Angiogenic Strategies and Nanocarrier-Based Delivery for Acute Radiation Dermatitis Therapy

Abstract

Radiotherapy (RT) is a cornerstone of cancer treatment, but often causes side effects. One of the most common is acute radiation dermatitis (ARD), a severe skin reaction affecting 95% of cancer patients. ARD arises from radiation-induced reactive oxygen species (ROS), which damage the skin and underlying blood vessels. This injury triggers inflammation and with repeated radiation exposure, the cumulative damage overwhelms the skin’s ability to repair itself. As a result, patients experience skin reactions ranging from erythema to ulceration, often accompanied by pain and discomfort, reducing quality of life. Current treatment strategies mainly focus on symptom management by reducing inflammation but lack robust scientific evidence and a clinical consensus. Critically, they also fail to address the underlying ROS-induced vascular injury, highlighting the need for new therapies that actively promote wound repair. As a foundational step toward a proangiogenic therapy for ARD, this thesis aimed to identify the optimal growth factor to stimulate angiogenesis, a key process in wound healing. Screening various angiogenic factors identified vascular endothelial growth factor (VEGF) as a strong candidate due to its ability to promote endothelial cell (EC) proliferation and migration. Although interleukin-6 (IL-6) showed angiogenic potential across different EC types, its proinflammatory effects make it unsuitable for the ARD environment. Notably, VEGF maintained its angiogenic activity on irradiated ECs, with GSEA indicating mechanisms involved in DNA damage repair and cell proliferation. Recognizing the challenges in delivering growth factors clinically, such as a short half-life and potential systemic side effects, this thesis focused on developing a “smart” drug delivery system. A novel ROS-responsive nanocarrier (NC) system was engineered for the ROS-triggered release of VEGF, designed to target the high-ROS environment of ARD. The developed dextran-based NCs were highly biocompatible and rapidly taken up by ECs, providing a strong foundation for the optimization of ROS-responsive VEGF release. In conclusion, this research validates VEGF as a potent therapeutic agent that promotes angiogenesis while supporting cell survival and repair after radiation. By pairing this with a ROS-responsive NC system, this work establishes a proof-of-concept for a targeted proangiogenic therapy. It also provides a solid base for future preclinical studies, aimed at translating this targeted therapy into an effective treatment to improve the well-being of cancer patients undergoing RT.