Surgical resection remains the first line of defense for most brain tumors, largely due to the low efficacy of existing chemotherapeutic and radiation techniques. Despite advanced MRI-based methods for the intra-operative monitoring of tumor resection, the tumor boundary remains elusive, making complete tumor removal exceedingly difficult. Improved molecular tools for the selective, real-time imaging of brain tumors would be highly beneficial both in the diagnostic stage and during image-guided surgical resection. Furthermore, new chemotherapeutics which can bypass the blood-brain barrier and deliver cytotoxic agents systemically and selectively to brain tumors are critically needed, especially in cases where surgery is not possible. In previous work, we sought to address these limitations with an engineered knottin peptide (EETI-2.5F), designed to target a series of integrins (αv-β3, αv-β5, and α5-β1) which are over-expressed in many types of cancer, including glioblastoma. In this work, we have shown that when conjugated to a near-IR fluorophore, this peptide can be used for the <i>in vivo</i> selective illumination of brain tumors in mice. Furthermore, using standard bioconjugation techniques, we have prepared a variety of knottin-drug conjugates designed to deliver cytotoxic payloads to brain tumor cells, and have shown that these conjugates are effective <i>in vitro</i> against several brain tumor cell lines. Early results warrant additional development of functionalized knottins for these applications, and further demonstrate the potentially high impact of knottin peptides as a platform for the treatment of brain tumors.

Engineered knottin peptide-drug conjugates selectively deliver small molecules to brain tumors in mice

251st National Meeting (2016)

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