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WIREs Nanomed Nanobiotechnol
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Role of particle size, shape, and stiffness in design of intravascular drug delivery systems: insights from computations, experiments, and nature

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Packaging of drug molecules within microparticles and nanoparticles has become an important strategy in intravascular drug delivery, where the particles are designed to protect the drugs from plasma effects, increase drug residence time in circulation, and often facilitate drug delivery specifically at disease sites. To this end, over the past few decades, interdisciplinary research has focused on developing biocompatible materials for particle fabrication, technologies for particle manufacture, drug formulation within the particles for efficient loading, and controlled release and refinement of particle surface chemistries to render selectivity toward disease site for site‐selective action. Majority of the particle systems developed for such purposes are spherical nano and microparticles and they have had low‐to‐moderate success in clinical translation. To refine the design of delivery systems for enhanced performance, in recent years, researchers have started focusing on the physicomechanical aspects of carrier particles, especially their shape, size, and stiffness, as new design parameters. Recent computational modeling studies, as well as, experimental studies using microfluidic devices are indicating that these design parameters greatly influence the particles’ behavior in hemodynamic circulation, as well as cell‐particle interactions for targeted payload delivery. Certain cellular components of circulation are also providing interesting natural cues for refining the design of drug carrier systems. Based on such findings, new benefits and challenges are being realized for the next generation of drug carriers. The current article will provide a comprehensive review of these findings and discuss the emerging design paradigm of incorporating physicomechanical components in fabrication of particulate drug delivery systems. WIREs Nanomed Nanobiotechnol 2016, 8:255–270. doi: 10.1002/wnan.1362 This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Therapeutic Approaches and Drug Discovery > Nanomedicine for Cardiovascular Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology
Representative results from studies on the effect of particle size on their margination and targeted binding. (a) Representative data of microspheres of 5, 10, 15, and 20 µm coated with recombinant P‐selectin glycoprotein ligand‐1 and allowed to adhere under shear flow (400 second−1 shear rate) over P‐selectin‐coated surfaces; in this diameter range the rate of adhesion was found to decrease with increase in diameter. (b) Representative data from the same studies where the shear required to dislodge firmly preadhered particles of the various diameters was studied and it was found that the larger particles required less shear stress to be dislodged. (a and b: Reprinted with permission from Ref . Copyright 2001 Elsevier). (c) Representative data where particles of 0.5–10 µm in diameter at equal volume was allowed to flow in a perfusion chamber over a monolayer of endothelial cells and nonspecific attachment of the particles to the cells versus the chamber borosilicate surface was analyzed; the graphs show variation of the surface density of the total number of particles (ntot, white pentagons), the number of particles adherent to the cells (nc, black boxes), and the number of particles adherent to the borosilicate surface (nd, white triangles) suggesting that particles of 1–2 µm diameter have much enhanced binding compared with particles close to 10 µm diameter. (Reprinted with permission from Ref . Copyright 2007 Dove Press) (d) The adhesion of sialyl Lewis acid (sLeA) decorated particles of various diameters binding to inflamed endothelium monolayer in a parallel plate flow chamber at various shear rates in presence of hematocrit, demonstrating that at high shear rate particles in the 2–5 µm diameter range undergo maximum adhesion to the target cell surface. (Reprinted with permission from Ref . Copyright 2010 Elsevier)
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Representative results of bioinspired designs and applications of particulate drug delivery systems (DDS). (a‐i) RBC‐shaped polymeric templates formed by hydrodynamic jetting and heat stretching methods and (a‐ii) synthetic RBCs (sRBCs) developed by layer‐by‐layer (LBL) assembly of proteins (e.g., albumin) on such templates; the sRBCs developed in this way could be applied for (a‐iii) Hemoglobin (Hb) encapsulation for oxygen delivery and (a‐iv) Heparin encapsulation for anticoagulant delivery. (Reprinted with permission from Ref . Copyright 2010 Taylor and Francis) (b‐i) The margination and adhesion of natural platelets that were mimicked on synthetic particle platforms made by LBL assembly of proteins on polymeric templates; these platelet‐mimetic particles shown in (b‐ii) were able to (b‐iii) adhere more to a target surface in vitro under flow and also (b‐iv) render high hemostatic efficacy in a tail bleeding model in vivo in mice. (Reprinted with permission from Ref . Copyright 2010 Elsevier) (c‐i) RBC‐mimetic hydrogel particles developed by the PRINT technology that were allowed to flow through (c‐ii) dextran‐labeled blood vessels in vivo; (c‐iii) Dyight 680‐labeled RBC‐mimetic particles were found to flow through the dextran‐labeled vessels similar to natural RBCs and resulted in overlay intravital microscopy images as shown in (c‐iv). (Reprinted with permission from Ref . Copyright 2008 Elsevier) (d‐i) Design of a thrombolytic DDS by conjugating the drug tissue plasminogen activator (tPA) on the surface of RBCs with the vision that these systems (RBC‐tPA) will stay in circulation to lyse embolic nascent clots from inside out while leaving mural and hemostatic clots unaffected; these RBC‐tPA systems were found to render high clot‐busting efficacy both (d‐iii) in vitro and (d‐iv) in vivo, when compared with action of free tPA. (Reprinted with permission from Ref . Copyright 2008 Springer)
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A schematic representation of the path of intravascularly administered particulate drug delivery systems (DDS), involving collision with blood components, margination across the RBC volume, nonspecific and specific attachment to target sites at the vessel wall and controlled release of payload at or past the wall; please note that the payload can itself be smaller nanoparticles that can traverse across the wall and accumulate within diseased tissue as further controlled release drug depots.
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Representative results from studies on the effect of particle shape on margination and targeted binding. (a) A schematic of an oblate spheroidal particle binding to the surface receptors of a target cell via ligands decorated on the particle surface, demonstrating that such adherent particles will undergo dislodging effects as a combination of torque and drag forces which are resisted by the extent and strength of ligand‐receptor interactions; this extent and area of interaction can be greater for nonspherical (e.g., spheroidal or discoidal) particles compared with the traditional spherical particles.(Reprinted with permission from Ref . Copyright 1995 Elsevier) (b) shows representative data of margination behavior of three different particle shapes (disc, quasi‐hemisphere, and sphere) of equivalent size, where the absolute number ‘n’ of sedimenting particles is correlated to the shear rate ‘S’, demonstrating that with increasing shear rate discoidal particles have a higher extent of margination and sedimentation, compared with spherical or quasi‐hemispherical particles. (Reprinted with permission from Ref . Copyright 2006 Dove Press) (C) Estimated adhesion probability of particles of various shapes versus their volume parameters (i.e., size), demonstrating that nonspherical particles have a higher adhesion probability than spherical particles at various size ranges. (Reprinted with permission from Ref . Copyright 2006 Elsevier)
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Therapeutic Approaches and Drug Discovery > Emerging Technologies
Therapeutic Approaches and Drug Discovery > Nanomedicine for Cardiovascular Disease
Nanotechnology Approaches to Biology > Nanoscale Systems in Biology

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