Dual Affinity to RBCs and Target Cells (DART) Enhances Both Organ- and Cell Type-Targeting of Intravascular Nanocarriers

Abstract

A long-standing goal of nanomedicine is to improve a drug’s benefit by loading it into a nanocarrier that homes solely to a specific target cell and organ. Unfortunately, nanocarriers usually end up with only a small percentage of the injected dose (% ID) in the target organ, due largely to clearance by the liver and spleen. Further, cell-type-specific targeting is rarely achieved without reducing target organ accumulation. To solve these problems, we introduce DART (dual affinity to RBCs and target cells), in which nanocarriers are conjugated to two affinity ligands, one binding red blood cells and one binding a target cell (here, pulmonary endothelial cells). DART nanocarriers first bind red blood cells and then transfer to the target organ’s endothelial cells as the bound red blood cells squeeze through capillaries. We show that within minutes after intravascular injection in mice nearly 70% ID of DART nanocarriers accumulate in the target organ (lungs), more than doubling the % ID ceiling achieved by a multitude of prior technologies, finally achieving a majority % ID in a target organ. Humanized DART nanocarriers in ex vivo perfused human lungs recapitulate this phenomenon. Furthermore, DART enhances the selectivity of delivery to target endothelial cells over local phagocytes within the target organ by 6-fold. DART’s marked improvement in both organ- and cell-type targeting may thus be helpful in localizing drugs for a multitude of medical applications.

Advances in Drug Delivery Systems Based on Red Blood Cells and Their Membrane-Derived Nanoparticles

“…Ferguson et al have shown that neither activation of the complement cascade nor complete blood count in mice are significantly changed upon treatment with RBC-hitchhiked liposomes with dual affinity. 177 Furthermore, this formulation does not elicit detectable impact on cardiac or pulmonary physiology in terms of oxygenation saturation in the blood, breathing rate, and heart rate. The only side effect reported in this study is a decrease in the hematocrit (the percentage of blood volume occupied by RBCs), which warrants further investigation.…”

“…176 Besides passive adsorption, binding of NPs to RBCs can be strengthened by surface functionalization with antibody. 177 We will discuss the surface chemistry of different NPs on the binding strength and the desorption capacity on RBCs in a later section.…”

“…The authors have successfully demonstrated how targeting ligands can maximize the accumulation of hitchhiked NPs at the desired sites of action and limit RES clearance. In a recent study, the RBC-hitchhiking system was further improved with dual affinity to RBCs and target cells . Specifically, anti-GPA antibody was conjugated on liposomes to target GPA, which was abundantly expressed on RBCs.…”

Tissue‐Targeted Drug Delivery Strategies to Promote Antigen‐Specific Immune Tolerance

“…Alternatively, biomaterials could be engineered to accumulate in the lungs following IV administration. Recent studies have shown that surface modification with cationic lipids [ 63 ] or ligands that allow NPs to hitchhike on red blood cells [ 76 ] enhance pulmonary accumulation of systemically injected biomaterials. Future work could adopt these strategies for lung‐targeted drug delivery materials to induce immune tolerance.…”

Targeted In Vivo Loading of Red Blood Cells Markedly Prolongs Nanocarrier Circulation

“…In this approach, drugs are loaded into isolated RBCs prior to reinfusion as a “natural” DDS. This approach improves the pharmacologic profile of small molecules and protein therapeutics. − An alternative strategy to prolong the circulation time of rapidly cleared therapeutics is coupling the therapeutics to the RBC membrane, either covalently − or via genetic modification of precursor reticulocytes , or via targeting of RBC membrane proteins using monoclonal antibodies (mAb) and their fragments. − This strategy has been extended to nanocarriers to either prolong their circulation time , or to promote delivery to specific vascular beds (RBC hitchhiking). − …”