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输送方法来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；这两种机制都取决于大分子中存在的特定碳水化合物结构。快速、剂量依赖的I型摄取很可能依赖于淋巴结内皮细胞屏障的突然和特定的“开放”，随后是大分子的外渗和摄取。较慢的、非剂量依赖的II型摄取可能包括受体介导的结外组织内皮细胞转运，随后通过淋巴管引流到结节。在这两种情况下，淋巴结都积累了非常显著的给药物质水平；例如，在注射后1小时，I型和II型的淋巴与肌肉的比率分别为11：1和稳定的25：1，并在不断增长。我们进一步假设，这两种机制可以结合在一起，迅速将更高剂量的药物或药物载体输送到淋巴结。这项探索性研究的目的是确定：(1)淋巴结内I型和II型摄取的途径是直接的(通过淋巴结的血管内皮细胞)还是通过其他地方的外溢然后通过淋巴管输送到结节；(2)大分子的哪些碳水化合物结构参与了全身淋巴的摄取，以及结节中的哪些细胞积累了相应类型的淋巴；以及(3)I型分子在高剂量时是否只激活自己的结内外溢，或者它们可以促进系统中其他分子向结节的输送。拟议的研究将提供糖结合物靶向全身淋巴结靶向机制的关键数据，这将为淋巴癌和其他涉及淋巴系统的疾病(潜在的艾滋病和其他免疫系统疾病)的系统疗法的发展开辟道路。

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).