Shape effects of filaments versus spherical particles in flow and drug delivery.
TL;DR: Highly stable, polymer micelle assemblies known as filomicelles are used to compare the transport and trafficking of flexible filaments with spheres of similar chemistry and show that long-circulating vehicles need not be nanospheres.
Abstract: Interaction of spherical particles with cells and within animals has been studied extensively, but the effects of shape have received little attention. Here we use highly stable, polymer micelle assemblies known as filomicelles to compare the transport and trafficking of flexible filaments with spheres of similar chemistry. In rodents, filomicelles persisted in the circulation up to one week after intravenous injection. This is about ten times longer than their spherical counterparts and is more persistent than any known synthetic nanoparticle. Under fluid flow conditions, spheres and short filomicelles are taken up by cells more readily than longer filaments because the latter are extended by the flow. Preliminary results further demonstrate that filomicelles can effectively deliver the anticancer drug paclitaxel and shrink human-derived tumours in mice. Although these findings show that long-circulating vehicles need not be nanospheres, they also lend insight into possible shape effects of natural filamentous viruses.
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TL;DR: By successively addressing each of the biological barriers that a particle encounters upon intravenous administration, innovative design features can be rationally incorporated that will create a new generation of nanotherapeutics, realizing a paradigmatic shift in nanoparticle-based drug delivery.
Abstract: Biological barriers to drug transport prevent successful accumulation of nanotherapeutics specifically at diseased sites, limiting efficacious responses in disease processes ranging from cancer to inflammation. Although substantial research efforts have aimed to incorporate multiple functionalities and moieties within the overall nanoparticle design, many of these strategies fail to adequately address these barriers. Obstacles, such as nonspecific distribution and inadequate accumulation of therapeutics, remain formidable challenges to drug developers. A reimagining of conventional nanoparticles is needed to successfully negotiate these impediments to drug delivery. Site-specific delivery of therapeutics will remain a distant reality unless nanocarrier design takes into account the majority, if not all, of the biological barriers that a particle encounters upon intravenous administration. By successively addressing each of these barriers, innovative design features can be rationally incorporated that will create a new generation of nanotherapeutics, realizing a paradigmatic shift in nanoparticle-based drug delivery.
4,457 citations
TL;DR: This Review focuses on recent progress important for the rational design of such nanoparticles and discusses the challenges to realizing the potential of nanoparticles.
Abstract: Engineered nanoparticles have the potential to revolutionize the diagnosis and treatment of many diseases; for example, by allowing the targeted delivery of a drug to particular subsets of cells. However, so far, such nanoparticles have not proved capable of surmounting all of the biological barriers required to achieve this goal. Nevertheless, advances in nanoparticle engineering, as well as advances in understanding the importance of nanoparticle characteristics such as size, shape and surface properties for biological interactions, are creating new opportunities for the development of nanoparticles for therapeutic applications. This Review focuses on recent progress important for the rational design of such nanoparticles and discusses the challenges to realizing the potential of nanoparticles.
3,239 citations
TL;DR: The rationales for these studies, the current progress in studies of the interactions of nanomaterials with biological systems, and a perspective on the long-term implications of these findings are provided.
Abstract: An understanding of the interactions between nanoparticles and biological systems is of significant interest. Studies aimed at correlating the properties of nanomaterials such as size, shape, chemical functionality, surface charge, and composition with biomolecular signaling, biological kinetics, transportation, and toxicity in both cell culture and animal experiments are under way. These fundamental studies will provide a foundation for engineering the next generation of nanoscale devices. Here, we provide rationales for these studies, review the current progress in studies of the interactions of nanomaterials with biological systems, and provide a perspective on the long-term implications of these findings.
2,969 citations
TL;DR: In this paper, the authors review the barriers to the delivery of cancer therapeutics and summarize strategies that have been developed to overcome these barriers and discuss design considerations for optimizing the nanoparticles to tumors.
Abstract: Recent advances in nanotechnology have offered new hope for cancer detection, prevention, and treatment. While the enhanced permeability and retention effect has served as a key rationale for using nanoparticles to treat solid tumors, it does not enable uniform delivery of these particles to all regions of tumors in sufficient quantities. This heterogeneous distribution of therapeutics is a result of physiological barriers presented by the abnormal tumor vasculature and interstitial matrix. These barriers are likely to be responsible for the modest survival benefit offered by many FDA-approved nanotherapeutics and must be overcome for the promise of nanomedicine in patients to be realized. Here, we review these barriers to the delivery of cancer therapeutics and summarize strategies that have been developed to overcome these barriers. Finally, we discuss design considerations for optimizing the delivery of nanoparticles to tumors.
2,688 citations
TL;DR: These findings suggest that HeLa cells readily internalize nonspherical particles with dimensions as large as 3 μm by using several different mechanisms of endocytosis, and it was found that rod-like particles enjoy an appreciable advantage when it comes to internalization rates.
Abstract: The interaction of particles with cells is known to be strongly influenced by particle size, but little is known about the interdependent role that size, shape, and surface chemistry have on cellular internalization and intracellular trafficking. We report on the internalization of specially designed, monodisperse hydrogel particles into HeLa cells as a function of size, shape, and surface charge. We employ a top-down particle fabrication technique called PRINT that is able to generate uniform populations of organic micro- and nanoparticles with complete control of size, shape, and surface chemistry. Evidence of particle internalization was obtained by using conventional biological techniques and transmission electron microscopy. These findings suggest that HeLa cells readily internalize nonspherical particles with dimensions as large as 3 μm by using several different mechanisms of endocytosis. Moreover, it was found that rod-like particles enjoy an appreciable advantage when it comes to internalization rates, reminiscent of the advantage that many rod-like bacteria have for internalization in nonphagocytic cells.
2,617 citations
Cites background from "Shape effects of filaments versus s..."
...Several reports have addressed the role of shape and size on cellular internalization (12, 15); however, no particle fabrication techniques currently available have the ability to independently alter one variable at a time, and monitor the effect of each variable....
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References
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Book•
01 Jan 1986
TL;DR: In this article, the viscoelasticity of polymeric liquids was studied in the context of rigid rod-like polymers and concentrated solutions of rigid rods like polymers.
Abstract: Introduction Static properties of polymers Brownian motion Dynamics of flexible polymers in dilute solution Many chain systems Dynamics of a polymer in a fixed network Molecular theory for the viscoelasticity of polymeric liquids Dilute solutions of rigid rodlike polymers Semidilute solutions of rigid rodlike polymers Concentrated solutions of rigid rodlike polymers Index.
10,225 citations
Book•
26 Nov 1998
TL;DR: In this article, the authors present a comprehensive overview of the properties and properties of complex fluids and their properties in terms of physics, chemistry, physics theory, and physics of complex fluid properties.
Abstract: Part I: Fundamentals 1. Introduction to Complex Fluids 1.3 Rheological Measurements and Properties 1.4 Kinematics and Stress 1.5 Flow, Slip, and Yield 1.6 Structural Probes of Complex Fluids 1.7 Computational Methods 1.8 The Stress Tensor 1.9 Summary 2. Basic Forces 2.1 Intoduction 2.3 Van der Waals Interactions 2.4 Electrostatic Interactions 2.5 Hydrogen-Bonding, Hydrophobic, and Other Interactions 2.6 Summary Part II: Polymers, Glassy Liquids, and Polymer Gels 3. Polymers 3.1 Introduction 3.2 Equilibrium Properties 3.3 Intrinsic Viscosity and Overlap Concentration 3.4 Elementary Molecular Theories 3.5 Linear Viscoelasticity and Time-Temperature Superposition 3.6 The Rheology of Dilute Polymer Solutions 3.7 The Rheology of Entangled Polymers 3.8 Summary 4. Glassy Liquids 4.1 Introduction 4.2 Phenomenology of the Glass Transition 4.3 Free-Volume Theories 4.4 Entropy Theories 4.5 Nonlinear Relaxation and Aging 4.6 Mode-Coupling Theory and Colloidal Hard-Sphere Glasses 4.7 Analog Models 4.8 Rheology of Glassy Liquids 4.9 Summary 5. Polymer Gels 5.1 Introduction 5.2 Gelation Theoies 5.3 Rheology of Chemical Gels and Near-Gels 5.4 Rheology of Physical Gels 5.5 Summary Part III: Suspensions 6. Particulate Suspensions 6.1 Introduction 6.2 Hard, and Slightly Deformable Spheres 6.3 Nonspherical Particles 6.4 Electrically Charged Particles 6.5 Particles in Viscoelastic Liquids: "Filled Melts" 6.6 Summary 7. Particulate Gels 7.1 Introduction 7.2 Particle Interactions in Suspensions 7.3 Rheology of Particulate Gels 7.4 Summary 8. Electro- and Magneto-Responsive Suspensions 8.1 Introduction 8.2 Electrorheological Fluids 8.3 Magnetorheological Fluids 8.4 Ferrofluids 8.5 Summary 9. Foams, Emulsions, and Blends 9.1 Introduction 9.2 Emulsion Preparation 9.3 Rheology of Emulsions and Immiscible Blends 9.4 Structure and Coarsening of Foams 9.5 Rheology of Foams 9.6 Summary Part IV: Liquid Crystals and Self-Assembling Fluids 10. Liquid Crystals 10.1 Introduction 10.2 Nematics 10.3 Cholesterics: Chiral Nemantics 10.4 Smectics 10.5 Summary 11. Liquid Crystalline Polymers 11.1 Introduction 11.2 Molecular Characteristics of Liquid Crystalline Polymers 11.3 Flow Properties of Nematic LCP's 11.4 Molecular Dynamics of Polymeric Nematics 11.5 Molecular Theory for the Rheology of Polymeric Nematics 11.6 Summary 12. Surfactant Solutions 12.1 Introduction 12.2 Methods of Predicting Microstructures 12.3 Disordered Micellar Solutions 12.4 Surfactant Liquid Crystals 12.5 Summary 13. Block Copolymers 13.1 Introduction 13.2 Thermodynamics of Block Copolymers 13.3 Rheology and Shear-Aligning of Block Copolymers 13.4 Summary Appendix: Momentum-Balance Equations in the Absence of Inertia
3,840 citations
TL;DR: Monodisperse biodegradable nanospheres were developed from amphiphilic copolymers composed of two biocompatible blocks and exhibited dramatically increased blood circulation times and reduced liver accumulation in mice.
Abstract: Injectable nanoparticulate carriers have important potential applications such as site-specific drug delivery or medical imaging. Conventional carriers, however, cannot generally be used because they are eliminated by the reticulo-endothelial system within seconds or minutes after intravenous injection. To address these limitations, monodisperse biodegradable nanospheres were developed from amphiphilic copolymers composed of two biocompatible blocks. The nanospheres exhibited dramatically increased blood circulation times and reduced liver accumulation in mice. Furthermore, they entrapped up to 45 percent by weight of the drug in the dense core in a one-step procedure and could be freeze-dried and easily redispersed without additives in aqueous solutions.
2,827 citations
"Shape effects of filaments versus s..." refers background in this paper
...The mononuclear phagocytic system (MPS) of the liver and the spleen constitutes the usual filtration and clearance pathway for circulating particulate...
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Journal Article•
TL;DR: Future applications of polymer vesicles will rely on exploiting unique property-performance relations, but results to date underscore the fact that biologically derived vesicle are but a small subset of what is physically and chemically possible.
Abstract: Vesicles are microscopic sacs that enclose a volume with a molecularly thin membrane. The membranes are generally self-directed assemblies of amphiphilic molecules with a dual hydrophilic-hydrophobic character. Biological amphiphiles form vesicles central to cell function and are principally lipids of molecular weight less than 1 kilodalton. Block copolymers that mimic lipid amphiphilicity can also self-assemble into vesicles in dilute solution, but polymer molecular weights can be orders of magnitude greater than those of lipids. Structural features of vesicles, as well as properties including stability, fluidity, and intermembrane dynamics, are greatly influenced by characteristics of the polymers. Future applications of polymer vesicles will rely on exploiting unique property-performance relations, but results to date already underscore the fact that biologically derived vesicles are but a small subset of what is physically and chemically possible.
2,423 citations
TL;DR: In vivo selection of phage display libraries was used to isolate peptides that home specifically to tumor blood vessels that enhanced the efficacy of the anticancer drug doxorubicin and reduced its toxicity.
Abstract: In vivo selection of phage display libraries was used to isolate peptides that home specifically to tumor blood vessels. When coupled to the anticancer drug doxorubicin, two of these peptides-one containing an alphav integrin-binding Arg-Gly-Asp motif and the other an Asn-Gly-Arg motif-enhanced the efficacy of the drug against human breast cancer xenografts in nude mice and also reduced its toxicity. These results indicate that it may be possible to develop targeted chemotherapy strategies that are based on selective expression of receptors in tumor vasculature.
2,176 citations