Investigation of systemic lymphatic uptake of macromolecules

描述（由申请人提供）：我们研究的总体目标是开发新的药物递送方法，用于治疗淋巴癌和其他涉及淋巴结的疾病。假设有两种分子机制可以促进大分子从血液到淋巴结的运输；两者都取决于大分子中存在的特定碳水化合物结构。快速、剂量依赖性的I型摄取很可能依赖于淋巴结内皮屏障的突然和特异性“开放”，随后是大分子的外渗和摄取。缓慢的、剂量无关的II型摄取可能包括在淋巴结外的组织中受体介导的跨内皮运输，随后通过淋巴管引流到淋巴结。在这两种情况下，淋巴结积累了非常显著水平的给药物质；例如，注射后1小时，I型和II型的淋巴结与肌肉的比例分别为11:1，处于稳定状态；25:1，处于生长状态。我们进一步假设，这两种机制可以结合起来，迅速将更高剂量的药物或药物载体输送到淋巴结。本探索性研究的目的是确定：(1)I型和II型在淋巴结中的摄取途径是直接（通过淋巴结的血管内皮）还是通过其他地方的外渗介导，然后通过淋巴管输送到淋巴结；(2)大分子的哪些碳水化合物结构参与了全身淋巴摄取，淋巴结中哪些细胞积累了各自的类型；(3) I型分子在高剂量时是否仅激活其自身的结内外渗，还是可以促进其他分子向淋巴结的全身递送。的影响。该研究将为糖缀合物靶向全身淋巴结的机制提供关键数据，这将为淋巴癌和其他涉及淋巴结的疾病（潜在的艾滋病和其他免疫系统疾病）的全身治疗的发展开辟道路。

DESCRIPTION (provided by applicant): The overall goal of our research is to develop novel drug delivery methodologies for treatment of lymphatic cancer and other conditions involving lymph nodes. Hypothetically, there are two molecular mechanisms that can facilitate transport of macromolecules from the blood to lymph nodes; both depend on specific carbohydrate structures present in the macromolecules. The fast, dose-dependent Type I uptake most likely relies on an abrupt and specific "opening" of the endothelial barrier in the lymph nodes, followed by extravasation and uptake of the macromolecules. The slower, dose-independent Type II uptake likely includes receptor-mediated transendothelial transport in the tissues outside the nodes with subsequent drainage to the nodes through the lymphatic vessels. In both cases, lymph nodes accumulate very significant levels of the administered material; e.g., lymph node: muscle ratios for type I and Type II at 1 hour after injection were 11:1 and stable and 25:1 and growing, respectively. We further hypothesize that both mechanisms can be combined to rapidly deliver even higher doses of drugs or drug carriers to lymph nodes. The objectives of this exploratory study are to determine: (1) whether the routes of the Type I and Type II uptake in the nodes are direct (through the vascular endothelium of lymph nodes) or mediated by extravasation elsewhere followed by delivery to the nodes through lymphatic vessels; (2) what carbohydrate structures of the macromolecules participate in the systemic lymphatic uptake and what cells in the nodes accumulate the respective type; and (3) whether type I molecules activate only their own intranodal extravasation at high doses or they can facilitate systemic delivery of other molecules to the nodes. Impact.The proposed study will provide key data on the mechanisms of systemic lymph node targeting with glycoconjugates, which will open the way for the development of systemic therapeutics for lymphatic cancer and other conditions involving lymph nodes (potentially, AIDS and other immune system disorders).