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用于治疗淋巴癌和其他涉及淋巴结的疾病的新型药物递送方法。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;两者都依赖于大分子中存在的特定碳水化合物结构。快速、剂量依赖性I型摄取最可能依赖于淋巴结中内皮屏障的突然和特异性“打开”，随后是大分子的外渗和摄取。较慢的剂量非依赖性II型摄取可能包括淋巴结外组织中受体介导的经内皮转运，随后通过淋巴管引流至淋巴结。在这两种情况下，淋巴结积聚非常显著水平的施用材料;例如，注射后1小时，I型和II型的淋巴结：肌肉比分别为11：1和稳定，25：1和生长。我们进一步假设，这两种机制可以结合起来，迅速提供更高剂量的药物或药物载体的淋巴结。本探索性研究的目的是确定：（1）淋巴结中I型和II型吸收的途径是否是直接的（通过淋巴结的血管内皮）或通过在别处外渗然后通过淋巴管递送至淋巴结来介导;（二）大分子的哪些碳水化合物结构参与全身淋巴吸收以及淋巴结中的哪些细胞积累相应的碳水化合物。类型;以及（3）I型分子是否仅在高剂量下激活其自身的结内外渗，或者它们可以促进其它分子向淋巴结的全身递送。影响：拟议的研究将提供关于糖缀合物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).