Abstract It is generally accepted that the presentation of multiple ligands on a nanoparticle (NP) surface can improve cell targeting; however, little work has been done to determine whether an ...optimal ligand density exists. We have recently developed a site-specific bioconjugation strategy that allows for distinct control of ligand density on a NP through the combined utilization of expressed protein ligation (EPL) and copper-free click chemistry. This EPL-Click conjugation strategy was applied to create superparamagnetic iron oxide (SPIO) NPs labeled with HER2/neu targeting affibodies at differing ligand densities. It was discovered that an intermediate ligand density provided statistically significant improvements in cell binding in comparison with higher and lower ligand densities. This intermediate optimal ligand density was conserved across NPs with differing hydrodynamic diameters, different HER2/neu targeting ligands and also to cells with lower receptor densities. Additionally, an intermediate optimal ligand density was also evident when NPs were labeled with folic acid. From the Clinical Editor The authors of this study investigated optimal ligand density with SPIO-based labeling and concluded that intermediate density appears to have the most optimal labeling properties from the standpoint of its T2* shortening effect.
The ability to modify and directly target nanoparticulate carriers has greatly increased their applicability in diagnostic and therapeutic studies. Generally essential to the targeting of ...nanoparticles is the bioconjugation of targeting ligands to the agent's surface. While bioconjugation techniques have steadily improved in recent years, the field is still plagued with inefficient conjugations reactions and/or the lack of site‐specific coupling. To overcome these limitations, click chemistry and expressed protein ligation (EPL) are combined to produce a highly efficient, site‐specific reaction. This new EPL–click conjugation strategy is applied to create superparamagnetic iron oxide nanoparticles (SPIO) labeled with HER2/neu affibodies. These HER2‐SPIO nanoparticles prove to be highly potent and receptor‐specific in both in vitro cell studies and murine tumor models. Moreover, when EPL–click‐derived HER2‐SPIO are compared with SPIO that had been labeled with HER2 affibodies using other popular bioconjugation methods, they produce a statistically significant improvement in contrast enhancement upon cell binding. The EPL–click system is also successfully extended to other nanoparticle platforms (i.e., liposomes and dendrimers) highlighting the versatility of the approach.
Click chemistry and expressed protein ligation (EPL) are combined to produce a highly efficient, site‐specific bioconjugation scheme. This new EPL–click conjugation strategy is applied to create superparamagnetic iron oxide nanoparticles (SPIO) labeled with HER2/neu affibodies. These HER2‐SPIO nanoparticles prove to be highly potent and receptor‐specific in both in vitro cell studies and murine tumor models.
Block copolymer-based vesicles have recently garnered a great deal of interest as nanoplatforms for drug delivery and molecular imaging applications due to their unique structural properties. These ...nanovesicles have been shown to direct their cargo to disease sites either through enhanced permeability and retention or even more efficiently via active targeting. Here, we show that the efficacy of nanovesicle targeting can be significantly improved when prepared from polymer–lipid blends compared with block copolymer alone. Polymer–lipid hybrid nanovesicles were produced from the aqueous coassembly of the diblock copolymer, poly(ethylene oxide)-block-polybutadiene (PEO-PBD), and the phospholipid, hydrogenated soy phosphatidylcholine (HSPC). The PEG-based vesicles, 117 nm in diameter, were functionalized with either folic acid or anti-HER2/neu affibodies as targeting ligands to confer specificity for cancer cells. Our results revealed that nanovesicles prepared from polymer–lipid blends led to significant improvement in cell binding compared to nanovesicles prepared from block copolymer alone in both in vitro cell studies and murine tumor models. Therefore, it is envisioned that nanovesicles composed of polymer–lipid blends may constitute a preferred embodiment for targeted drug delivery and molecular imaging applications.
Abstract Recent advances in material science and chemistry have led to the development of nanoparticles with diverse physicochemical properties, e.g. size, charge, shape, and surface chemistry. ...Evaluating which physicochemical properties are best for imaging and therapeutic studies is challenging not only because of the multitude of samples to evaluate, but also because of the large experimental variability associated with in vivo studies (e.g. differences in tumor size, injected dose, subject weight, etc.). To address this issue, we have developed a lanthanide-doped nanoparticle system and analytical method that allows for the quantitative comparison of multiple nanoparticle compositions simultaneously. Specifically, superparamagnetic iron oxide (SPIO) with a range of different sizes and charges were synthesized, each with a unique lanthanide dopant. Following the simultaneous injection of the various SPIO compositions into tumor-bearing mice, inductively coupled plasma mass spectroscopy (ICP-MS) was used to quantitatively and orthogonally assess the concentration of each SPIO composition in serial blood samples and the resected tumor and organs. The method proved generalizable to other nanoparticle platforms, including dendrimers, liposomes, and polymersomes. This approach provides a simple, cost-effective, and non-radiative method to quantitatively compare tumor localization, biodistribution, and blood clearance of more than 10 nanoparticle compositions simultaneously, removing subject-to-subject variability.
The ability to modify the physical, chemical, and biologic properties of nanoparticles has led to their use as multifunctional platforms for drug delivery and diagnostic imaging applications. ...Typically, these applications involve functionalizing the nanoparticles with targeting agents. Antibodies remain an attractive choice as targeting agents because of their large epitope space and high affinity; however, implementation of antibody-nanoparticle conjugates is plagued by low coupling efficiencies and the high cost of reagents. Click chemistry may provide a solution to this problem, with reported coupling efficiencies nearing 100%. Although click chemistries have been used to functionalize nanoparticles with small molecules, they have not previously been used to functionalize nanoparticles with antibodies. Concerns associated with extending this procedure to antibodies are that reaction catalysts or the ligands required for cross-linking may result in loss of functionality. We evaluated the efficiency of conjugations between antibodies and superparamagnetic iron oxide nanoparticles using click chemistry as well as the functionality of the product. The results were compared with conjugates formed through carbodiimide cross-linking. The click reaction allowed for a higher extent and efficiency of labeling compared with carbodiimide, thus requiring less antibody. Further, conjugates prepared via the click reaction exhibited improved binding to target receptors.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In 2013, two years after South Sudan's formation as the world's newest nation, a costly civil war erupted that has ensnared the South Sudanese people and the nation's developmental and consolidation ...process for more than five years. The article explores the current conflict against its historical backdrop, proposing a greater role for religious leaders in the peace and reconciliation processes. It draws upon original interview data generated in 2018 from dozens of South Sudanese informants as a direct window into the effects of the conflict and into the prospects for peace and reconciliation within the context.
The preparation of size‐tunable PEGylated, iodine‐loaded nanoparticles is investigated for biomedical applications. Di‐iodination of polyvinyl phenol and encapsulation of the iodinated polymer via ...directed self‐assembly with an amphiphilic polyethylene glycol‐based diblock copolymer are reported. Nanoparticles with iodine loadings up to 45 wt% are achieved using a rapid, scalable process. The size of the nanoparticles can be readily tuned between 35 and 130 nm by increasing the ionic strength of the antisolvent used during nanoparticle self‐assembly. The resulting PEGylated iodine‐loaded nanoparticles have potential applications in nanomedicine for 1) quantitative biodistribution analysis via inductively coupled plasma mass spectrometry (ICP‐MS) or 2) X‐ray contrast in biomedical imaging. For quantitative biodistribution studies using ICP‐MS, a limit of detection of 2 µg mL−1 in mouse serum is achieved. For biomedical imaging, the X‐ray attenuation rates are comparable to currently commercially available iodine‐based contrast agents. Therefore, encapsulation of the iodinated polymer enables formulation of trackable, size tunable nanoparticles as a versatile platform for developing nanomedicines.
A highly iodinated polymer is achieved by aromatic substitution and encapsulated by directed self‐assembly with an amphiphilic polyethylene glycol‐based block copolymer. The nanoparticles can be detected using inductively coupled plasma mass spectrometry or provide X‐ray contrast with comparable attenuation to commercial products. Therefore, encapsulation of the iodinated polymer via Flash NanoPrecipitation provides a versatile platform for achieving size tunable, trackable nanoparticles.
With the continued advancements in cellular and molecular biology, especially in the areas of genomics, proteomics and metabolomics, the scientific research community is gaining ground in uncovering ...the tortuous details associated with cancer. Molecular imaging has undergone a similar progression and is showing promise as a future method to aid in the early detection of malignancies, locating metastatic disease, staging tumors, evaluating the availability of therapeutic targets, and monitoring the efficacy of treatment. A subset of molecular imaging contrast agents known as "activatable molecular probes" has generated a particularly high level of excitement in the imaging community. Activatable molecular probes are designed to elicit a detectable change in signal upon enzymatic activity or in response to specific biomolecular interactions. In many cases, these unique characteristics allow for very high signal-to-background ratios compared with conventional targeted contrast agents and they open up the possibility of imaging intracellular targets. In this review, we will discuss some of the activatable probes recently developed for optical and magnetic resonance imaging platforms and their use in the visualization of cancer biomarkers in vivo.
Systemic lupus erythematosus (SLE) is a debilitating disease that affects at least 5 million people worldwide. Currently, there are limited approved treatment options for patients with SLE, and a ...great need remains for therapies to achieve important treatment goals such as reductions in flares, prevention of organ damage, clinical low disease activity or remission. The purpose of this article is to review the current health authority guidance for the development of drugs to treat SLE and discuss some of the challenges in the development of drugs for SLE from a regulatory perspective. Given the substantial number of failed late-stage clinical trials in this indication despite the inclusion of large numbers of subjects, reviewing the regulatory guidance and complexities surrounding the development of drugs for the treatment of SLE is crucial to understand the complexities of the disease itself and the challenges and limitations to conducting successful trials evaluating the impact of treatment of new agents in SLE. As only one new drug (belimumab, trade name BENLYSTA®) with a novel mechanism of action has been approved over the last six decades, the prescribing information for belimumab will be reviewed in the context of the guidance.https://doi.org/10.21423/jrs-v07delvecchio
Herein, we studied the impact of empty LNP (eLNP), component of mRNA-based vaccine, on anti-viral pathways and immune function of cells from young and aged individuals. eLNP induced maturation of ...monocyte derived dendritic cells (MDDCs). We further show that eLNP upregulated CD40 and induced cytokine production in multiple DC subsets and monocytes. This coincided with phosphorylation of TANK binding kinase 1 (pTBK1) and interferon response factor 7 (pIRF7). In response to eLNP, healthy older adults (>65 yrs) have decreased CD40 expression, and IFN-γ output compared to young adults (<65 yrs). Additionally, cells from older adults have a dysregulated anti-viral signaling response to eLNP stimulation, measured by the defect in type I IFN production, and phagocytosis. Overall, our data show function of eLNP in eliciting DC maturation and innate immune signaling pathways that is impaired in older adults resulting in lower immune responses to SARS-CoV-2 mRNA-based vaccines.
PDF
