Specific Delivery of Auristatins to Tumor Cells using pHLIP

Abstract

Localized delivery is vital for the successful development of novel and effective therapeutics for the treatment of cancer. Currently, most targeting methods rely upon expression of protein biomarkers to promote tumor targeting and killing. Despite their promises, such strategies suffer from two major drawbacks: Biomarkers are not specific to cancer cells, which can result in off-target toxicity, and cancer cells have a tendency to evolve quickly, which can lead to a loss of biomarkers and therapy resistance. However, nearly all solid tumors have a low extracellular pH, regardless of their tissue or cellular origin. Moreover, tumors’ aggressiveness and metastatic potential are fostered at low extracellular pH. For these reasons, acidosis is a hallmark of tumor progression and may provide an opportunity for tumor-targeted therapy. The targeting and delivery described herein is based on the pH(Low) Insertion Peptide (pHLIP), a unique delivery peptide that can selectively target tumors in mice based solely on their acidity rather than a specific marker. Our group focuses on developing new strategies to inhibit cancer cell growth by delivering therapeutics to cells using pHLIP. We hypothesize that the localized targeting achievable with pHLIP when combined with potent therapeutics will synergize to create an efficacious treatment for cancer. In the present study, we investigate the efficacy of pHLIP to deliver the highly potent and clinically validated microtubule inhibitor monomethyl auristatin E (MMAE) to cancer cells in vitro in a pH dependent manner. We show that pHLIP and one of its variants chosen to optimize targeting, can induce a potent cytotoxic effect in cancer cells, including triple negative breast cancer cells, against which none of the current targeting strategies are effective. Furthermore, we demonstrate that these pHLIP-MMAE drug conjugates effectively target breast tumors in mice.