DNA Aptamer-Polymer\nConjugates for Selective Targeting\nof Integrin α4β1<sup>+</sup> T‑Lineage Cancers

Selective therapeutic targeting of T-cell malignancies\nis difficult\ndue to the shared lineage between healthy and malignant T cells. Current\nfront-line chemotherapy for these cancers is largely nonspecific,\nresulting in frequent cases of relapsed/refractory disease. The development\nof targeting approaches for effectively treating T-cell leukemia and\nlymphoma thus remains a critical goal for the oncology field. Here,\nwe report the discovery of a DNA aptamer, named HR7A1, that displays\nlow nanomolar affinity for the integrin α4β1 (VLA-4),\na marker associated with chemoresistance and relapse in leukemia patients.\nAfter truncation of HR7A1 to a minimal binding motif, we demonstrate\nelevated binding of the aptamer to T-lineage cancer cells over healthy\nimmune cells. Using cryo-EM and competition studies, we find that\nHR7A1 shares an overlapping binding site on α4β1 with\nfibronectin and VCAM-1, which has implications for sensitizing blood\ncancers to chemotherapy. We last characterize barriers to <i>in vivo</i> aptamer translation, including serum stability,\ntemperature-sensitive binding, and short circulation half-life, and\nsynthesize an aptamer-polymer conjugate that addresses these challenges.\nFuture work will seek to validate <i>in vivo</i> targeting\nof α4β1<sup>+</sup> tumors with the conjugate, establishing\nan aptamer-based biomaterial that can be readily adapted for targeted\ntreatment of T-cell malignancies.