The validation of metal–phenolic nanoparticles (MPNs) in preclinical imaging studies represents a growing field of interest due to their versatility in forming predesigned structures with unique properties. Before MPNs can be used in medicine, their pharmacokinetics must be optimized so that accumulation in nontargeted organs is prevented and toxicity is minimized. Here, we report the fabrication of MPNs made of a coordination polymer core that combines In(III), Cu(II), and a mixture of the imidazole 1,4-bis(imidazole-1-ylmethyl)-benzene and the catechol 3,4-dihydroxycinnamic acid ligands. Furthermore, a phenolic-based coating was used as an anchoring platform to attach poly(ethylene glycol) (PEG). The resulting MPNs, with effective hydrodynamic diameters of around 120 nm, could be further derivatized with surface-embedded molecules, such as folic acid, to facilitate in vivo targeting and multifunctionality. The prepared MPNs were evaluated for in vitro plasma stability, cytotoxicity, and cell internalization and found to be biocompatible under physiological conditions. First, biomedical evaluations were then performed by intrinsically incorporating trace amounts of the radioactive metals 111In or 64Cu during the MPN synthesis directly into their polymeric matrix. The resulting particles, which had identical physicochemical properties to their nonradioactive counterparts, were used to perform in vivo single-photon emission computed tomography (SPECT) and positron emission tomography (PET) in tumor-bearing mice. The ability to incorporate multiple metals and radiometals into MPNs illustrates the diverse range of functional nanoparticles that can be prepared with this approach and broadens the scope of these nanoconstructs as multimodal preclinical imaging agents.
Background The discovery and development of new medicines requires high-throughput screening of possible therapeutics in a specific model of the disease. Infrared thermal imaging (IRT) is a modern assessment method with extensive clinical and preclinical applications. Employing IRT in longitudinal preclinical setting to monitor arthritis onset, disease activity and therapeutic efficacies requires a standardized framework to provide reproducible quantitative data as a precondition for clinical studies. Methods Here, we established the accuracy and reliability of an inexpensive smartphone connected infrared (IR) camera against known temperature objects as well as certified blackbody calibration equipment. An easy to use protocol incorporating contactless image acquisition and computer-assisted data analysis was developed to detect disease-related temperature changes in a collagen-induced arthritis (CIA) mouse model and validated by comparison with two conventional methods, clinical arthritis scoring and paw thickness measurement. We implemented IRT to demonstrate the beneficial therapeutic effect of nanoparticle drug delivery versus free methotrexate (MTX) in vivo. Results The calibrations revealed high accuracy and reliability of the IR camera for detecting temperature changes in the rheumatoid arthritis animal model. Significant positive correlation was found between temperature changes and paw thickness measurements as the disease progressed. IRT was found to be superior over the conventional techniques specially at early arthritis onset, when it is difficult to observe subclinical signs and measure structural changes. Conclusion IRT proved to be a valid and unbiased method to detect temperature changes and quantify the degree of inflammation in a rapid and reproducible manner in longitudinal preclinical drug efficacy studies.
Introduction and aim Ectopic ACTH secretion (EAS) is mostly secondary to thoracic/abdominal neuroendocrine tumours (NETs) or small cell-lung carcinoma (SCLC). We studied the diagnostic accuracy of CT with 68Ga-Dota derivatives (68Ga-SSTR) PET in localizing ACTH-secreting tumor in patients with EAS. Materials and methods 68Ga-SSTR-PET/CT was performed and compared with the nearest enhanced CT in 18 cases (16 primary and 2 recurrent neoplasms). Unspecific, indeterminate and false-positive uptakes were assessed using conventional imaging, follow-up or histology. Results We diagnosed 13 thoracic (9 primary and 2 recurrent bronchial carcinoids, 2 SCLCs) and 1 abdominal (pancreatic NET) tumors. Eight ACTH-secreting tumors were promptly identified at EAS diagnosis (’overt’, four pulmonary carcinoids with two recurrences and two SCLC); six EAS have been discovered during the subsequent follow-up (’covert’, five bronchial carcinoids and one pancreatic NET). At the time of EAS diagnosis, imaging was able to correctly detect the ACTH-secreting tumour in 8/18 cases (6 new diagnosis and 2 recurrences). During the follow-up, six out of initially ten ‘occult’ cases became ‘covert’. At last available follow-up, CT and 68Ga-SSTR-PET/CT were able to diagnose 11/18 and 12/18 ACTH-secreting tumours, respectively (11/14 and 12/14 considering only overt and covert cases, respectively). Four cases have never been localized by conventional or nuclear imaging (’occult EAS’), despite an average follow-up of 5 years. Conclusion The 68Ga-SSTR-PET/CT is useful in localizing EAS, especially to enhance positive prediction of the suggestive CT lesions and to detect occult neoplasms.
Albumin is widely used in pharmaceutical applications to alter the pharmacokinetic profile, improve efficacy, or decrease the toxicity of active compounds. Various drug delivery systems using albumin have been reported, including microparticles. Macroaggregated albumin (MAA) is one of the more common forms of albumin microparticles, which is predominately used for lung perfusion imaging when labeled with radionuclide technetium-99m (99mTc). These microparticles are formed by heat-denaturing albumin in a bulk solution, making it very challenging to control the size and dispersity of the preparations (coefficient of variation, CV, ∼50%). In this work, we developed an integrated microfluidics platform to create more tunable and precise MAA particles, the so-called microfluidic-MAA (M2A2). The microfluidic chips, prepared using off-stoichiometry thiol-ene chemistry, consist of a flow-focusing region followed by an extended and water-heated curing channel (85 °C). M2A2 particles with diameters between 70 and 300 μm with CVs between 10 and 20% were reliably prepared by adjusting the flow rates of the dispersed and continuous phases. To demonstrate the pharmaceutical utility of M2A2, particles were labeled with indium-111 (111In) and their distribution was assessed in healthy mice using nuclear imaging. 111In-M2A2 behaved similarly to 99mTc-MAA, with lung uptake predominately observed early on followed by clearance over time by the reticuloendothelial and renal systems. Our microfluidic chip represents an elegant and controllable method to prepare albumin microparticles for biomedical applications.
The controlled self-assembly of peptide-and protein-based pharmaceuticals is of central importance for their mode of action and tuning of their properties. Peptide YY 3-36 (PYY 3-36) is a 36-residue peptide hormone that reduces food intake when peripherally administered. Herein, we describe the synthesis of a PYY 3-36 analogue functionalized with a metal-ion-binding 2,2'bipyridine ligand that enables self-assembly through metal complexation. Upon addition of Cu II , the bipyridine-modified PYY 3-36 peptide binds stoichiometric quantities of metal ions in solution and contributes to the organization of higher-order assemblies. In this study, we aimed to explore the size effect of the self-assembly in vivo by using non-invasive quantitative single-photon emission computed tomography/computed tomography (SPECT/CT) imaging. For this purpose, bipyridinemodified PYY 3-36 was radiolabeled with a chelator holding 111 In III , followed by the addition of Cu II to the bipyridine ligand. SPECT/ CT imaging and biodistribution studies showed fast renal clearance and accumulation in the kidney cortex. The radiolabeled bipyridyl-PYY 3-36 conjugates with and without Cu II presented a slightly slower excretion 1 h post injection compared to the unmodified-PYY 3-36 , thus demonstrating that higher self-assemblies of the peptide might have an effect on the pharmacokinetics.
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