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WIREs Nanomed Nanobiotechnol
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Probing the biological obstacles of nanomedicine with gold nanoparticles

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Despite massive growth in nanomedicine research to date, the field still lacks fundamental understanding of how certain physical and chemical features of a nanoparticle affect its ability to overcome biological obstacles in vivo and reach its intended target. To gain fundamental understanding of how physical and chemical parameters affect the biological outcomes of administered nanoparticles, model systems that can systematically manipulate a single parameter with minimal influence on others are needed. Gold nanoparticles are particularly good model systems in this case as one can synthetically control the physical dimensions and surface chemistry of the particles independently and with great precision. Additionally, the chemical and physical properties of gold allow particles to be detected and quantified in tissues and cells with high sensitivity. Through systematic biological studies using gold nanoparticles, insights toward rationally designed nanomedicine for in vivo imaging and therapy can be obtained. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology
Gold nanoparticles can be tailored to a wide variety of sizes, shapes, and surface chemistries
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Next generation designs in nanomedicine involve particles that respond to physiological cues from the tumor microenvironment. Two such designs are small particles that assemble into larger structures at tumors (small‐to‐large assembly), the other is larger particles that disassemble in to smaller particles at tumors (large‐to‐small disassembly). The small‐to‐large disassembly process forms large particles at the tumor that are too large to diffuse out and therefore are retained, whereas the particles not localized to the tumor are quickly cleared from the body. The large‐to‐small disassembly process has large structures that have long circulation times that once at the tumor site, disassembles into small particles that have greater perfusion throughout the tumor tissue
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Particles having coatings that resist nonspecific binding like PEG not only have less accumulation within the liver, but the particles that do accumulate have quicker clearance from the organ when compared to opsonized particles. Particles that are less than 10 nm in size tend to have greater amounts of the injected dose go through efficient renal clearance and less accumulate within the liver. Moreover, the particles that do accumulate in the liver have quicker clearance rates than larger‐sized particles. Therefore, smaller particles tend to have a greater clearance rate overall from the body than larger‐sized counterparts. Particles that are greater than 10 nm in size have little to no renal clearance and rely heavily on hepatobiliary clearance, which is a significantly slower process. Rod‐shaped particles offer the ability to clear the renal system despite having a length greater than the glomerular pore size. Even with lengths significantly larger than the pore size, as long as the diameter of the rod is smaller than the pore there is a possibility for clearance. Spherical‐shaped particles having diameters larger than the pore size are excluded from passing. Rod‐shaped particles that are able to clear the renal system offer an opportunity to load more imaging or therapeutic agents as they have greater volumes and surface areas than would spheres that can pass through similar pore sizes
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Particles with coatings that prevent nonspecific binding like PEG have greater tumor accumulation and less RES organ accumulation than particles that have been opsonized. Smaller‐sized nanoparticles tend to have greater tumor perfusion whereas larger particles tend to remain at the periphery near the vessel. This is due to the greater diffusivity of smaller particles through tissues. Particles with greater aspect ratios are seen to have higher tumor accumulation than more spherical‐shaped counterparts. The enhancement is believed to be a result of having greater diffusivity within tissues and having greater margination toward the vessel walls when in circulation
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Particle coatings that prevent nonspecific binding of proteins such as PEG, also provide particles with protection against nonspecific cellular internalization. Opsonized particles on the other hand are highly likely to be nonspecifically internalized by cells. Affinity ligands on the surface of particles aid in the internalization of particles within specific cells having surface receptors complimentary to the ligand. Particles that are smaller than 10 nm do not have efficient cellular internalization due to the membrane having to adopt a shape with high curvature which is not energetically favored. Particles within the 10–100 nm size range are at sizes that the cellular membrane can accommodate and wrap around in a short period. Internalization is not kinetically favored for particles that are larger than 100 nm due to the long wrapping times required to cover the significantly larger surface areas. When increasing the aspect ratio of a particle, internalization becomes less efficient as the membrane must adopt configurations with greater surface area to volume ratios which are not energetically favored
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Nanoparticles with neutral coatings (zeta potential near zero) tend to have less protein adsorption and fewer adsorbed species compared to counterparts having charged (anionic or cationic) surfaces. Proteins adsorb with less affinity and less surface density to smaller particles than larger particles. Proteins have less affinity and are less prone to denature on particle morphologies having higher curvatures
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