(110d) Redox-Adaptive Protein Intracellular Delivery For Targeted p53 Therapy

Specific induction of cell death in tumors is considered one of the most desired and effective anticancer therapies.  A potent chemotherapy option is directly arming the cancer cells with executioner proteins or apoptotic-inducing proteins that are not targeted by anti-apoptotic maneuvers found in many tumors.  We have developed a new method to treat breast cancer by using Redox-Adaptive Protein Intracellular Delivery (RAPID).  RAPID is a platform to deliver proteins in native forms into cells.  The key design feature of RAPID is to first encapsulate protein molecules in a thin layer of water soluble, positively charged, protease degradable polymer to form nanometer-sized nanocapsules.  The nanocapsule shell facilitates uptake of the protein content into cells, and protects the protein both during in vivo circulation and endocytosis.   To endow the nanocapsules biodegradability once entered the target cells, the polymer shell is crosslinked with a disulfide containing, redox-sensitive crosslinkers that can be degraded once encountering the reducing intracellular environment.   In this presentation, we will describe using RAPID to deliver the cellular guardian transcription factor p53.  It controls the normal cell homeostasis and is mutated in a large number of breast cancers, including those hard to treat triple negative breast cancers.  We hypothesized that delivering functional forms of p53 to tumor cells defective in p53-dependent apoptosis can resurrect the pathway and lead to tumor clearance.  This presentation will cover three topics: 1) demonstration that recombinant p53 can indeed be delivered to breast cancer cells and lead to either senescence or apoptosis of cancer cells; 2) establishment of a new nanocapsule synthesis strategy that allows modification of the particle surface with targeting ligands using “Click” chemistry; and 3) the use of p53 nanocapsules on tumors grafted onto nude mice.   THE RAPID method will be general applicable to a variety of therapeutic proteins and human diseases.