An oxalate-bridged oxidovanadium(IV) binuclear complex that improves the in vitro cell uptake of a fluorescent glucose analog

The decay of terbium-161 results in the emission of β¯-particles as well as conversion and Auger electrons, which makes terbium-161 interesting for therapeutic purposes. The aim of this study was to use dual-isotope SPECT imaging in order to demonstrate visually that terbium-161 and lutetium-177 are interchangeable without compromising the pharmacokinetic profile of the radiopharmaceutical. The 161Tb- and 177Lu-labeled somatostatin (SST) analogues DOTATOC (agonist) and DOTA-LM3 (antagonist) were tested in vitro to demonstrate equal properties regarding distribution coefficients and cell uptake into SST receptor-positive AR42J tumor cells. The radiopeptides were further investigated in AR42J tumor-bearing nude mice using the method of dual-isotope (terbium-161/lutetium-177) SPECT/CT imaging to enable the visualization of their distribution profiles in the same animal. Equal pharmacokinetic profiles were demonstrated for either of the two peptides, irrespective of whether it was labeled with terbium-161 or lutetium-177. Moreover, the visualization of the sub-organ distribution confirmed similar behavior of 161Tb- and 177Lu-labeled SST analogues. The data were verified in quantitative biodistribution studies using either type of peptide labeled with terbium-161 or lutetium-177. While the radionuclide did not have an impact on the organ distribution, this study confirmed previous data of a considerably higher tumor uptake of radiolabeled DOTA-LM3 as compared to the radiolabeled DOTATOC.

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Variably Sized and Multi-Colored Silica-Nanoparticles Characterized by Fluorescence Correlation Methods for Cellular Dynamics

Materials ◽

10.3390/ma14010019 ◽

2020 ◽

Vol 14 (1) ◽

pp. 19

Author(s):

Chan-Gi Pack ◽

Bjorn Paulson ◽

Yeonhee Shin ◽

Min Kyo Jung ◽

Jun Sung Kim ◽

...

Keyword(s):

Electron Microscopy ◽

Correlation Spectroscopy ◽

Cell Uptake ◽

Core Shell ◽

Therapeutic Effects ◽

Ferrite Core ◽

Shell Nanoparticles ◽

Fluorescence Correlation ◽

Correlation Methods

Controlling the uptake of nanoparticles into cells so as to balance therapeutic effects with toxicity is an essential unsolved problem in the development of nanomedicine technologies. From this point of view, it is useful to use standard nanoparticles to quantitatively evaluate the physical properties of the nanoparticles in solution and in cells, and to analyze the intracellular dynamic motion and distribution of these nanoparticles at a single-particle level. In this study, standard nanoparticles are developed based on a variant silica-based nanoparticle incorporating fluorescein isothiocyanate (FITC) or/and rhodamine B isothiocyanate (RITC) with a variety of accessible diameters and a matching fluorescent cobalt ferrite core-shell structure (Fe2O4/SiO2). The physical and optical properties of the nanoparticles in vitro are fully evaluated with the complementary methods of dynamic light scattering, electron microscopy, and two fluorescence correlation methods. In addition, cell uptake of dual-colored and core/shell nanoparticles via endocytosis in live HeLa cells is detected by fluorescence correlation spectroscopy and electron microscopy, indicating the suitability of the nanoparticles as standards for further studies of intracellular dynamics with multi-modal methods.

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Experimental and theoretical explorations of nanocarriers’ multistep delivery performance for rational design and anticancer prediction

Science Advances ◽

10.1126/sciadv.aba2458 ◽

2021 ◽

Vol 7 (6) ◽

pp. eaba2458

Author(s):

Weier Bao ◽

Falin Tian ◽

Chengliang Lyu ◽

Bin Liu ◽

Bin Li ◽

...

Keyword(s):

Physical Properties ◽

Rational Design ◽

Theoretical Models ◽

Cell Uptake ◽

Anticancer Efficacy ◽

Delivery Performance ◽

Simulation Based ◽

Multistep Process

The poor understanding of the complex multistep process taken by nanocarriers during the delivery process limits the delivery efficiencies and further hinders the translation of these systems into medicine. Here, we describe a series of six self-assembled nanocarrier types with systematically altered physical properties including size, shape, and rigidity, as well as both in vitro and in vivo analyses of their performance in blood circulation, tumor penetration, cancer cell uptake, and anticancer efficacy. We also developed both data and simulation-based models for understanding the influence of physical properties, both individually and considered together, on each delivery step and overall delivery process. Thus, beyond finding that nanocarriers that are simultaneously endowed with tubular shape, short length, and low rigidity outperformed the other types, we now have a suit of theoretical models that can predict how nanocarrier properties will individually and collectively perform in the multistep delivery of anticancer therapies.

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Synthesis and tumour cell uptake studies of gadolinium(III)–phosphonium complexes

Scientific Reports ◽

10.1038/s41598-020-79893-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Andrew J. Hall ◽

Amy G. Robertson ◽

Leila R. Hill ◽

Louis M. Rendina

Keyword(s):

Glioblastoma Multiforme ◽

Tumour Cell ◽

In Vitro Cytotoxicity ◽

Cell Uptake ◽

Solution Stability ◽

T98g Cell ◽

Human Glioblastoma Multiforme ◽

Theranostic Agents ◽

Uptake Studies

AbstractThe synthesis of a new series of Gd(III)-arylphosphonium complexes is described and the solution stability of selected compounds is reported. Their lipophilicity and uptake in human glial (SVG p12) and human glioblastoma multiforme (T98G) cell lines are presented. The in vitro cytotoxicity of all complexes was determined to be low at therapeutically-relevant concentrations. Selected Gd(III) complexes are potential candidates for further investigation as theranostic agents.

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Surface-Engineered Dendrimeric Nanoconjugates for Macrophage-Targeted Delivery of Amphotericin B: Formulation Development andIn VitroandIn VivoEvaluation

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.04213-14 ◽

2015 ◽

Vol 59 (5) ◽

pp. 2479-2487 ◽

Cited By ~ 40

Author(s):

Keerti Jain ◽

Ashwni Kumar Verma ◽

Prabhat Ranjan Mishra ◽

Narendra Kumar Jain

Keyword(s):

Drug Release ◽

Amphotericin B ◽

Human Erythrocytes ◽

Antileishmanial Activity ◽

Cell Uptake ◽

Antiparasitic Activity ◽

Content Type ◽

Drug Localization

ABSTRACTThe present study aimed to develop an optimized dendrimeric delivery system for amphotericin B (AmB). Fifth-generation (5.0G) poly(propylene imine) (PPI) dendrimers were synthesized, conjugated with mannose, and characterized by use of various analytical techniques, including Fourier transform infrared spectroscopy (FTIR),1H nuclear magnetic resonance (1H-NMR) spectroscopic analysis, and atomic force microscopy (AFM). Mannose-conjugated 5.0G PPI (MPPI) dendrimers were loaded with AmB and evaluated for drug loading efficiency,in vitrodrug release profile, stability, hemolytic toxicity to human erythrocytes, cytotoxicity to and cell uptake by J774A.1 macrophage cells, antiparasitic activity against intracellularLeishmania donovaniamastigotes,in vivopharmacokinetic and biodistribution profiles, drug localization index, toxicity, and antileishmanial activity. AFM showed the nanometric size of the MPPI dendrimers, with a nearly globular architecture. The conjugate showed a good entrapment efficiency for AmB, along with pH-sensitive drug release. Highly significant reductions in toxicity toward human erythrocytes and macrophage cells, without compromising the antiparasitic activity of AmB, were observed. The dendrimeric formulation of AmB showed a significant enhancement of the parasiticidal activity of AmB toward intramacrophagicL. donovaniamastigotes. In thein vitrocell uptake studies, the formulation showed selectivity toward macrophages, with significant intracellular uptake. Further pharmacokinetic and organ distribution studies elucidated the controlled delivery behavior of the formulation. The drug localization index was found to increase significantly in macrophage-rich organs.In vivostudies showed a biocompatible behavior of MPPIA, with negligible toxicity even at higher doses, and promising antileishmanial activity. From the results, we concluded that surface-engineered dendrimers may serve as optimized delivery vehicles for AmB with enhanced activity and low or negligible toxicity.

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ROS-triggered self-accelerating drug release nanosystem with charge conversion for enhanced cancer therapy

10.21203/rs.3.rs-16551/v1 ◽

2020 ◽

Author(s):

Xinyi Zhang ◽

Tiantian Zhu ◽

Yaxin Miao ◽

Lu Zhou ◽

Weifang Zhang

Keyword(s):

Drug Release ◽

Tumor Tissue ◽

Anticancer Therapy ◽

Cell Uptake ◽

Oxygen Species ◽

Anticancer Drug Delivery ◽

Tocopheryl Succinate ◽

Delivery Platform

Abstract Background: The enhancement tumor retention and of cellular uptake of drugs are important factors in maximizing anticancer therapy and minimizing side effects of encapsulated drugs. Herein, a delivery nanoplatform with a pH-triggered charge-reversal capability and self-amplifiable reactive oxygen species (ROS) level inducing drug release pattern was constructed by encapsulating doxorubicin (DOX) in pH/ROS-responsive polymeric micelle.Results: The surface charge of this system can be converted from negative to positive for enhanced tumor cell uptake in response to the weakly acidic tumor tissue. In addition, methionine-based system was dissociated in a ROS-rich intracellular environment, resulting in a phase transition and the release of DOX. Then, the exposed α-tocopheryl succinate (α-TOS) segments can be capable of producing ROS, which further induced the self-amplifiable disassembly of the micelles and drug release. Conclusions: We confirmed efficient DOX delivery into cancer cells, upregulation of tumoral ROS level and induction of the apoptotic capability in vitro. The system exhibited outstanding tumor inhibition capability in vivo, indicating that dual stimuli nanosytem would be great potential as an anticancer drug delivery platform.

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Schiff base-containing dextran nanogel as pH-sensitive drug delivery system of doxorubicin: Synthesis and characterization

Journal of Biomaterials Applications ◽

10.1177/0885328218783969 ◽

2018 ◽

Vol 33 (2) ◽

pp. 170-181 ◽

Cited By ~ 13

Author(s):

Hongying Su ◽

Wen Zhang ◽

Yayun Wu ◽

Xiaodong Han ◽

Gang Liu ◽

...

Keyword(s):

Drug Delivery ◽

Schiff Base ◽

Drug Release ◽

Drug Delivery System ◽

Delivery System ◽

Ph Sensitive ◽

Cell Uptake ◽

Stimuli Responsive ◽

Drug Release Profile

Stimuli-responsive hydrogels have been widely researched as carrier systems, due to their excellent biocompatibility and responsiveness to external physiologic environment factors. In this study, dextran-based nanogel with covalently conjugated doxorubicin (DOX) was developed via Schiff base formation using the inverse microemulsion technique. Since the Schiff base linkages are acid-sensitive, drug release profile of the DOX-loaded nanogel would be pH-dependent. In vitro drug release studies confirmed that DOX was released much faster under acidic condition (pH 2.0, 5.0) than that at pH 7.4. Approximately 66, 28, and 9% of drug was released in 72 h at pH 2.0, 5.0, and 7.4, respectively. Cell uptake by the human breast cancer cell (MCF-7) demonstrated that the DOX-loaded dextran nanogel could be internalized through endocytosis and distributed in endocytic compartments inside tumor cells. These results indicated that the Schiff base-containing nanogel can serve as a pH-sensitive drug delivery system. And the presence of multiple aldehyde groups on the nanogel are available for further conjugations of targeting ligands or imaging probes.

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EXTH-45. MICROGLIA-SPECIFIC DISRUPTION OF SIALIC ACID-SIGLEC-9/E INTERACTIONS: A NOVEL IMMUNOTHERAPY AGAINST GLIOBLASTOMA?

Neuro-Oncology ◽

10.1093/neuonc/noab196.684 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi173-vi173

Author(s):

Philip Schmassmann ◽

Tomás A Martins ◽

Michal Stanczak ◽

Marie-Françoise Ritz ◽

Tala Shekarian ◽

...

Keyword(s):

Immune Response ◽

Sialic Acid ◽

Therapeutic Potential ◽

Adaptive Immune Response ◽

Cell Uptake ◽

Immune Checkpoints ◽

Sequencing Data ◽

Ki 67 ◽

Spatio Temporal

Abstract Recently, ‘don’t eat me’-signals like CD47 have emerged as novel innate immune checkpoints, enabling cancer cells to evade clearance by phagocytes such as monocyte-derived macrophages (MDM) or microglia (MG). Here, we aim at defining the role of inhibitory Siglec-9 in human and its mouse homologue Siglec-E in MG-centered immunotherapy against GBM. TCGA RNA-sequencing data revealed a significant correlation between high expression of immunoinhibitory SIGLEC9 and poor survival in GBM patients (log-rank p = 0.02). Siglec-E blockade increased murine MG mediated GBM cell in vitro phagocytosis (normalized phagocytosis of 1.00 in isotype vs. 1.76 in anti-Siglec-E antibody, p < 0.001). By employing a CT-2A orthotopic GBM mouse model with MG-specific spatio-temporal deletion of Siglece (Sall1 CreERT2 x Siglece flox ), we observed high MG-proliferation upon Siglec-E knockdown (Ki-67+ MG 14.8% in Cre- vs. 34.9% in Cre+, p < 0.0001) accompanied by an enhanced microglial GBM-cell uptake (5.6% in Cre- vs. 12.3% in Cre+, p < 0.001). This beneficial response was counteracted by an accentuated influx of pro-tumorigenic MDM in the Cre+ group (CD163high CD86low MDM of total MDM 47.1% in Cre- vs. 65.3% in Cre+, p = 0.002), which prevented an efficient adaptive anti-tumor immune response and survival benefit. Currently, we are investigating the cross-talk between GBM-associated MG and MDM upon Siglec-E knockdown by scRNAseq of the tumor-infiltrating immune compartment, including TCR-clonotype tracking. By genetically targeting sialic acids, the ligand for Siglec receptors, on CT-2A cells (GNE-KO), we observed a strong innate and adaptive immune response with less exhausted tumor-infiltrating CD8+ T-cells (14.8% in WT vs. 5.9% in GNE-KO, p = 0.003), which resulted in a prolonged survival (30d in WT vs. 41d post-tumor-injection in GNE-KO, p = 0.03). These data identify the sialic-acid-Siglec-E pathway as an anti-phagocytic signal in a pre-clinical GBM model, and demonstrate its therapeutic potential in GBM immunotherapy.

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[18F]AZD2461, an Insight on Difference in PARP Binding Profiles for DNA Damage Response PET Imaging

Molecular Imaging and Biology ◽

10.1007/s11307-020-01497-6 ◽

2020 ◽

Vol 22 (5) ◽

pp. 1226-1234

Author(s):

Florian Guibbal ◽

Samantha L. Hopkins ◽

Anna Pacelli ◽

Patrick G. Isenegger ◽

Michael Mosley ◽

...

Keyword(s):

Pet Imaging ◽

Parp Inhibitor ◽

Parp Inhibitors ◽

Cell Uptake ◽

Pancreatic Cell ◽

Anti Cancer ◽

Damage Response ◽

Automated Procedures

Abstract Background Poly (ADP-ribose) polymerase (PARP) inhibitors are extensively studied and used as anti-cancer drugs, as single agents or in combination with other therapies. Most radiotracers developed to date have been chosen on the basis of strong PARP1–3 affinity. Herein, we propose to study AZD2461, a PARP inhibitor with lower affinity towards PARP3, and to investigate its potential for PARP targeting in vivo. Methods Using the Cu-mediated 18F-fluorodeboronation of a carefully designed radiolabelling precursor, we accessed the 18F-labelled isotopologue of the PARP inhibitor AZD2461. Cell uptake of [18F]AZD2461 in vitro was assessed in a range of pancreatic cell lines (PSN-1, PANC-1, CFPAC-1 and AsPC-1) to assess PARP expression and in vivo in xenograft-bearing mice. Blocking experiments were performed with both olaparib and AZD2461. Results [18F]AZD2461 was efficiently radiolabelled via both manual and automated procedures (9 % ± 3 % and 3 % ± 1 % activity yields non-decay corrected). [18F]AZD2461 was taken up in vivo in PARP1-expressing tumours, and the highest uptake was observed for PSN-1 cells (7.34 ± 1.16 %ID/g). In vitro blocking experiments showed a lesser ability of olaparib to reduce [18F]AZD2461 binding, indicating a difference in selectivity between olaparib and AZD2461. Conclusion Taken together, we show the importance of screening the PARP selectivity profile of radiolabelled PARP inhibitors for use as PET imaging agents.

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The Precision of in vitro Methods and Algorithms for Predicting the Bioavailability of Dietary Iron

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831.75.6.436 ◽

2005 ◽

Vol 75 (6) ◽

pp. 436-445 ◽

Cited By ~ 10

Author(s):

Sean Lynch

Keyword(s):

Iron Absorption ◽

Heme Iron ◽

Iron Bioavailability ◽

Cell Uptake ◽

In Vitro Tests ◽

Cellular Iron ◽

Non Heme Iron ◽

Human Volunteers ◽

Dialyzable Iron

Three factors determine how much iron will be absorbed from a meal. They are the physiological mechanisms that regulate uptake by and transfer through the enterocytes in the upper small intestine, the quantity of iron in the meal, and its availability to the cellular iron transporters. Established methods exist for predicting the effect of physiological regulation and for measuring or estimating meal iron content. Three approaches to estimating bioavailability have been advocated. Two are in vitro screening procedures: measurement of dialyzable iron and Caco-2 cell uptake, both carried out after in vitro simulated gastric and pancreatic digestion. The third is the use of algorithms based on the predicted effects of specific meal components on absorption derived from isotopic studies in human volunteers. The in vitro procedures have been very useful for identifying and characterizing factors that affect non-heme iron absorption, but direct comparisons between absorption predicted from the in vitro tests and measurements in human volunteers have only been made in a limited number of published studies. The available data indicate that dialysis and Caco-2 cell uptake are useful for ranking meals and single food items in terms of predicted iron bioavailability, but may not reflect the magnitudes of the effects of factors that influence absorption accurately. Algorithms based on estimates of the amounts of heme iron and of enhancers and inhibitors of non-heme iron absorption in foods make it possible to classify meals or diets as being of high, medium, or low bioavailability. The precision with which meal iron bioavailability can be predicted in a population, for which a specific algorithm has been developed, is improved by measuring the content of the most important enhancers and inhibitors. However, the accuracy of such predictions appears to be much lower when the algorithm is applied to meals eaten by different populations.

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