The primary sequelae resulting from radical mastectomy and sentinel lymph node removal during the treatment of breast cancer is the development of lymphedema in related limbs. Estimates of the frequency of post-cancer lymphedema range from 20%-90%, depending upon the metrics used to measure development of the condition. There is significant social and monetary cost associated with lymphedema, including increased healthcare costs associated with the increased susceptibility to infection in oedematous tissue. Over the past decade, a number of soluble factors and techniques have been described that promote regrowth of lymphatics in vivo, although appropriate delivery vehicles remain a challenge. Recently, a formulation containing recombinant VEGF-C was found to reduce lymphedema in an acute sheep model of secondary lymphedema. Additional studies demonstrated increased efficacy of lymphatic regeneration associated with lymph node autotransplantation in conjunction with VEGF-C administration in a rat model. Unfortunately, VEGF-C release occurred rapidly in both situations, which apparently reduced effectiveness. It is the goal of this proposal to define a delivery formulation which will release prolymphangiogenic factors in a controlled slow release, promoting lymphatic regeneration and reducing lymphedema. To accomplish this goal, we will (i) Define a novel formulation based on natural plant products for the controlled release of lymphangiogenic factors (ii) Test the biocompatibility of this formulation in cultured sheep lymphatic endothelial cells and (iii) Map th effects of this formulation in reducing lymphedema in a proven animal model of secondary lymphedema in conjunction with lymph node autotransplantation. We have partnered with a group with demonstrated expertise in the mechanisms and resolution of lymphedema to develop novel, slow-release delivery systems to treat lymphedema through regrowth of interrupted lymphatic vessels. This work will ultimately reduce post-treatment costs associated with breast cancer, and may be applied to other conditions to promote lymphatic regrowth and appropriate drainage of interstitial fluid.
Public Health Relevance Statement: Public Health Relevance: Radical mastectomy and sentinel node removal during breast cancer treatment may lead to development of secondary lymphedema in a significant number of patients. These complications can lead to extensive health- care costs, increased patient morbidity, and increased susceptibility to secondary infection. This proposal aims to use established mediators that promote lymphatic regrowth in conjunction with autologous lymph node transplantation, and hence reduce edema in a novel, biocompatible slow-delivery system to treat secondary lymphedema and alleviate these negative consequences to breast-cancer survivors.
Project Terms: Ablation; Acute; Address; Affect; Aftercare; angiogenesis; Animal Model; Animals; Autologous; base; Biocompatible; biomaterial compatibility; breast cancer diagnosis; Breast Cancer Treatment; Cancer Survivor; Cell Culture System; Cell Culture Techniques; Cell Survival; Chronic; Clinical; Combined Modality Therapy; controlled release; cost; Development; dosage; Drainage procedure; Drug Delivery Systems; Drug Formulations; Edema; Effectiveness; Ensure; Excision; Failure (biologic function); Frequencies (time pattern); Gelatin; Goals; Health Care Costs; In Vitro; in vivo; in vivo Model; Infection; innovation; Intercellular Fluid; Interruption; Ipsilateral; Lead; Life; Limb structure; Liquid substance; Lymph node excision; lymph nodes; Lymphatic; Lymphatic Endothelial Cells; Lymphatic Endothelium; Lymphatic System; Lymphatic vessel; Lymphedema; malignant breast neoplasm; Malignant Neoplasms; Maps; Mastectomy; Measures; Mediator of activation protein; Metric; Micelles; Modeling; Monitor; Morbidity - disease rate; Morphology; Natural regeneration; novel; Operative Surgical Procedures; Patients; Phenotype; Physiological; Plants; Pre-Clinical Model; Predisposition; Process; public health relevance; Quality of life; Radical Mastectomy; Rattus; Recombinants; Recruitment Activity; Regulation; Research Personnel; Resolution; secondary infection; Sentinel Lymph Node; Sheep; social; success; Survivors; System; Techniques; Testing; Therapeutic; Tissues; Transplantation; Treatment Cost; United States; uptake; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factors; Work; Zein
