Convective diffusion of nanoparticles from the epithelial barrier toward regional lymph nodes

Drug delivery using nanoparticles as drug carriers has recently attracted the attention of many investigators. Targeted delivery of nanoparticles to the lymph nodes is especially important to prevent cancer metastasis or infection, and to diagnose disease stage. However, systemic injection of nanoparticles often results in organ toxicity because they reach and accumulate in all the lymph nodes in the body. An attractive strategy would be to deliver the drug-loaded nanoparticles to a subset of draining lymph nodes corresponding to a specific site or organ to minimize systemic toxicity. In this respect, mucosal delivery of nanoparticles to regional draining lymph nodes of a selected site creates a new opportunity to accomplish this task with minimal toxicity. One example is the delivery of nanoparticles from the vaginal lumen to draining lymph nodes to prevent the transmission of HIV in women. Other known examples include mucosal delivery of vaccines to induce immunity. In all cases, molecular and particle transport by means of diffusion and convective diffusion play a major role. The corresponding transport processes have common inherent regularities and are addressed in this review. Here we use nanoparticle delivery from the vaginal lumen to the lymph nodes as an example to address the many aspects of associated transport processes. In this case, nanoparticles penetrate the epithelial barrier and move through the interstitium (tissue) to the initial lymphatics until they finally reach the lymph nodes. Since the movement of interstitial liquid near the epithelial barrier is retarded, nanoparticle transport was found to take place through special foci present in the epithelium. Immediately after nanoparticles emerge from the foci, they move through the interstitium due to diffusion affected by convection (convective diffusion). Specifically, the convective transport of nanoparticles occurs due to their convection together with interstitial fluid through the interstitium toward the initial lymph capillaries. Afterwards, nanoparticles move together with the lymph flow along the initial lymph capillaries and then enter the afferent lymphatics and ultimately reach the lymph node. As the liquid moves through the interstitium toward the initial lymph capillaries due to the axial movement of lymph along the lymphatics, the theory for coupling between lymph flow and concomitant flow through the interstitium is developed to describe this general case. The developed theory is applied to interpret the large uptake of Qdots by lymph nodes during inflammation, which is induced by pre-treating mouse vagina with the surfactant Nonoxynol-9 prior to instilling the Qdots. Inflammation is viewed here to cause broadening of the pores within the interstitium with the concomitant formation of transport channels which function as conduits to transport the nanoparticles to the initial lymph capillaries. We introduced the term "effective channels" to denote those channels which interconnect with foci present in the epithelial barrier and which function to transport nanoparticles to initial lymph capillaries. The time of transport toward the lymph node, predicated by the theory, increases rapidly with increasing the distance y0 between the epithelial barrier and the initial lymph capillaries. Transport time is only a few hours, when y0 is small, about some R (where R is the initial lymph capillary radius), due to the predomination of a rather rapid convection in this case. This transport time to the lymph nodes may be tens of hours (or longer) when y0 is essentially larger and the slow diffusion controls the transport rate in a zone not far from the epithelial barrier, where convection is weak at large y0. Accounting for transport by diffusion only, which is mainly considered in many relevant publications, is not sufficient to explain our nanoparticle uptake kinetics because the possibility of fast transport due to convection is overlooked. Our systematic investigations have revealed that the information about the main transport conditions, namely, y0 and the pore broadening up to the dimension of the interstitial transport channels, is necessary to create the quantitative model of enhanced transport during inflammation with the use of the proposed model as a prerequisite. The modeling for convective diffusion of nanoparticles from the epithelial barrier to the lymph node has been mainly accomplished here, while the diffusion only scenario is accounted for in other studies. This first modeling is a semi-quantitative one. A more rigorous mathematical approach is almost impossible at this stage because the transport properties of the model are introduced here for the first time. These properties include: discovery of foci in the epithelium, formation of transport channels, definition of channels interconnecting with foci (effective foci and channels), generation of flow in the interstitium toward the initial lymph capillaries due to axial flow within afferent lymphatics, deformation of this flow due to hydrodynamic impermeability of the squamous layer with the formation of the hydrodynamic stagnation zone near the epithelial barrier, predomination of slow diffusion transport within the above zone, and predomination of fast convection of nanoparticles near the initial lymph capillaries.