Treating Melanoma Metastases with a Novel Photodynamic Approach
Abstract
Melanoma takes ~10,000 lives every year in the United States, which accounts for ~ 75% of all skin cancer related death. Melanoma has high metastatic potential. Once metastases occur, the average 3-year survival rate is only less than 15%. Radical surgical is often not an option for metastatic melanoma, and the metastases are also often refractory to radiotherapy and chemotherapy. Hence, there is a critical need to develop novel and minimally invasive therapy modality for metastatic melanoma. One promising treatment modality is photodynamic therapy (PDT). PDT produces localized tissue damage with light after prior administration of a photosensitizing drug called photosensitizer. PDT has a favorable toxicity compared to chemotherapy because photosensitizers are not toxic in the dark. The treatment is also highly selective given that photo-irradiation covers only diseased tissues, leaving the surrounding normal tissues unharmed. One limitation of PDT, however, is that light has limited penetration through body tissues (< 1 cm). It is possible to deliver light, via an optic fiber, to certain regions in the lung. The approach, however, has a number of limitations, such as inefficiency to treat large tumor and multiple tumors. The objective of this project is to develop a novel PDT derivative that can break the shallow-penetration-depth limitation of conventional PDT so that it can be used to treatment melanoma spared to the lung. Our strategy is to use X-ray, which has essentially unlimited tissue penetration ability, as the energy source to trigger the PDT process. The key element of our technology is an integrated nanosystem, comprised of a scintillator nanoparticle core and a silica coating shell that is loaded with a photosensitizer, merocyanine 540 (MC540). Upon X-ray irradiation, the scintillator core functions as a transducer, converting X-ray photons to visible light photons. The visible photons, in turn, activate the near-by MC540 to produce cytotoxic 1O2 and kill surrounding cells. Owing to the excellent transmittance of X-ray, X-PDT can be activated in virtually any part of a body. Meanwhile, it inherits the advantages of conventional PDT, including high selectivity, minimal invasiveness, and no incurred resistance. All of these characteristics make X-PDT a novel and appealing methodology for metastatic melanoma therapy. Notably, to minimize contralateral damage, we will use low-energy X-ray as the energy sources, and the irradiation itself causes minimal side effects to normal tissues. This project aims to investigate and optimize X-ray inducible PDT (X-PDT) for melanoma treatment, and the studies will be conducted in a mouse lung metastasis model. We will conjugate onto the surface of the abovementioned nanosystem a melanoma targeting ligand called NAPamide. After systematic injection, the nanoparticles are expected to home to metastatic melanoma cells in the lung. With low-energy X-ray externally applied to the lung area, the X-PDT process is activated, causing cancer cell death while not damaging normal tissues. The success of this project will generate a novel treatment methodology for melanoma, which is listed as one of the Fiscal Year 2014 (FY14) Peer Reviewed Cancer Research Program (PRCRP) Congressionally Directed Topic Areas. It is noted that by virtue of work, the melanoma incident rate of active duty military personnel is about 62% greater than the general population. Hence, there is clearly a gap in melanoma treatment that may affect the general population but have a particularly profound impact on military health (which is stated as one of the FY14 PRCRP Military Relevance Focus Areas).
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510270
Entities
People
- Jin Xie
Organizations
- United States Army
- University of Georgia