(197f) Layer-By-Layer Nanoparticles for Interleukin-12 Delivery

Antonio Barberio, Santiago Correa, Erik C. Dreaden, Mariane B Melo, Darrell J. Irvine, Paula T. Hammond

1 Department of Chemical Engineering, MIT

2 Koch Institute for Integrated Cancer Research, MIT

3 Department of Biological Engineering, MIT

Abstract:

Immunotherapy has become a popular target for cancer treatment as it allows for a more diverse application of treatment. Rather than target treatment towards the many highly specific types of cancer, immunotherapies aim to trigger the immune system to fight the malignancy, making them applicable across many tissues and oncogenic mutations. One option for this type of immune treatment is the delivery of a general immune stimulator such as a cytokine. One such cytokine is interleukin-12 (IL-12). Systemic IL-12 delivery was attempted in the past but led to intolerable off target toxicities at effective doses. This work focuses on delivering a single-chain version of IL-12 in a layer-by-layer nanoparticle to reduce the off-target toxicity issue, using principles of electrostatic assembly to create a protective coating that can also provide targeting and stealth properties for systemic delivery. The particle will incorporate layer-by-layer technology to tailor its delivery properties to maximize the efficacy of IL-12 in the tumor and reduce its off target effects. Layer by layer nanoparticles are created by using alternating material intermolecular interactions such as electrostatic charge to build a multi-component coating on a nanoparticle core. The addition of layered materials allows for optimized targeting, delivery, and combinations of different payloads. The delivery system is designed to deliver IL-12 both from the core of the particle and from the layers. IL-12 is loaded into the core of the particle by encapsulation into a negatively charged liposome. The cytokine is loaded into the layers of the particle via interactions with the layering materials, including serum proteins and carrier polyelectrolyte backbones. One of the main challenges of this work is achieving effective delivery of a cytokine that must achieve activity by binding to an external membrane receptor in a nanoparticle that may be internalized. To address this issue materials that trigger exocytosis or rapidly degrade in the tumor micro environment to release the drug in the extracellular space are tested in the layers. In addition to optimizing the materials for drug release, different terminal layer materials are tested for optimal targeting of the particle. The particle must effectively target the tumor, but it must also deliver the cytokine to T and natural killer cells that express the Il-12 receptor for the treatment to be effective. This work attempts to produce a clinically relevant form of systemic IL-12 therapy and make future combination therapies with IL-12 a possibility to obtain in a systemically deliverable package.