuroendocrine system are often metastatic at the time of initial diagnosis [1], and patients with untreated, isolated NE tumor (NET) liver metastases have a
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