Potential role of size and hemodynamics in the efficacy of vascular-targeted spherical drug carriers.

Targeting of drug carriers to the vascular wall is of interest for localized delivery of therapeutics in many human diseases. Nanometer-sized spherical particles are widely proposed for use as carriers for vascular targeting, yet very little evidence has been presented as to their ability to interact with the vascular wall. Thus, this work focuses on elucidating the effect of particle size along with hemodynamics, blood rheology, and vessel size on the adhesion efficiency of targeted polymeric spheres to inflamed endothelium in vitro via parallel plate flow chamber assays. We find that the binding efficiency of spheres to the endothelium from blood flow generally increased with increasing particle size, wall shear rate and channel height for particle sizes from 100 nm up to 10 microm. However, nano-sized particles showed minimal adhesion to the endothelium from blood flow in horizontal (gravity or anti-gravity direction) and vertical channels on the order of small to medium-sized venules and arteries when compared to micron-sized spheres. Furthermore, adhesion of nanospheres was not enhanced with pulsatility in flow. Overall, the presented data suggests that spheres 2-5 microm in size are optimal for targeting the wall in medium to large vessels relevant in several cardiovascular diseases.

[1]  C. Smith,et al.  Kinetics of LFA-1 Mediated Adhesion of Human Neutrophils to ICAM-1—Role of E-Selectin Signaling Post-Activation , 2009, Annals of Biomedical Engineering.

[2]  Samir Mitragotri,et al.  Control of endothelial targeting and intracellular delivery of therapeutic enzymes by modulating the size and shape of ICAM-1-targeted carriers. , 2008, Molecular therapy : the journal of the American Society of Gene Therapy.

[3]  H. Goldsmith,et al.  Flow behavior of erythrocytes. II. Particle motions in concentrated suspensions of ghost cells , 1979 .

[4]  D. Hammer,et al.  Characterization of biodegradable drug delivery vehicles with the adhesive properties of leukocytes. , 2002, Biomaterials.

[5]  U. Rothe,et al.  Selectins as new targets for immunoliposome-mediated drug delivery. A potential way of anti-inflammatory therapy. , 1998, Pharmaceutica acta Helvetiae.

[6]  L. Liebovitch,et al.  Effects of human neutrophil chemotaxis across human endothelial cell monolayers on the permeability of these monolayers to ions and macromolecules , 1988, Journal of cellular physiology.

[7]  G. Nash,et al.  Rheological properties of the blood influencing selectin-mediated adhesion of flowing leukocytes. , 2003, American journal of physiology. Heart and circulatory physiology.

[8]  Daniel A Hammer,et al.  Adhesive dynamics simulations of the shear threshold effect for leukocytes. , 2007, Biophysical journal.

[9]  J. Hanes,et al.  Enhanced adhesion of ligand‐conjugated biodegradable particles to colitic venules , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[10]  V. Muzykantov.  Targeting of superoxide dismutase and catalase to vascular endothelium. , 2001, Journal of controlled release : official journal of the Controlled Release Society.

[11]  Mohammad F. Kiani,et al.  Targeting Microparticles to Select Tissue via Radiation-Induced Upregulation of Endothelial Cell Adhesion Molecules , 2002, Pharmaceutical Research.

[12]  Stasia A. Anderson,et al.  Magnetic resonance contrast enhancement of neovasculature with αvβ3‐targeted nanoparticles , 2000 .

[13]  C. Hunt,et al.  Liposome disposition in vivo. III. Dose and vesicle-size effects. , 1981, Biochimica et biophysica acta.

[14]  M P Bevilacqua,et al.  Endothelial-leukocyte adhesion molecules. , 1993, Annual review of immunology.

[15]  T. Springer,et al.  Rolling and transient tethering of leukocytes on antibodies reveal specializations of selectins. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[16]  S A Wickline,et al.  Magnetic resonance contrast enhancement of neovasculature with alpha(v)beta(3)-targeted nanoparticles. , 2000, Magnetic resonance in medicine.

[17]  R. Bicknell.  Vascular targeting and the inhibition of angiogenesis. , 1994, Annals of oncology : official journal of the European Society for Medical Oncology.

[18]  M J Pearson,et al.  Influence of erythrocyte aggregation on leukocyte margination in postcapillary venules of rat mesentery. , 2000, American journal of physiology. Heart and circulatory physiology.

[19]  P. Dellaripa,et al.  Nutritional Issues in Vasculitis , 2008 .

[20]  P. Bagchi,et al.  Hydrodynamic interaction between erythrocytes and leukocytes affects rheology of blood in microvessels. , 2007, Biorheology.

[21]  Steven M. Slack,et al.  Fluid Dynamic and Hemorheologic Considerations , 1993 .

[22]  S. Davis,et al.  Non-phagocytic uptake of intravenously injected microspheres in rat spleen: influence of particle size and hydrophilic coating. , 1991, Biochemical and biophysical research communications.

[23]  D. Ku,et al.  Pulsatile Flow and Atherosclerosis in the Human Carotid Bifurcation: Positive Correlation between Plaque Location and Low and Oscillating Shear Stress , 1985, Arteriosclerosis.

[24]  Mauro Ferrari,et al.  The margination propensity of spherical particles for vascular targeting in the microcirculation , 2008, Journal of nanobiotechnology.

[25]  Silvia Muro,et al.  Endothelial Targeting of High-Affinity Multivalent Polymer Nanocarriers Directed to Intercellular Adhesion Molecule 1 , 2006, Journal of Pharmacology and Experimental Therapeutics.

[26]  A. Koch,et al.  Increased Production of the Soluble Tumor‐Associated Antigens CA19‐9, CA125, and CA15‐3 in Rheumatoid Arthritis , 2007, Annals of the New York Academy of Sciences.

[27]  J. Lindner,et al.  Molecular Imaging of Inflammation in Atherosclerosis With Targeted Ultrasound Detection of Vascular Cell Adhesion Molecule-1 , 2007, Circulation.

[28]  Aliasger K Salem,et al.  Leukocyte-inspired biodegradable particles that selectively and avidly adhere to inflamed endothelium in vitro and in vivo , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[29]  M. Lawrence,et al.  Microparticle adhesive dynamics and rolling mediated by selectin‐specific antibodies under flow , 2007, Biotechnology and bioengineering.

[30]  D. Hammer,et al.  The forward rate of binding of surface-tethered reactants: effect of relative motion between two surfaces. , 1999, Biophysical journal.

[31]  N Tateishi,et al.  Erythrocyte flow and elasticity of microvessels evaluated by marginal cell-free layer and flow resistance. , 1996, The American journal of physiology.

[32]  S I Simon,et al.  Analysis of tight junctions during neutrophil transendothelial migration. , 2000, Journal of cell science.

[33]  S. Simon,et al.  Dynamic shifts in LFA-1 affinity regulate neutrophil rolling, arrest, and transmigration on inflamed endothelium. , 2006, Blood.

[34]  J. Schnitzer.  Vascular targeting as a strategy for cancer therapy. , 1998, The New England journal of medicine.

[35]  M Ferrari,et al.  The adhesive strength of non-spherical particles mediated by specific interactions. , 2006, Biomaterials.

[36]  D. A. Hammer,et al.  Quantifying rolling adhesion with a cell-free assay: E-selectin and its carbohydrate ligands. , 1997, Biophysical journal.

[37]  A. Koutsiaris,et al.  Volume flow and wall shear stress quantification in the human conjunctival capillaries and post-capillary venules in vivo. , 2007, Biorheology.

[38]  S. Slack,et al.  Particle diameter influences adhesion under flow. , 2001, Biophysical journal.

[39]  Eric J. Kunkel,et al.  Threshold Levels of Fluid Shear Promote Leukocyte Adhesion through Selectins (CD62L,P,E) , 1997, The Journal of cell biology.

[40]  M. Bevilacqua,et al.  Endothelial-leukocyte adhesion molecules in human disease. , 1994, Annual review of medicine.

[41]  D. Hammer,et al.  Cell-free rolling mediated by L-selectin and sialyl Lewis(x) reveals the shear threshold effect. , 2000, Biophysical journal.

[42]  J. Hanes,et al.  Polymeric particles conjugated with a ligand to VCAM‐1 exhibit selective, avid, and focal adhesion to sites of atherosclerosis , 2008, Biotechnology and bioengineering.

[43]  Mauro Ferrari,et al.  Design maps for nanoparticles targeting the diseased microvasculature. , 2008, Biomaterials.

[44]  C. Weyand,et al.  Medium- and large-vessel vasculitis. , 2003, The New England journal of medicine.

[45]  R K Jain,et al.  Role of erythrocytes in leukocyte-endothelial interactions: mathematical model and experimental validation. , 1996, Biophysical journal.

[46]  Akitoshi Yoshida,et al.  Noninvasive evaluation of wall shear stress on retinal microcirculation in humans. , 2006, Investigative ophthalmology & visual science.

[47]  Rakesh K Jain,et al.  Red blood cells augment leukocyte rolling in a virtual blood vessel. , 2002, Biophysical journal.

[48]  S. Slack,et al.  Chapter 2 Fluid dynamic and hemorheologic considerations , 1993 .

[49]  J. Kitchener,et al.  The surface chemistry and flotation of scheelite. I. Solubility and surface characteristics of precipitated calcium tungstate , 1979 .

[50]  A. Popel,et al.  A two-phase model for flow of blood in narrow tubes with increased effective viscosity near the wall. , 2001, Biorheology.

[51]  Paul C. Johnson,et al.  The cell-free layer in microvascular blood flow. , 2009, Biorheology.

[52]  Aleksander S Popel,et al.  Temporal and spatial variations of cell-free layer width in arterioles. , 2007, American journal of physiology. Heart and circulatory physiology.

[53]  Daniel A Hammer,et al.  Quantifying nanoparticle adhesion mediated by specific molecular interactions. , 2008, Langmuir : the ACS journal of surfaces and colloids.

[54]  S I Simon,et al.  Neutrophil transendothelial migration is independent of tight junctions and occurs preferentially at tricellular corners. , 1997, Journal of immunology.

[55]  R M Heethaar,et al.  Blood platelets are concentrated near the wall and red blood cells, in the center in flowing blood. , 1988, Arteriosclerosis.

[56]  M. Ferrari,et al.  A Theoretical Model for the Margination of Particles within Blood Vessels , 2005, Annals of Biomedical Engineering.

[57]  R K Jain,et al.  Selectin- and integrin-mediated T-lymphocyte rolling and arrest on TNF-alpha-activated endothelium: augmentation by erythrocytes. , 1995, Biophysical journal.

[58]  F. Millero,et al.  Conditions for the occurrence of large near-wall excesses of small particles during blood flow. , 1988, Microvascular research.

[59]  G. Nash,et al.  Characteristics of leucocyte adhesion directly observed in flowing whole blood in vitro , 2001, British journal of haematology.

[60]  Cheng Zhu,et al.  Mechanical switching and coupling between two dissociation pathways in a P-selectin adhesion bond. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[61]  D. Hammer,et al.  Characterization of biodegradable drug delivery vehicles with the adhesive properties of leukocytes II: effect of degradation on targeting activity. , 2005, Biomaterials.