(331h) Modified Peroxamide-Based Reactive Oxygen Species (ROS)-Responsive Doxorubicin Prodrug

Toxic side effects are common with systemic chemotherapies and impair the successful completion of treatment for many patients with cancer. Doxorubicin (Dox) is commonly used to treat various cancers including breast, bladder, lymphoma, and leukemia, but ~4-36% of patients experience potentially lethal cardiotoxicity in a dose-dependent manner. Although nanoparticle (NP)-based therapeutics have made tremendous progress, it is still a great challenge to meet the goals due to the two desired but conflicting concepts of sustained and controlled release. A stimulus-responsive linker approach can address these challenges by deactivating potent but toxic drugs upon conjugation to a polymer and reactivating them upon release triggered by a stimulus-responsive mechanism. Reactive oxygen species (ROS) can be used as a powerful internal stimulus, as the ROS level in cancerous cells (e.g., ~100 mM) can go up to ~5,000 times higher than those in healthy cells (e.g., ~20 nM).

Here, we present two ROS-responsive Dox prodrug-based NP systems that can deliver Dox in a sustained manner during systemic circulation while achieving controlled drug release at tumor sites. Our ROS-responsive Dox prodrug was physically encapsulated in polylactic acid (PLA)-polyethylene glycol (PEG) (PLA-PEG) NPs or chemically conjugated to PEG-poly-L-lysine (PLL) (PEG-PLL). The NP designs showed average sizes of <~100 nm with very stable Dox release profile in PBS at pH 7.4. While both NP designs showed ROS-responsive Dox releases up to ~70-80% within 48 hrs under 50-100 mM H₂O₂ and horseradish peroxidase (HRP) concentrations, the physically-encapsulated NPs showed faster Dox release in the first few hrs. The surface modification of NPs with hyaluronic acid (HA), a natural polysaccharide that can specifically bind to CD44, resulted in an increase in cellular uptake and efficacy against MDA-MB-231 breast cancer cell line. The therapeutic efficacy and off-target toxicity of our NPs were also investigated in vivo using an orthotopic xenograft tumor model using the MDA-MB-231 cell line.