Red blood cell-hitchhiking boosts delivery of nanocarriers to chosen organs by orders of magnitude

Abstract

Drug delivery by nanocarriers (NCs) has long been stymied by dominant liver uptake and limited target organ deposition, even when NCs are targeted using affinity moieties. Here we report a universal solution: red blood cell (RBC)-hitchhiking (RH), in which NCs adsorbed onto the RBCs transfer from RBCs to the first organ downstream of the intravascular injection. RH improves delivery for a wide range of NCs and even viral vectors. For example, RH injected intravenously increases liposome uptake in the first downstream organ, lungs, by ~40-fold compared with free NCs. Intra-carotid artery injection of RH NCs delivers >10% of the injected NC dose to the brain, ~10× higher than that achieved with affinity moieties. Further, RH works in mice, pigs, and ex vivo human lungs without causing RBC or end-organ toxicities. Thus, RH is a clinically translatable platform technology poised to augment drug delivery in acute lung disease, stroke, and several other diseases.

Conjugate of Doxorubicin to Albumin‐Binding Peptide Outperforms Aldoxorubicin

“…The lower AUC of ABD–Dox than free Dox in the spleen is consistent with the ability of albumin to reduce opsonization, which reduces subsequent uptake by macrophages that are present at a high level in the spleen, while also directing cellular uptake of albumin and its conjugates via FcRn receptors in the liver and spleen that then recycle albumin in these organs back into the systemic circulation. The markedly high accumulation of AlDox in lungs compared with ABD–Dox is likely, we speculate, due to the its nonspecific binding to the cysteines and lysines on blood cells such as red blood cells that have been previously reported to increase the accumulation of nanocarriers absorbed on their surface into the lungs . Nonspecific binding to blood cells also decreases the plasma availability of AlDox, which is consistent with the pharmacokinetic data, and could explain its lower accumulation in tumors compared with ABD–Dox.…”

Materials for Immunotherapy

“…e) Colorized SEM images of polystyrene nanoparticles (left) and lysozyme‐dextran nanogels (right) attached to the surface of murine red blood cells (scale bars, 1 µm). Reproduced with permission . Copyright 2018, Nature Publishing Group.…”

Vascular Drug Delivery Using Carrier Red Blood Cells: Focus on RBC Surface Loading and Pharmacokinetics

“…Several RBC-based drug delivery approaches have entered clinical trials, including RBC-encapsulated asparaginase (Erytech, Phase 3) and dexamethasone (EryDel, Phase 3). Novel advanced strategies are emerging, including genetic molecular modifications of RBC [2,3], modulation of the immune system by RBC-coupled antigens [3,4], and vascular transfer of RBC-coupled nanocarriers (RBC hitchhiking) [5][6][7].Both encapsulation into and coupling to the surface of RBC fundamentally transform the key parameters of absorption, distribution, metabolism, and elimination (ADME) of drugs and drug delivery systems (DDS), including diverse nanocarriers. To our knowledge, studies of the pharmacokinetics (PK) and pharmacodynamics (PD) of RBC-based DDS are lacking, despite great relevance for industrial development and clinical utility.In order to help to close this gap of knowledge, in this paper we undertook the first attempt to define specific, salient parameters controlling behavior of RBC/DDS in the body.…”

“…Several RBC-based drug delivery approaches have entered clinical trials, including RBC-encapsulated asparaginase (Erytech, Phase 3) and dexamethasone (EryDel, Phase 3). Novel advanced strategies are emerging, including genetic molecular modifications of RBC [2,3], modulation of the immune system by RBC-coupled antigens [3,4], and vascular transfer of RBC-coupled nanocarriers (RBC hitchhiking) [5][6][7].…”