Engineering pH-responsive biomaterials for cancer immunotherapy

Abstract

Recent advances in immunotherapy have transformed cancer treatment, while highlighting the complex interactions between the immune system and tumors. For delivery of unstable molecules or immunogenic agents, these therapies often employ nanoformulations to deliver therapeutics to diseased tissue while minimizing off-target toxicity. However, delivery of these carriers is severely limited by numerous biological barriers, preventing therapies from reaching sufficient therapeutic concentrations. Carrier accumulation can be enhanced by incorporation of passive and active targeting, and/or stimuli-responsive elements to help steer the carrier to the appropriate diseased tissues, cells, and intracellular compartments. In this work, we seek to engineer new therapies to enhance targeting and delivery of cancer therapeutics by combining both active and passive targeting strategies. Part I motivates tumor-associated macrophages as immunotherapy targets (Chapter 1), leading into our first approach in which we identified a novel targeting ligand that binds to human tumor-associated macrophages and monocytes (Chapter 2). Part II discusses the challenges of peptide delivery in oncology applications (Chapter 3), prefacing our designed peptide-polymer conjugates that passively accumulate in tumors and respond to external pH to facilitate intracellular peptide delivery upon cellular internalization. Using this strategy, we designed a polymeric delivery system to safely deliver (Chapter 4) a variety of immunogenic peptides (Chapters 5, 6, and 7). Part III outlines the challenges in delivering therapeutics past the blood-brain barrier (Chapter 8), and reports the progress on the development of targeted nanoparticles for brain cancer treatment (Chapter 9).