Molecular Weight-dependent Lymphatic Transfer of Fluorescein Isothiocyanate-labeled Dextrans after Intrapulmonary Administration and Effects of Various Absorption Enhancers on the Lymphatic Transfer of Drugs in Rats

Abstract

We have developed a new method to evaluate the transfer of macromolecular drugs to intrapulmonary lymph nodes in rats after intrapulmonary administration. By using this method, we observed that the transfer of fluorescein isothiocyanate dextrans (FDs) to the intrapulmonary lymph nodes was markedly higher than that to iliac lymph node, a non-intrapulmonary lymph node. The transfer of FDs to the intrapulmonary lymph nodes increased with increasing their molecular weights and the threshold for a high lymph node-to-plasma level ratio (CLN/CP) was between 10 and 20 kDa. The effects of absorption enhancers on the transfer of FDs to intrapulmonary lymph nodes were also examined in rats. Absorption enhancers used in this study were EDTA, sodium glycocholate (Na-GC), mixed micelles (MM), N-lauryl-beta-D-maltopyranoside (LM), sodium caprate (Na-Cap). The transfer of FD-20, FD-40 and FD-70 to intrapulmonary lymph nodes after intrapulmonary administration increased in the presence of LM. In particular, the lymphatic transfer of FD-40 was remarkably increased in the presence of LM. Similarly, Na-GC and MM improved the transfer of FD-40 to intrapulmonary lymph nodes. These results suggest that absorption enhancers such as LM, Na-GC and MM are effective for improving the transfer of macromolecular drugs to intrapulmonary lymph nodes.

From sewer to saviour — targeting the lymphatic system to promote drug exposure and activity

“…Under basal conditions or after intentional induction, lymphoid tissue may also play a role in the uptake of nanomaterials from the lungs 150 . Several studies have demonstrated uptake of inhaled nanoparticles, including liposomes 154 , 20-70 kDa dextrans 155 , non-cationic organic and inorganic nanoparticles of ≤ 34 nm 156 and antigen carrying lipid nanocapsules 157 into lung lymph nodes. Several other studies have inferred lung lymphatic involvement in the systemic availability of inhaled solid lipid nanoparticles 158 , liposomes 159 and 50-900 nm polystyrene nanoparticles 160 .…”

Lymph-directed immunotherapy – Harnessing endogenous lymphatic distribution pathways for enhanced therapeutic outcomes in cancer

“…Studies have previously shown local uptake of pulmonary administered nanoparticles [220], including liposomes [221], dextrans [222] and solid lipid nanoparticles [223] into lung lymph nodes. For example, Choi et al showed that the physicochemical properties of nanoparticles (inorganic/organic hybrid particles and quantum dots) dictate trafficking across the alveolar barrier, as well as distribution and clearance [224].…”

Lymphatic Uptake of Pulmonary Delivered Radiolabelled Solid Lipid Nanoparticles

“…500 nm (Leak and Ferrans Lee, 1991;McIntire et al, 1998). Moreover, phagocytic activity of bronchoalveolar macrophages seem to be responsible for engulfing foreign particles, thus acting as vectors to the lymphatics (Langenback et al, 1990;Hanatani et al, 1995;Corry et al, 1984). Correlation between submicrometric mean diameter, deep lung deposition and lymphatic uptake is expected to be the basis for pulmonary drug delivery using colloidal carriers.…”

“…However, after intravenous administration, uptake of colloidal particles by the mononuclear phagocytic system (MPS) reduces circulation time and decreases targeting, thus limiting their application. Alternative administration routes have been studied indicating that nanoparticles can migrate to regional draining lymph nodes after subcutaneous or intraperitoneal injection (Wolf et al, 1994;Hanatani et al, 1995). An interesting approach for targeting drug carriers to the lymphatics involved the latter, resulting in significant lymphatic uptake, although particles (500 nm) remained in the abdominal cavity and targeting was restricted to thoracic lymph fluid, mediastinal and renal lymph nodes (Hanatani et al, 1995).…”