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Osteopontin (OPN) is produced by tumor cells as well as by myeloid cells and is enriched in the tumor microenvironment (TME) of many cancers. Given the roles of OPN in tumor progression and immune suppression, the study hypothesized that targeting OPN with aptamers with high affinity and specificity could be a promising therapeutic strategy. Bi-specific aptamers targeting ligands for cellular internalization were conjugated to siRNAs to suppress OPN, and therapeutic leads were selected based on target engagement and in vivo activity. These aptamers were selected as therapeutic leads based on 70–90% OPN inhibition in cancer (GL261, 344SQ, 4T1B2b) and myeloid (DC2.4) cells relative to scramble controls. Therapeutic activity was demonstrated using both aptamers in a breast cancer brain metastasis model. Targeted inhibition of OPN in tumor cells and myeloid cells using bifunctional aptamers internalized by specific cell types and suppressing OPN expression once internalized may have clinical potential in cancer treatment.
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