Poster Session 1, 10:30 AM - 11:15 AM: Concourse [B13]

Polymer-Directed Enzyme Prodrug Therapy in Triple Negative Breast Cancer

Presenter: Ryan Matthew Levitan

Faculty Sponsor: Vincent Rotello

School: UMass Amherst

Research Area: Biochemistry and Molecular Biology

ABSTRACT

Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype characterized by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) expression. Because TNBC lacks these therapeutic targets, current treatment relies primarily on non-specific chemotherapies, which cause substantial systemic toxicity and fail to prevent high rates of recurrence and metastasis. Enzyme prodrug therapy has emerged as a promising treatment for cancer, enabling localized activation of cytotoxic agents within tumors to minimize off-target toxicity. While this approach is promising, current delivery strategies like antibody-enzyme conjugates and vectors coding for the prodrug-activating enzyme struggle with inefficient delivery, immunogenicity, and uneven vector expression.

It has been demonstrated that Poly(oxanorborneneimide) polymers (PONI) featuring cationic guanidinium (Guan) moieties are capable of high efficiency (≥90%) direct cytosolic enzyme delivery while retaining enzymatic activity. Furthermore, the addition of a sulfobetaine zwitterionic block (Zwit) significantly improved tumor accumulation and slowed clearance by the reticuloendothelial system. Using the diblock copolymer PONI-Guan-Zwit, E. coli recombinant oxygen insensitive nitroreductase NfsB will be delivered to catalyze the activation of the DNA crosslinking prodrug 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB1954). Through in vitro delivery and functional characterization, polymer-directed enzyme prodrug therapy will be evaluated as a targeted and potentially less toxic therapeutic strategy for triple negative breast cancer.

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