title: The Effect of Polymeric Nanoparticles on Biocompatibility of Carrier Red Blood Cells.
abstract: Red blood cells (RBCs) can be used for vascular delivery of encapsulated or surface-bound drugs and carriers. Coupling to RBC prolongs circulation of nanoparticles (NP, 200 nm spheres, a conventional model of polymeric drug delivery carrier) enabling their transfer to the pulmonary vasculature without provoking overt RBC elimination. However, little is known about more subtle and potentially harmful effects of drugs and drug carriers on RBCs. Here we devised high-throughput in vitro assays to determine the sensitivity of loaded RBCs to osmotic stress and other damaging insults that they may encounter in vivo (e.g. mechanical, oxidative and complement insults). Sensitivity of these tests is inversely proportional to RBC concentration in suspension and our results suggest that mouse RBCs are more sensitive to damaging factors than human RBCs. Loading RBCs by NP at 1:50 ratio did not affect RBCs, while 10-50 fold higher NP load accentuated RBC damage by mechanical, osmotic and oxidative stress. This extensive loading of RBC by NP also leads to RBCs agglutination in buffer; however, addition of albumin diminished this effect. These results provide a template for analyses of the effects of diverse cargoes loaded on carrier RBCs and indicate that: i) RBCs can tolerate carriage of NP at doses providing loading of millions of nanoparticles per microliter of blood; ii) tests using protein-free buffers and mouse RBCs may overestimate adversity that may be encountered in humans.
authors.affiliation: Department of Pharmacology and Center for Translational Targeted Therapeutics and Nanomedicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Daniel
authors.initials: D
authors.lastname: Pan
authors.affiliation: Department of Pharmacology and Center for Translational Targeted Therapeutics and Nanomedicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Omayra
authors.initials: O
authors.lastname: Vargas-Morales
authors.affiliation: Department of Pharmacology and Center for Translational Targeted Therapeutics and Nanomedicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Blaine
authors.initials: B
authors.lastname: Zern
authors.affiliation: Department of Chemical Engineering and Center for Bioengineering, University of California Santa Barbara, Santa Barbara, California, United States of America.
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Anselmo
authors.affiliation: Department of Chemical Engineering and Center for Bioengineering, University of California Santa Barbara, Santa Barbara, California, United States of America.
authors.forename: Vivek
authors.initials: V
authors.lastname: Gupta
authors.affiliation: Department of Chemical Engineering and Center for Bioengineering, University of California Santa Barbara, Santa Barbara, California, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Zakrewsky
authors.affiliation: Department of Chemical Engineering and Center for Bioengineering, University of California Santa Barbara, Santa Barbara, California, United States of America.
authors.forename: Samir
authors.initials: S
authors.lastname: Mitragotri
authors.affiliation: Department of Pharmacology and Center for Translational Targeted Therapeutics and Nanomedicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Muzykantov
mesh_terms: D000418:Albumins / Q000008:administration & dosage / Q000737:chemistry; D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry*; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000379:methods; D004906:Erythrocyte Count / Q000379:methods; D004912:Erythrocytes / Q000737:chemistry* / Q000378:metabolism*; D008297:Male; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry*; D012680:Sensitivity and Specificity
chemical_list: D000418:Albumins; D001672:Biocompatible Materials; D004337:Drug Carriers; D011108:Polymers