Surface engineered nanospheres with enhanced drainage into lymphatics and uptake by macrophages of the regional lymph nodes

Abstract

The concept of steric stabilization as used in colloid science is applied to carefully manipulate the drainage and lymphatic distribution of subcutaneously administered model polystyrene nanospheres. A wide range of synthetic polyoxyethylene (POE)/polyoxypropylene (POP) block co-polymers of poloxamine and poloxamer series have been used to produce sterically stabilized nanospheres. We have found a correlation between the length of the stabilizing POE chains of the block co-polymers and nanosphere drainage and passageway across tissue lymph interface in dermal lymphatic capillaries in the rat footpads; the longer the POE chains, the faster the particle drainage. Nanospheres conditioned with block co-polymers of POE chains of 5-15 ethylene oxide units are effectively opsonized in lymphatics; a process which dramatically enhances sequestration (up to 40% of the administered dose) by macrophages of the regional lymph nodes. If the dimensions of the stabilizing POE chains of the poloxamines and poloxamers exceed the range of the Van der Waals force of attraction, opsonization fails to occur and rapidly drained engineered vehicles escape clearance by macrophages of the regional nodes, reach the systemic circulation and remain in the blood for prolonged periods. These observations suggest that a lymphatic delivery composition based on polymer-coated particles will be advantageous for many applications in clinical and experimental medicine.

Lymph node localisation of biodegradable nanospheres surface modified with poloxamer and poloxamine block co‐polymers

“…The popliteal node was responsible for the greatest uptake by the lymph nodes in each case. The coating of polystyrene nanospheres (60 nm) with the same block co-polymers has been reported previously [2]. In these experiments there was a greater drainage from the injection site with increasing hydrophilicity.…”

“…Since colloid passage through the interstitium to the initial lymphatics is facilitated by aqueous channels [18], it is not surprising that the nanosphere movement was inhibited, considering the hydrophobicity of the PLGA nanospheres. Previous work has investigated the mechanism of uptake of colloids from the interstitium into the initial lymphatics [2,19,20]. Two pathways of colloid transport were proposed, one being via extracellular dispersed particle flow directly into the initiallymphatic vessels, and the other by intracellular carriage after phagocytosis by macrophages within the interstitium.…”

“…Nanospheres which do drain into the lymphatic system are effectively sequestered by the regional lymph nodes, with the majority of lymphatic uptake in the primary, popliteal node. The phagocytic cells of the subcapsular sinus of the cortex and the classical macrophages of the medulla in both the popliteal and iliac nodes are mainly responsible for the phagocytosis of nanospheres [2]. Any nanospheres which are then not sequestered by the lymph node macrophages and reach the general circulation can be removed by the Kupffer cells of the liver.…”

“…The results presented herein for PLGA nanospheres are, therefore, far superior to previous results obtained with other biodegradable nanospheres. Only results obtained with model polystyrene nanospheres have produced higher lymph node uptake [2].…”

“…The concept of surface modification, wherein model polystyrene nanospheres have been coated with block co-polymers that provide a sterically stabilised surface, has been used previously to control the rate of drainage from a subcutaneous injection site and to manipulate the lymphatic distribution [2].…”