BIRC5 Promoter-Driven Nanodrugs Suppress BIRC5-Positive Cancers Independent of ABCB1 Status and IDO1 Expression
Abstract
Introduction BIRC5 (survivin), an inhibitor of apoptosis protein, is overexpressed in most tumors and is associated with drug resistance, proliferation, and metastasis, while being largely undetectable in normal differentiated tissues. This unique expression pattern makes BIRC5 an exceptionally selective therapeutic target, offering the potential to maximize anticancer efficacy while minimizing systemic toxicity to healthy tissues. However, few BIRC5-targeted agents have advanced to late-stage clinical trials. Methods We developed two nanodrug formulations using poly-L-lysine–modified NH2-Fe3O4 magnetite nanoparticles (PL-MNPs) for selective targeting of BIRC5-positive cancer cells. We further evaluated their anti-cancer efficacy in vitro and in vivo (zebrafish xenograft model), using cancer cell models that expressed BIRC5 and exhibited ABCB1-mediated drug resistance and IDO1-induced immune therapy insensitivity. Results The PL-MNPs delivered plasmids driven by the BIRC5 promoter (pBIRC5) encoding either antisense BIRC5 mRNA (As-BIRC5) or a dominant-negative BIRC5 protein (dN-BIRC5), for tumor-specific BIRC5 inhibition. These nanodrugs demonstrated robust in vitro and in vivo anti-cancer activity in multiple BIRC5-positive cell lines (MIA PaCa-2, NTUB1, NTU0.017, SK-OV-3, KB, and KB-TAX50). The activity was preserved across cancer types and independent of ABCB1-mediated drug resistance, while maintaining cancer cell specificity, and was not affected by IDO1 expression, a…
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