Strategies towards standardizing calibration methods for magnetic particle imaging (MPI) signal quantification: solution <i>vs.</i> cellular environments.

Magnetic Particle Imaging (MPI) is a powerful technique for non-invasive imaging and iron quantification using superparamagnetic iron oxide nanoparticles (SPIONs), with applications ranging from in vivo cell tracking to tracer distribution and biodistribution studies. As the MPI community continues to grow and diversify, there is an increasing recognition of the need for standardized approaches in signal quantification to ensure reproducibility, comparability, and reliable interpretation of results across studies. A key area where standardization is particularly needed is in the construction of calibration curves for quantitative MPI. In this study, we demonstrate that calibration curves derived from SPIONs in solution differ markedly from those obtained in cellular environments. We therefore propose calibrating MPI signal against the number of labelled cells, a strategy that accounts for altered SPION behaviours in the cellular environment and enables more accurate estimation of intracellular iron content. Another critical but often overlooked factor in MPI quantification is the influence of SPION concentration and spatial distribution within the sample. We show that even modest variations in concentration can significantly affect MPI signal intensity, challenging the commonly assumed linear relationship between signal and iron content. Our findings reveal that variations in concentration can introduce nonlinearities in signal response, thereby altering calibration curves and impacting the accuracy and reproducibility of MPI-based quantification. By systematically examining the effects of environmental context and SPION concentration, our study provides a framework for biologically relevant MPI calibration strategies and supports the development of more standardized, reproducible quantification protocols

Intracellular delivery of nano-formulated antituberculosis drugs enhances bactericidal activity

Tuberculosis kills more people worldwide than any other infectious disease. Treatment requires multiple drug therapy administered over long periods (6–24 months). The emergence of multidrug‐resistant strains is a major problem, and with few new drugs in the pipeline, a novel modus operandi is urgently required. Solid drug nanoparticles (SDNs), a new development in nanomedicine, offer a fresh therapeutic approach. Here, we show that SDNs are more effective (50‐fold) at killing pathogenic mycobacteria than aqueous forms of the same drug and can target mycobacteria internalised by macrophages, where bacilli reside. We demonstrate synthesis of dual and triple drug loaded SDNs, facilitating combination tuberculosis therapy. Our results suggest that by employing SDNs of existing antibiotics, it may be possible to improve drug delivery and therefore reduce drug dosage to lessen side effects and fight drug resistance

Colorectal cancer after bariatric surgery (Cric-Abs 2020): Sicob (Italian society of obesity surgery) endorsed national survey

Background The published colorectal cancer (CRC) outcomes after bariatric surgery (BS) are conflicting, with some anecdotal studies reporting increased risks. The present nationwide survey CRIC-ABS 2020 (Colo-Rectal Cancer Incidence-After Bariatric Surgery-2020), endorsed by the Italian Society of Obesity Surgery (SICOB), aims to report its incidence in Italy after BS, comparing the two commonest laparoscopic procedures-Sleeve Gastrectomy (SG) and Roux-en-Y gastric bypass (GBP). Methods Two online questionnaires-first having 11 questions on SG/GBP frequency with a follow-up of 5-10 years, and the second containing 15 questions on CRC incidence and management, were administered to 53 referral bariatric, high volume centers. A standardized incidence ratio (SIR-a ratio of the observed number of cases to the expected number) with 95% confidence intervals (CI) was calculated along with CRC incidence risk computation for baseline characteristics. Results Data for 20,571 patients from 34 (63%) centers between 2010 and 2015 were collected, of which 14,431 had SG (70%) and 6140 GBP (30%). 22 patients (0.10%, mean age = 53 +/- 12 years, 13 males), SG: 12 and GBP: 10, developed CRC after 4.3 +/- 2.3 years. Overall incidence was higher among males for both groups (SG: 0.15% vs 0.05%; GBP: 0.35% vs 0.09%) and the GBP cohort having slightly older patients. The right colon was most affected (n = 13) and SIR categorized/sex had fewer values < 1, except for GBP males (SIR = 1.07). Conclusion Low CRC incidence after BS at 10 years (0.10%), and no difference between procedures was seen, suggesting that BS does not trigger the neoplasm development

Enabling Real‐Time, Non‐Ionizing 3D Imaging of Implantable Magnetic Cements Using Magnetic Particle Imaging

Abstract Magnetic Particle Imaging (MPI) is a non‐ionizing tomographic technique capable of real‐time 3D imaging with unmatched temporal resolution, reaching up to 46 vol/s. These features make MPI a promising tool for the monitoring of implantable resin composites, particularly in scenarios requiring frequent safe, and dynamic assessment. However, integrating magnetic responsiveness into medical materials without compromising their structural and biological integrity remains a challenge. In this study, it is presented the first strategy to enable MPI signal generation in a commercial implantable cement by depositing a continuous iron thin film onto its surface. This structured magnetic layer introduces directional magnetic anisotropy, resulting in an angle‐dependent MPI signal. This directional dependence can be explored to noninvasively track for the position and orientation of the implant, potentially benefiting applications in confined anatomical regions. In vitro assays confirmed that the incorporation of the magnetic layer does not compromise cytocompatibility. Altogether, these findings demonstrate that magnetic thin films can serve as anisotropic contrast sources for MPI, expanding the range of new possibilities for imaging implantable materials with orientation‐sensitive contrast and without ionizing radiation.</jats:p

Relationship Between Particle And Biological Properties Of Emulsion-Templated, Freeze-Dried Lopinavir Nanoparticle Dispersions

Background Nanomedicine has the potential to enhance bioavailability and delivery of low-solubility compounds to sanctuary sites. Lopinavir (LPV) is a protease inhibitor (PI) with low bioavailability (<2%) that requires boosting with ritonavir. We assessed relationships between size (z-average), surface charge (zeta potential), and polydispersity with cytotoxicity, cellular accumulation ratio (CAR), and transcellular permeability of a LPV nanodispersion library. Methods Seventy-four dispersions containing 0.1 micro Ci 3H-LPV were generated. Cellular accumulation in lymphocytes (CEM), monocytes (THP1), monocyte-derived macrophages (ATHP1), hepatic (HepG2), and intestinal (Caco-2) cells as well as apical to basolateral (A>B) permeability across Caco-2 monolayers was determined. Data were log transformed and models to describe relationships between particle properties and biological characteristics were constructed using multiple linear regression. Results Median (range) z-average, polydispersity, and zeta potential were 436 (184 to 3145) nm, 0.3 (0.1 to 0.9), and –3.7 (–56.7 to 39.7) mV, respectively. Dispersions exhibiting higher and lower values than aqueous solutions were observed for all biological characteristics. Cytotoxicity of dispersions was lower in all cells compared to aqueous LPV and predictable from models containing z-average and zeta potential (e.g., r = 0.47; p = 0.001 for CEM). A number of dispersions exhibited higher CAR than for aqueous LPV. E.g., median (range) CAR was 17.0 (2.8 to 105.1) in CEM compared to 13.1 for aqueous LPV. In HepG2 (r = –0.38), Caco-2 (r = –0.39), THP1 (r = –0.14), and CEM (r = –0.09) inverse correlations with polydispersity were observed but in phagocytic ATHP1 cells a direct relationship was evident (r = 0.28). In all cells, CAR was predictable from models containing z-average and polydispersity (e.g., r = 0.41; p = 0.006 for Caco-2). The rate of A>B permeation across Caco-2 cells was 6.3 (1.8 to 20.7)%/h compared to 2.5%/h for aqueous LPV but no relationship with particle properties was seen. Conclusions Understanding relationships between particle and biological properties will facilitate generation of effective nanomedicines. We have generated some LPV nanodispersions with greatly enhanced cellular accumulation and transcellular permeability but reduced cytotoxicity. Following careful safety evaluation, the ability to nano-enhance PI could increase bioavailability and thereby alter the requirement for boosting

High relaxivity contrast agents for magnetic resonance imaging (MRI)

The development of Gd(III)-based contrast agents for MRI applications has intensified in recent years due to the paramagnetic ion’s long electron spin relaxation time and large effective magnetic moment, µeff. Secondly, the exploitation of the long lived luminescent properties of the Ln(III) ions has lead to the development of luminescent lanthanide probes for sensing, time resolved immunoassay and imaging applications. Herein a series of novel Ln-DO3A based complexes are reported. Modulation of relaxivity, r1, (Gd) and emission intensity (Eu, Tb, Sm and Dy) has been achieved in three ways: Firstly, mono- and bis-methyl Ln-dpp-DO3A based complexes have been prepared, where dpp is a pendant diphenylphosphinamide moiety. These show pH responsive relaxivity (Gd) and luminescence (Eu) with calculated pKa values of 8.65 (± 0.09) and 8.59 (± 0.14). Sensitised emission of Eu(III), Tb(III), Dy(III) and Sm(III) has been observed following excitation of the dpp antenna at λex ~ 270 nm. Relaxivities have been measured as r1 = 7.9 mMˉ¹sˉ¹and r1 = 8.2 mMˉ¹sˉ¹ in acidic media, q = 2 and r1 = 5.4 mMˉ¹sˉ¹ and r1 = 4.4 mMˉ¹sˉ¹ in basic media, q = 1 for the mono- and bis-methyl Gd-dpp-DO3A complexes respectively. The pH responsive behaviour has been attributed to the reversible ligation of the dpp moiety. Secondly, non-covalent attachment of the mono- and bis-methyl Gd-dpp-DO3A-based complexes to Human Serum Albumin (HSA) at pH 7.4 resulted in a 64% (r1 = 11.7 mMˉ¹sˉ ¹) and a 146% (r1 = 16.0 mMˉ¹sˉ¹) enhancement in relaxivity, with binding affinities, K, determined from luminescence studies as K = 22,268 ± 12% Mˉ¹and K = 20,059 ± 14% Mˉ¹ for the mono- and bis-methyl dpp Eu-dpp-DO3A complexes respectively. The negatively charged [Gd-dpp-aDO3A]3ˉ complex was developed in order to improve the observed relaxivity of the HSA bound species: r1 = 16.0 mMˉ¹sˉ¹, K = 17,915 (± 14%) Mˉ¹. Competitive binding studies with the fluorescent probes dansylsarcosine and warfarin showed each of the dpp complex analogues to bind preferentially to HSA site II, only the S-enantiomer of the mono-methyl Gd-dpp-DO3A showed an affinity for site I. Finally, an accumulation and activation strategy following enzyme activity has been demonstrated. Neutral q = 2 Gd(III) ethyl and acetoxymethyl ester Ln-DO3MA based complexes have shown decreased relaxivity in the presence of carbonate due to the inner sphere water molecule displacement by bidentate anion binding. The binding is suppressed by the introduction of negative charge to the complex following enzymatic hydrolysis of the ester groups, resulting in ~ 84% relaxivity enhancement (Gd) as well as Eu luminescence quenching. The high observed relaxivity of the ethyl ester model: r1 = 10.2 mMˉ¹sˉ¹ is attributed to the extremely short observed water exchange lifetime, τm = 7.9 ns

High relaxivity contrast agents for magnetic resonance imaging (MRI)

The development of Gd(III)-based contrast agents for MRI applications has intensified in recent years due to the paramagnetic ion’s long electron spin relaxation time and large effective magnetic moment, µeff. Secondly, the exploitation of the long lived luminescent properties of the Ln(III) ions has lead to the development of luminescent lanthanide probes for sensing, time resolved immunoassay and imaging applications. Herein a series of novel Ln-DO3A based complexes are reported. Modulation of relaxivity, r1, (Gd) and emission intensity (Eu, Tb, Sm and Dy) has been achieved in three ways: Firstly, mono- and bis-methyl Ln-dpp-DO3A based complexes have been prepared, where dpp is a pendant diphenylphosphinamide moiety. These show pH responsive relaxivity (Gd) and luminescence (Eu) with calculated pKa values of 8.65 (± 0.09) and 8.59 (± 0.14). Sensitised emission of Eu(III), Tb(III), Dy(III) and Sm(III) has been observed following excitation of the dpp antenna at λex ~ 270 nm. Relaxivities have been measured as r1 = 7.9 mMˉ¹sˉ¹and r1 = 8.2 mMˉ¹sˉ¹ in acidic media, q = 2 and r1 = 5.4 mMˉ¹sˉ¹ and r1 = 4.4 mMˉ¹sˉ¹ in basic media, q = 1 for the mono- and bis-methyl Gd-dpp-DO3A complexes respectively. The pH responsive behaviour has been attributed to the reversible ligation of the dpp moiety. Secondly, non-covalent attachment of the mono- and bis-methyl Gd-dpp-DO3A-based complexes to Human Serum Albumin (HSA) at pH 7.4 resulted in a 64% (r1 = 11.7 mMˉ¹sˉ ¹) and a 146% (r1 = 16.0 mMˉ¹sˉ¹) enhancement in relaxivity, with binding affinities, K, determined from luminescence studies as K = 22,268 ± 12% Mˉ¹and K = 20,059 ± 14% Mˉ¹ for the mono- and bis-methyl dpp Eu-dpp-DO3A complexes respectively. The negatively charged [Gd-dpp-aDO3A]3ˉ complex was developed in order to improve the observed relaxivity of the HSA bound species: r1 = 16.0 mMˉ¹sˉ¹, K = 17,915 (± 14%) Mˉ¹. Competitive binding studies with the fluorescent probes dansylsarcosine and warfarin showed each of the dpp complex analogues to bind preferentially to HSA site II, only the S-enantiomer of the mono-methyl Gd-dpp-DO3A showed an affinity for site I. Finally, an accumulation and activation strategy following enzyme activity has been demonstrated. Neutral q = 2 Gd(III) ethyl and acetoxymethyl ester Ln-DO3MA based complexes have shown decreased relaxivity in the presence of carbonate due to the inner sphere water molecule displacement by bidentate anion binding. The binding is suppressed by the introduction of negative charge to the complex following enzymatic hydrolysis of the ester groups, resulting in ~ 84% relaxivity enhancement (Gd) as well as Eu luminescence quenching. The high observed relaxivity of the ethyl ester model: r1 = 10.2 mMˉ¹sˉ¹ is attributed to the extremely short observed water exchange lifetime, τm = 7.9 ns.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Controllable and tuneable growth of NaYbF₄:Tm(0.5%)Fe(5%)@Na(Yb/Y)F₄-core@shell structures and the effect of their geometry on upconversion luminescence

Controllable and tuneable core@shell UCNPs with enhanced UC efficiency through varied energy transfer pathways arising from geometric alteration.</jats:p

Luminescence Study of Eu(III) Analogues of Esterase-Activated Magnetic Resonance Contrast Agents

A model for an accumulation and enzyme-activation strategy of a magnetic resonance contrast agent was investigated via the luminescence of Eu(III) analogues. Neutral q = 2 Eu(III) ethyl and acetoxymethyl ester LnaDO3A-based complexes showed increased emission intensity in the presence of serum concentrations of carbonate because of inner-sphere water molecule displacement by the anion. The affinity for carbonate is suppressed by the introduction of negative charge to the complex following enzymatic hydrolysis of the ester groups, resulting in quenching of Eu(III) luminescence and changes in spectral form. The conversion of neutral, carboxylic ester-containing complexes into free acid forms by enzymatic hydrolysis using pig liver esterase was demonstrated by luminescence (Eu) and 1H NMR spectroscopic investigations (Y). These studies demonstrated that the concept of inhibition of anion binding as a result of enzyme activation is feasible