Two types of systemic lymphatic uptake of macromolecules

Objectives The goal of our studies was to investigate systemic lymphatic uptake of macromolecules to provide the framework for development of systemic (intravenous) antineoplastic preparations for the treatment of lymphatic cancer.

Methods Polypeptides glycosylated with poly-α-D-glucose (graft copolymers, developed by our group earlier) and proteins glycosylated with mannose-6-phosphate-rich oligosaccharides were labeled with 89Zr and fluorophores and administered IV to rats and cynomolgus monkeys. Dynamic PET imaging data (0-30 min post injection) and multiple whole-body images (over at least 48 hours) were acquired using a PET/CT imaging system consisting of microPET Focus 220 and CereTom NL 3000 scanners. Images were analyzed to determine the kinetics and patterns of the label accumulation in lymph nodes. Microdistribution of the fluorescence was investigated in rats by fluorescence microscopy in unfixed cryosections.

Results The data shows that macromolecules glycosylated with poly-a-D-glucose and mannose-6-phosphate-rich oligosaccharides (type I and II, respectively) have significantly different pharmacokinetics. Type II accumulates in the nodes only after administration at high doses (>10 mg/kg) and the accumulation is fast (complete by ca. 1 hour, up to 6% ID/g). Type I accumulates in the nodes after administration of any doses (10 μg to 10 mg/kg), and the process of accumulation is slower (up to 24 hours, up to 30% ID/g). In rodents, but not in monkeys, type I accumulation is accompanied by edemas. The microdistribution of type I and II macromolecules overlap in some but not all nodes.

Conclusions Macromolecules can accumulate in lymph nodes by at least two different mechanisms, depending, most likely, on the specific carbohydrate structures present in the macromolecules. The resultant pharmacokinetics of both types can be useful for development of novel systemic antineoplastic preparations.