Improving delivery of nanoparticles to tissue endothelium by Erythrocyte Hitchhiking

Abstract

Nanoparticles have become integral part of designing drug delivery systems for efficient cargo loading and targeted delivery. However, their complete therapeutic potential seems far from being completely achieved. This happens because of the biological barriers that impede the delivery of nanoparticles. With the advent of targeted strategies, this delivery problem is one step closer to being circumvented. While small molecule and antibody targeting ligands largely rely on convection until they are in a molecular contact with the receptor, cell-based targeting is dependent on physiological tropism to target sites and is been increasingly investigated. In this work, we use erythrocytes as secondary drug delivery vehicles to target nanoparticles to the lungs and the spleen. First, we use the physiological squeezing of erythrocytes through narrow lung capillaries to induce shear responsive nanoparticles dislodgement. With a chemotherapeutic (DOX) being loaded in these particles, a 10-fold higher drug dose was delivered to the lungs, which significantly improved survival in lung metastasis model. We also showed the potential of this technology to incorporate other chemo drugs and attach to and detach from human erythrocytes. Next, we modified this platform by engineering material properties to facilitate efficient erythrocyte adsorption and incorporated a biologic (CXCL10). By delivering high amounts of chemokine in and around the metastatic sites, we not only improved lung metastasis survival, but also were able to convert the physiological adversity of lung metastasis into a unique immunotherapy opportunity, with the local restorative response generated in the lung being able to successfully resist distant tumor growth post re-challenge. Lastly, by mimicking handoff of bacterial pathogens from erythrocytes to antigen presenting cells (APCs) in spleen, we were able to engineer an erythrocyte hitchhiking system which can deliver particles to the spleen and not lung. This strategy represents a novel way of targeting the spleen without sacrifice of the carrier cell and lead to immune modulation. All in all, erythrocyte hitchhiking represents a great platform to selectively deliver wide range of nanoparticles encapsulating any form of therapeutic cargos to vascularized organs.