(131c) Synthetic Red Blood Cells for Drug Delivery Applications

Authors: 
Mitragotri, S., University of California
Zahr, A. S., Schepens Eye Research Institute, Harvard Medical School
Bhaskar, S., University of Michigan
Lahann, J., University of Michigan


Particulate medicine offers significant advantages over conventional drug delivery methods including sustained release, reduced side-effects and effective targeting to diseased tissues. Numerous materials and methodologies have been proposed to design effective drug carriers, however, some of the major hurdles including rapid clearance of particles and low targeting efficiency have not been effectively addressed. We describe a novel biomimetic strategy for fabrication of particles that mimic the physical and functional properties of body's own circulating cells such as red blood cells (RBCs). Red blood cells (RBCs), the most ubiquitous cell type in the human blood, constitute highly specialized entities with unique shape, size, mechanical flexibility and material composition, all of which are optimized for extraordinary circulation time (~120 days) and biological performance (oxygen delivery). Inspired by this natural example, we synthesized particles that mimic the key structural and functional attributes of RBCs, but have the potential to include additional functionalities, such as drug delivery or molecular imaging. We started with appropriately sized polymeric particles and used them as a template to induce the change in shape and mechanical properties to form RBC-like particles. A modified layer-by-layer technique of protein deposition was used to deposit alternate layers of proteins inherent to RBCs such as hemoglobin and complementary polyelectrolytes such as Poly(4-styrene sulfonate) to form a dense shell. This was followed by dissolution of the polymeric core to yield synthetic RBCs around 5 μm in size and biconcave discoidal shape, typical of natural RBCs. Synthetic RBCs were extremely flexible with elastic modulus (E) ~ 1.2 ± 0.57 MPa as determined by AFM, which was significantly lower compared to template polymeric particles (E ~ 2700 ± 1500 MPa). Synthetic RBCs can find great applications in therapeutic delivery of drugs since they exhibited high loading capacity of therapeutics (~ 70 μg/mg particles). Heparin (~12kDa) and dextran (3kDa and 10kDa) were released in a controlled manner from synthetic RBCs over a period of several days. Synthetic RBCs exhibited high oxygen carrying capacity comparable to mouse blood on a per particle basis, upon adequate deposition of Hb as measured with the chemiluminescence reaction of luminol with Hb. Thus, synthetic RBC open new avenues in the fabrication of carriers for drug delivery and artificial blood synthesis .