Computed tomography enables 3D anatomic imaging at a high spatial resolution, but requires delivery of an x-ray contrast agent to distinguish tissues with similar or low x-ray attenuation. Gold nanoparticles (AuNPs) have gained recent attention as an x-ray contrast agent due to exhibiting a high x-ray attenuation, nontoxicity and facile synthesis and surface functionalization for colloidal stability and targeted delivery. Potential diagnostic applications include blood pool imaging, passive targeting and active targeting, where actively targeted AuNPs could enable molecular imaging by computed tomography. This article summarizes the current state of knowledge for AuNP x-ray contrast agents within a paradigm of key structure-property-function relationships in order to provide guidance for the design of AuNP contrast agents to meet the necessary functional requirements in a particular application. Functional requirements include delivery to the site of interest (e.g., blood, tumors or microcalcifications), nontoxicity during delivery and clearance, targeting or localization at the site of interest and contrast enhancement for the site of interest compared with surrounding tissues. Design is achieved by strategically controlling structural characteristics (composition, mass concentration, size, shape and surface functionalization) for optimized properties and functional performance. Examples from the literature are used to highlight current design trade-offs that exist between the different functional requirements.
The high concentration of mineral present in bone and pathological calcifications is unique compared with all other tissues and thus provides opportunity for targeted delivery of pharmaceutical drugs, including radiosensitizers and imaging probes. Targeted delivery enables accumulation of a high local dose of a therapeutic or imaging contrast agent to diseased bone or pathological calcifications. Bisphosphonates (BPs) are the most widely utilized bone-targeting ligand due to exhibiting high binding affinity to hydroxyapatite mineral. BPs can be conjugated to an agent that would otherwise have little or no affinity for the sites of interest. This article summarizes the current state of knowledge and practice for the use of BPs as ligands for targeted delivery to bone and mineral deposits. The clinical history of BPs is briefly summarized to emphasize the success of these molecules as therapeutics for metabolic bone diseases. Mechanisms of binding and the relative binding affinity of various BPs to bone mineral are introduced, including common methods for measuring binding affinity in vitro and in vivo. Current research is highlighted for the use of BP ligands for targeted delivery of BP conjugates in various applications, including (1) therapeutic drug delivery for metabolic bone diseases, bone cancer, other bone diseases, and engineered drug delivery platforms; (2) imaging probes for scintigraphy, fluorescence, positron emission tomography, magnetic resonance imaging, and computed tomography; and (3) radiotherapy. Last, and perhaps most importantly, key structure-function relationships are considered for the design of drugs with BP ligands, including the tether length between the BP and drug, the size of the drug, the number of BP ligands per drug, cleavable tethers between the BP and drug, and conjugation schemes.
Synthetic hydroxyapatite (HA) whiskers have been utilized as a new, biocompatible reinforcement for orthopedic biomaterials. High-density polyethylene (HDPE) was reinforced with either the synthesized HA whiskers or a commercially available spherical HA powder using a novel powder processing technique that facilitated uniform dispersion of the reinforcements in the matrix prior to compression molding. Composites were processed for up to 60 vol % HA whiskers and up to 50 vol % spherical HA. The mechanical properties of the new composite biomaterials were examined by uniaxial tensile tests. As expected, increased volume fraction of either reinforcement type over 0-50 vol % resulted in increased elastic modulus, a maximum in ultimate tensile stress, and decreased work to failure. Composites reinforced with HA whiskers had higher elastic modulus, ultimate tensile strength, and work to failure relative to composites reinforced with spherical HA. Thus, HA whisker-reinforced HDPE composites possessed improved mechanical properties over those reinforced with spherical HA. HA whisker-reinforced composites were anisotropic due to alignment of the whiskers in the matrix during processing.
Overview Biological Materials ScienceHydroxyapatite (HA)-reinforced polymer biocomposites offer a robust system to engineer synthetic bone substitutes with tailored mechanical, biological, and surgical functions. The basic design rationale has been to reinforce a tough, biocompatible polymer matrix with a bioactive HA filler. A large number of studies have investigated modifications to the biocomposite structure and composition, aimed at improving the mechanical properties, often through modified or novel processing methods. In this article, the effects of the polymer composition and molecular orientation; the HA/polymer interface; and the HA-reinforcement content, morphology, preferred orientation, and size are reviewed with respect to mechanical properties, drawing frequent comparisons between various HA-reinforced polymer composites and bone tissue.
Gold nanoparticles (Au NPs) have been investigated for a number of biomedical applications, including drug and gene delivery vehicles, thermal ablation therapy, diagnostic sensors, and imaging contrast agents. Surface functionalization with molecular groups exhibiting calcium affinity can enable targeted delivery of Au NPs to calcified tissue, including damaged bone tissue. Therefore, the objective of this study was to investigate the binding affinity of functionalized Au NPs for targeted delivery to bone mineral, using hydroxyapatite (HA) crystals as a synthetic analog in vitro. Au NPs were synthesized to a mean particle size of 10-15 nm and surface functionalized with either L-glutamic acid, 2-aminoethylphosphonic acid, or alendronate, which exhibit a primary amine for binding gold opposite carboxylate, phosphonate, or bisphosphonate groups, respectively, for targeting calcium. Bisphosphonate functionalized Au NPs exhibited the most rapid binding kinetics and greatest binding affinity to HA, followed by glutamic acid and phosphonic acid. All functional groups reached complete binding after 24 h. Equilibrium binding constants in de-ionized water, determined by nonlinear regression of Langmuir isotherms, were 3.40, 0.69, and 0.25 mg/L for bisphosphonate, carboxylate, and phosphonate functionalized Au NPs, respectively. Functionalized Au NPs exhibited lower overall binding in fetal bovine serum compared to de-ionized water, but relative differences between functional groups were similar.
Gold nanoparticles (Au NPs) have attracted interest as an X-ray contrast agent due to exhibiting high X-ray attenuation, colloidal stability, vascular retention, and facile surface functionalization for targeted delivery to cells and tissues. However, the effects of Au NP size on X-ray attenuation and binding affinity to a targeted surface are not well-understood. Therefore, the effect of Au NP size on X-ray attenuation was investigated by preparing mercaptosuccinic acid functionalized Au NPs exhibiting a mean particle diameter of 5, 13, 35, or 76 nm, as well as chloroauric acid control, at gold concentrations up to ∼50 mM (∼10 g/L). The X-ray attenuation of Au NP and chloroauric acid solutions increased with decreased photon energy and increased linearly with increased gold concentration, but was independent of the particle diameter. The effects of Au NP size on substrate binding affinity were investigated by preparing bisphosphonate functionalized Au NPs exhibiting a mean particle diameter of 5, 13, 35, or 76 nm and measuring binding isotherms using hydroxyapatite (HA) crystals as a model for bone mineral or microcalcifications. Decreased Au NP diameter resulted in an increased number of Au NPs but decreased mass of gold adsorbed onto HA crystal surfaces, and thus a lower binding affinity to HA. Therefore, the results of this study suggest that for targeted labeling of HA, or calcified tissue, an increased Au NP diameter will improve detection due to a greater of mass of gold labeling surfaces and thus greater X-ray attenuation.
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