Flow and adhesion of drug carriers in blood vessels depend on their shape: a study using model synthetic microvascular networks.

Development of novel carriers and optimization of their design parameters has led to significant advances in the field of targeted drug delivery. Since carrier shape has recently been recognized as an important design parameter for drug delivery, we sought to investigate how carrier shape influences their flow in the vasculature and their ability to target the diseased site. Idealized synthetic microvascular networks (SMNs) were used for this purpose since they closely mimic key physical aspects of real vasculature and at the same time offer practical advantages in terms of ease of use and direct observation of particle flow. The attachment propensities of surface functionalized spheres, elliptical/circular disks and rods with dimensions ranging from 1microm to 20microm were compared by flowing them through bifurcating SMNs. Particles of different geometries exhibited remarkably different adhesion propensities. Moreover, introduction of a bifurcation as opposed to the commonly used linear channel resulted in significantly different flow and adhesion behaviors, which may have important implications in correlating these results to in vivo behavior. This study provides valuable information for design of carriers for targeted drug delivery.

[1]  Mauro Ferrari,et al.  Intravascular Delivery of Particulate Systems: Does Geometry Really Matter? , 2008, Pharmaceutical Research.

[2]  Samir Mitragotri,et al.  Role of target geometry in phagocytosis. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[3]  S. Alper,et al.  Hemodynamic shear stress and its role in atherosclerosis. , 1999, JAMA.

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

[5]  S M Moghimi,et al.  Long-circulating and target-specific nanoparticles: theory to practice. , 2001, Pharmacological reviews.

[6]  J. Richie,et al.  Targeted nanoparticle-aptamer bioconjugates for cancer chemotherapy in vivo. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[7]  D. Discher,et al.  Shape effects of filaments versus spherical particles in flow and drug delivery. , 2007, Nature nanotechnology.

[8]  G S Kansas,et al.  Monocyte rolling, arrest and spreading on IL-4-activated vascular endothelium under flow is mediated via sequential action of L-selectin, beta 1-integrins, and beta 2-integrins , 1994, The Journal of cell biology.

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

[10]  Samir Mitragotri,et al.  Physical approaches to biomaterial design. , 2009, Nature materials.

[11]  R. Langer,et al.  Drug delivery and targeting. , 1998, Nature.

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

[13]  Samir Mitragotri,et al.  Designer Biomaterials for Nanomedicine , 2009 .

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

[15]  M Ferrari,et al.  The effect of shape on the margination dynamics of non-neutrally buoyant particles in two-dimensional shear flows. , 2008, Journal of biomechanics.

[16]  S. Mitragotri,et al.  Making polymeric micro- and nanoparticles of complex shapes , 2007, Proceedings of the National Academy of Sciences.

[17]  Eric Pridgen,et al.  Factors Affecting the Clearance and Biodistribution of Polymeric Nanoparticles , 2008, Molecular pharmaceutics.

[18]  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.

[19]  Daniel S Kohane,et al.  Microparticles and nanoparticles for drug delivery. , 2007, Biotechnology and bioengineering.

[20]  Kapil Pant,et al.  A physiologically realistic in vitro model of microvascular networks , 2009, Biomedical microdevices.

[21]  David Schrama,et al.  Antibody targeted drugs as cancer therapeutics , 2006, Nature Reviews Drug Discovery.

[22]  S. Bhatia,et al.  Magnetic Iron Oxide Nanoworms for Tumor Targeting and Imaging , 2008, Advanced materials.

[23]  M. U. Nollert,et al.  Design Considerations for a Microfluidic Device to Quantify the Platelet Adhesion to Collagen at Physiological Shear Rates , 2009, Annals of Biomedical Engineering.

[24]  E. Ruoslahti,et al.  Cancer treatment by targeted drug delivery to tumor vasculature in a mouse model. , 1998, Science.

[25]  R. J. Lee,et al.  Targeted drug delivery via the folate receptor. , 2000, Advanced drug delivery reviews.

[26]  Michael Doran,et al.  A novel multishear microdevice for studying cell mechanics. , 2009, Lab on a chip.

[27]  Stephanie E. A. Gratton,et al.  The effect of particle design on cellular internalization pathways , 2008, Proceedings of the National Academy of Sciences.

[28]  Daniel Irimia,et al.  Synthetic microvascular networks for quantitative analysis of particle adhesion , 2008, Biomedical microdevices.

[29]  M Ferrari,et al.  Flow chamber analysis of size effects in the adhesion of spherical particles , 2007, International journal of nanomedicine.