Pluronics, also known as poloxamers, are amphiphilic triblock copolymers widely employed in drug delivery systems due to their tunable self-assembly and biocompatibility. Among them, Pluronic F68 (Poloxamer 188) exhibits thermoresponsive behavior in aqueous solution, forming ordered supramolecular structures at high concentrations and temperatures. In this work, we investigate the morphological and rheological properties of a 45 wt% Pluronic F68 aqueous system at different temperatures through a combination of experimental and computational approaches. Rheological measurements and Small-Angle X-ray Scattering (SAXS) confirm the formation of a body-centered cubic (BCC) structure at higher temperatures and highlight the emergence of viscoelastic solid-like behavior. To support and extend these findings, Dissipative Particle Dynamics (DPD) simulations are employed to model the nanostructure evolution and the impact of temperature on self-assembly and material properties. This integrated approach provides a consistent framework to characterize the temperature-induced transition from fluid-like to solid-like states and sets the groundwork for future simulation studies incorporating drug cargo. The results offer valuable insights into the design of thermoresponsive drug delivery systems and demonstrate the potential of DPD in capturing complex structure-property relationships in amphiphilic polymer systems.
- Keywords
- Dissipative particle dynamics, Drug delivery systems, Pluronics, Rheology, Self-assembly,
- MeSH
- Scattering, Small Angle MeSH
- Drug Carriers * chemistry MeSH
- Poloxamer * chemistry MeSH
- Surface Properties MeSH
- Rheology MeSH
- Temperature MeSH
- Particle Size MeSH
- Water * chemistry MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Drug Carriers * MeSH
- Poloxamer * MeSH
- Water * MeSH
Targeted Alpha Therapy (TAT) offers a promising approach to treat cancer, particularly micrometastases, by utilizing the short range and high linear energy transfer of alpha particles emitted by radionuclides. 211At (half-life 7.2h) is one of the promising alpha emitters (only one alpha emitted during decay) that has been identified for nuclear medicine applications. It belongs to the halogen family and shares chemical properties with iodine, an element used for imaging (123I, 124I and 131I) and also widely used to treat thyroid cancer (131I). This chemical similarity enables the use of Iodine as an analogue for biodistribution and dosimetry studies while using 211At for treatment in a theranostic approach. In this study, an alpha beam accelerated by SPIRAL2, was used to produce 211At via the reaction 209Bi(α, 2n)211At on the NFS beam line. The production cross section of 211At increases with increasing alpha energy up to 31 MeV. However, above 28.6 MeV, the production of 210At occurs via the 209Bi(α, 3n)210At reaction. 210At decays to 210Po, a highly toxic alpha-emitting radionuclide with a half-life of 138.3 days which cannot be separated chemically. Therefore, it is crucial to have a thorough understanding of the rise in 210At production to optimize the generation of 211At while minimizing the production of 210At To achieve this, 209Bi targets were irradiated at various alpha beam energies between 28 to 31 MeV with high precision thanks to the characteristics of SPIRAL2 accelerator and 210,211At cross sections were measured by using γ-ray spectroscopy. The incident particle flux was monitored using an instrumented Faraday cup. This flux measurement combined with the number of detected γ-rays allowed to determine the production cross sections of 210,211At as a function of energy. The results are in good agreement with experimental values recommended by the International Atomic Energy Agency (IAEA) for 211At and provide supplemental data for 210At between 28.6 and 31 MeV. The data collected in this study will help optimize the energy range of interest for the production of 211At and give 211At its rightful place as a radionuclide for TAT.
- Keywords
- Production cross sections, Radionuclides: (210–211)At, α-particle induced reactions on (209)Bi, γ-ray spectroscopy,
- Publication type
- Journal Article MeSH
An International Workshop on Standards and Measurements for Alpha-Emitting Radionuclides in Therapeutic Nuclear Medicine was held on 22-23 February 2024 at the Bureau International des Poids et Mesures (BIPM) and online. The workshop brought together members of the medical and metrology communities who play crucial roles in developing Targeted Alpha Therapy (TAT) radiopharmaceuticals. The workshop aimed to discuss ways to improve radioactivity measurements of alpha-emitting radionuclides for TAT. Through the presentations and discussions that took place over the two days of the workshop, information was exchanged, and recommendations for improvements that could lead to improved safety and effectiveness in TAT were proposed. This paper summarizes the topics and important ideas that were discussed at the workshop and presents recommendations for all the communities involved in the development of TAT radiopharmaceuticals to consider.
- MeSH
- Alpha Particles * therapeutic use MeSH
- Humans MeSH
- Nuclear Medicine MeSH
- Radiopharmaceuticals * therapeutic use MeSH
- Radioisotopes * therapeutic use standards MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Radiopharmaceuticals * MeSH
- Radioisotopes * MeSH
This study highlights how the choice of milling method can significantly influence the final properties of powdered materials. Using inverse gas chromatography (IGC), we gained deeper insights into how surface characteristics evolve with milling time across different processing techniques. The findings reveal that powders produced via dry and wet milling exhibit distinctly different surface properties. Notably, both milled naproxen samples showed increased surface energy compared to the unprocessed drug, with a marked increase in specific interactions indicating a rearrangement of surface functional groups as a result of milling. Dry-milled samples exhibited higher surface free energy, greater cohesiveness, and reduced wettability. In contrast, wet milling yielded finer particles with better wettability, lower surface energy, and reduced cohesion attributes that make them more favorable for further processing. Differences were also observed in the morphology index and relative morphology index. Dry-milled powders exhibited greater nanoroughness, whereas wet-milled samples displayed flatter, smoother surface. Overall, the study suggests that wet milling tends to produce powders with more desirable handling and manufacturing properties. These insights into surface properties provide a valuable framework for selecting the most suitable milling method helping to avoid potential issues related to powder behavior in downstream applications.
- Keywords
- Ball milling, Dry milling, Inverse gas chromatography, Nanoroughness, Surface energy, Wet milling,
- MeSH
- Chromatography, Gas MeSH
- Chemistry, Pharmaceutical methods MeSH
- Technology, Pharmaceutical methods MeSH
- Naproxen * chemistry MeSH
- Surface Properties MeSH
- Powders chemistry MeSH
- Drug Compounding * methods MeSH
- Wettability MeSH
- Particle Size MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Naproxen * MeSH
- Powders MeSH
Design and development of functionalized and biocompatible drug delivery systems (DDS) for site-specific release of small molecules is emerging as a means to target disease sites while sparing healthy tissue. Cell penetrating short peptides capable of self-assembly and drug encapsulation represent one scaffold with which selective DDSs can be rationally designed due to their chemical diversity, biocompatibility, tunable bioactivity, ease of functionality, and high loading capacity. Herein, we designed and synthesized two tetra peptides, BOC-YWWD (PB1 with Trp-Trp-Sequence) and BOC-WYWD (PB2 without Trp-Trp sequence). Structural rigidification of these two peptides with Zn(II) in the self-assembled state were characterized by the density functional theory (DFT) method and demonstrated to shift self-assembly of their characteristic emission from the ultraviolet to visible range allowing for visualization of cellular entry. PB1-Zn, unlike PB2-Zn, exhibits cell penetrating capabilities and is photo and thermally stable and biocompatible. Self-assembled PB1-Zn effectively encapsulated the chemotherapeutic drug Doxorubicin (Dox) and facilitated intracellular drug delivery. To test the utility of PB1-Zn as a DDS, we chemically modified PB1-Zn with folic acid to target folate receptor α (FLOR1), commonly overexpressed on the surface of cancer cells. In HeLa cervical cancer cells, this chemical conjugation with folic acid significantly improved the ability of Dox to activate the pro-apoptotic DNA damage response and trigger oxidative stress and mitochondrial dysfunction critical for the cancer cell killing actions of the drug. However, PB1-Zn failed to facilitate Dox delivery into the lung cancer epithelial cell line, A549, which does not express high levels of FLOR1. Our results represent an important proof of concept describing the fabrication of fluorescent Zn(II) coordinated, self-assembled short peptides containing the sequential Trp-Trp unit that may be used to develop superior imaging reagents and site-specific DDSs.
- Keywords
- Apoptosis, Cell penetrating peptide, Cellular imaging, Folate receptor, Site-specific drug delivery,
- MeSH
- Biocompatible Materials * chemistry pharmacology chemical synthesis MeSH
- Doxorubicin * pharmacology chemistry MeSH
- Folate Receptors, GPI-Anchored * metabolism MeSH
- HeLa Cells MeSH
- Drug Delivery Systems MeSH
- Humans MeSH
- Molecular Structure MeSH
- Drug Carriers * chemistry MeSH
- Oligopeptides * chemistry pharmacology MeSH
- Cell-Penetrating Peptides * chemistry pharmacology chemical synthesis MeSH
- Cell Proliferation drug effects MeSH
- Antineoplastic Agents * pharmacology chemistry MeSH
- Drug Screening Assays, Antitumor MeSH
- Materials Testing MeSH
- Particle Size MeSH
- Cell Survival drug effects MeSH
- Zinc * chemistry MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Biocompatible Materials * MeSH
- Doxorubicin * MeSH
- Folate Receptors, GPI-Anchored * MeSH
- Drug Carriers * MeSH
- Oligopeptides * MeSH
- Cell-Penetrating Peptides * MeSH
- Antineoplastic Agents * MeSH
- Zinc * MeSH
Traffic-related ultrafine particles (UFPs) are an emerging health concern affecting the brain and increasing the risk of Alzheimer's disease (AD). PI3K/AKT signaling is known to contribute to neuronal survival and to be altered in AD. The nasal olfactory mucosa (OM) is a sensory tissue exposed directly to ambient air, and a starting point for olfactory neural circuits towards the brain. Evidence of air pollution-induced transcriptional regulation via microRNAs (miRNA) and DNA methylation (DNAmet) is accumulating and air pollutant-mediated disturbances in PI3K/AKT signaling have been reported. By utilizing a highly translational human-based in vitro model of OM, we aimed to investigate possible gene regulatory mechanisms in PI3K/AKT signaling induced by UFPs, and to compare the responses between cognitively healthy and individuals with AD. miRNA expression was analyzed using next-generation sequencing (NGS) and chip-based methylation analysis was performed to detect differentially methylated loci (DML). These data were combined with previously published transcriptomics analysis (mRNA) to construct an mRNA-miRNA-DNAmet-integrative network. Protein level changes were studied by immunoassays. We observed UFP-induced reductions in viability and increases in oxidative stress and DNA damage without eminent cell death. Integrative network analysis revealed multiple connections of miRNAs to differentially expressed genes in the PI3K/AKT pathway, and effects were most prominent in AD cells. Similarly, in AD cells DML were identified in transcription factor and apoptosis genes, downstream of PI3K/AKT signaling. Conclusively, traffic-related UFPs influence gene regulation of PI3K/AKT signaling to modulate OM cell survival, with existing AD pathology resulting in heightened vulnerability to UFP effects.
- Keywords
- Alzheimer’s disease (AD), DNA methylation (DNAmet), integrative mRNA-miRNA-DNAmet analysis, MicroRNA (miRNA), Olfactory mucosa (OM), PI3K/AKT signaling, Ultrafine particle (UFP),
- MeSH
- Alzheimer Disease MeSH
- Olfactory Mucosa * drug effects metabolism cytology MeSH
- Phosphatidylinositol 3-Kinases metabolism MeSH
- Air Pollutants * toxicity MeSH
- Humans MeSH
- DNA Methylation MeSH
- MicroRNAs metabolism MeSH
- Particulate Matter * toxicity MeSH
- Proto-Oncogene Proteins c-akt metabolism MeSH
- Gene Expression Regulation * drug effects MeSH
- Signal Transduction drug effects MeSH
- Vehicle Emissions * toxicity MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Phosphatidylinositol 3-Kinases MeSH
- Air Pollutants * MeSH
- MicroRNAs MeSH
- Particulate Matter * MeSH
- Proto-Oncogene Proteins c-akt MeSH
- Vehicle Emissions * MeSH
Microplastics (MP) are being released into the environment at an increasing rate, causing extensive pollution in soils and affecting biota and processes. Although the use of biodegradable plastic has increased, its effects on the soil microbial community are not yet well understood. A controlled mesocosm experiment was conducted to investigate the response of soil microbial communities to increasing amounts of starch-polybutylene adipate terephthalate MPs (PBAT-BD-MPs) added to the soil. The experiment included microbes, earthworms, springtails, and plants. The PBAT-BD-MPs were added to the soil column at doses ranging from 0 to 0.8 % w/w of soil dry mass, and the columns were incubated for 11 weeks under controlled climatic conditions. Bacterial and fungal amplicon sequencing was used to investigate the dose-dependent response of the soil microbial communities' alpha and beta diversity. The alpha diversity indices of the bacterial and fungal communities increased with increasing PBAT-BD-MP concentration. Bacterial richness was highest at the highest MP concentration (0.8 %). A similar trend was observed in the fungal community, with a significant increase in fungal richness as PBAT-BD-MP concentration increased. The alpha diversity of both bacterial and fungal communities significantly increased in MP treatments compared to the control treatment. At the highest MP concentration (0.8 %), the abundance of the bacterial phylum Planctomycetes showed a significant increase, while Firmicutes showed a significant decrease. The abundance of the fungal phyla Ascomycota and Mortierellomycota also significantly increased at the highest PBAT-BD-MP concentration compared to the control group. Alongside changes in the soil microbial community, we observed a rise in soil respiration as the concentration of PBAT-BD-MPs increased. Our three-month mesocosm study demonstrates that the introduction of biodegradable microplastics into the natural standard soil environment in realistic concentrations (0-0.025-0.05-0.2-0.8 %) and particle size distribution alters the soil bacterial and fungal community.
- Keywords
- Bacteria, CLIMECS, Fungi, Polybutylene adipate terephthalate PBAT, Soil respiration,
- MeSH
- Bacteria drug effects MeSH
- Biodegradation, Environmental MeSH
- Biodegradable Plastics * MeSH
- Fungi drug effects MeSH
- Soil Pollutants * toxicity MeSH
- Microbiota * drug effects MeSH
- Microplastics * toxicity MeSH
- Oligochaeta MeSH
- Soil Microbiology * MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Biodegradable Plastics * MeSH
- Soil Pollutants * MeSH
- Microplastics * MeSH
PURPOSE: Prostate-specific membrane antigen (PSMA) radioligand therapy is a promising treatment for metastatic castration-resistant prostate cancer (mCRPC). Several beta or alpha particle-emitting radionuclide-conjugated small molecules have shown efficacy in late-stage mCRPC and one, [[177Lu]Lu]Lu-PSMA-617, is FDA approved. In addition to tumor upregulation, PSMA is also expressed in kidneys and salivary glands where specific uptake can cause dose-limiting xerostomia and potential for nephrotoxicity. The PSMA inhibitor 2-(phosphonomethyl)pentanedioic acid (2-PMPA) can prevent kidney uptake in mice, but also blocks tumor uptake, precluding its clinical utility. Preferential delivery of 2-PMPA to non-malignant tissues could improve the therapeutic window of PSMA radioligand therapy. METHODS: A tris(isopropoxycarbonyloxymethyl) (TrisPOC) prodrug of 2-PMPA, JHU-2545, was synthesized to enhance 2-PMPA delivery to non-malignant tissues. Mouse pharmacokinetic experiments were conducted to compare JHU-2545-mediated delivery of 2-PMPA to plasma, kidney, salivary glands, and C4-2 prostate tumor xenograft. Imaging studies were conducted in rats and mice to measure uptake of PSMA PET tracers in kidney, salivary glands, and prostate tumor xenografts with and without JHU-2545 pre-treatment. RESULTS: JHU-2545 resulted in approximately 3- and 53-fold greater exposure of 2-PMPA in rodent salivary glands (18.0 ± 0.97 h*nmol/g) and kidneys (359 ± 4.16 h*nmol/g) versus prostate tumor xenograft (6.79 ± 0.19 h*nmol/g). JHU-2545 also blocked rodent kidneys and salivary glands uptake of the PSMA PET tracers [68Ga]Ga-PSMA-11 and [18 F]F-DCFPyL by up to 85% with little effect on tumor. CONCLUSIONS: JHU-2545 pre-treatment may enable greater cumulative administered doses of PSMA radioligand therapy, possibly improving safety and efficacy.
- Keywords
- Kidneys, PSMA, Prostate cancer, Radioligand therapy, Salivary glands,
- MeSH
- Antigens, Surface * metabolism MeSH
- Glutamate Carboxypeptidase II * metabolism MeSH
- Rats MeSH
- Kidney * drug effects diagnostic imaging metabolism radiation effects MeSH
- Humans MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Radiation-Protective Agents * pharmacology pharmacokinetics MeSH
- Salivary Glands * drug effects diagnostic imaging metabolism radiation effects MeSH
- Tissue Distribution MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Humans MeSH
- Male MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Antigens, Surface * MeSH
- FOLH1 protein, human MeSH Browser
- Glutamate Carboxypeptidase II * MeSH
- Radiation-Protective Agents * MeSH
DNA nanostructures (DNs) have gained popularity in various biomedical applications due to their unique properties, including structural programmability, ease of synthesis and functionalization, and low cytotoxicity. Effective utilization of DNs in biomedical applications requires a fundamental understanding of their interactions with living cells and the mechanics of cellular uptake. Current knowledge primarily focuses on how the physicochemical properties of DNs, such as mass, shape, size, and surface functionalization, affect uptake efficacy. However, the role of cellular mechanics and morphology in DN uptake remains largely unexplored. In this work, we show that cells subjected to geometric constraints remodel their actin cytoskeleton, resulting in differential mechanical force generation that facilitates DN uptake. The length, number, and orientation of F-actin fibers are influenced by these constraints, leading to distinct mechanophenotypes. Overall, DN uptake is governed by F-actin forces arising from filament reorganisation under geometric constraints. These results underscore the importance of actin dynamics in the cellular uptake of DNs and suggest that leveraging geometric constraints to induce specific cell morphology adaptations could enhance the uptake of therapeutically designed DNs.
- MeSH
- Actins metabolism chemistry MeSH
- Cytoskeleton * metabolism chemistry MeSH
- DNA * chemistry metabolism MeSH
- Humans MeSH
- Actin Cytoskeleton * metabolism chemistry MeSH
- Nanostructures * chemistry MeSH
- Surface Properties MeSH
- Particle Size MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Actins MeSH
- DNA * MeSH
The development of stimuli-responsive drug delivery systems enables targeted delivery and environment-controlled drug release, thereby minimizing off-target effects and systemic toxicity. We prepared and studied tailor-made dual-responsive systems (thermo- and pH-) based on synthetic diblock copolymers consisting of a fully hydrophilic block of poly[N-(1,3-dihydroxypropyl)methacrylamide] (poly(DHPMA)) and a thermoresponsive block of poly[N-(2,2-dimethyl-1,3-dioxan-5-yl)methacrylamide] (poly(DHPMA-acetal)) as drug delivery and smart stimuli-responsive materials. The copolymers were designed for eventual medical application to be fully soluble in aqueous solutions at 25 °C. However, they form well-defined nanoparticles with hydrodynamic diameters of 50-800 nm when heated above the transition temperature of 27-31 °C. This temperature range is carefully tailored to align with the human body's physiological conditions. The formation of the nanoparticles and their subsequent decomposition was studied using dynamic light scattering (DLS), transmission electron microscopy (TEM), isothermal titration calorimetry (ITC), and nuclear magnetic resonance (NMR). 1H NMR studies confirmed that after approximately 20 h of incubation at pH 5, which closely mimics tumor microenvironment, approximately 40% of the acetal groups were hydrolyzed, and the thermoresponsive behavior of the copolymers was lost. This smart polymer response led to disintegration of the supramolecular structures, possibly releasing the therapeutic cargo. By tuning the transition temperature to the values relevant for medical applications, we ensure precise and effective drug release. In addition, our systems did not exhibit any cytotoxicity against any of the three cell lines. Our findings underscore the immense potential of these nanoparticles as eventual advanced drug delivery systems, especially for cancer therapy.
- Keywords
- RAFT polymerization, drug delivery systems, pH-sensitive polymers, self-assembling block copolymers, thermoresponsive polymers,
- MeSH
- Biocompatible Materials * chemistry chemical synthesis pharmacology MeSH
- Doxorubicin * pharmacology chemistry MeSH
- Hydrogen-Ion Concentration MeSH
- Drug Delivery Systems * MeSH
- Humans MeSH
- Nanoparticles * chemistry MeSH
- Polymers * chemistry MeSH
- Surface Properties MeSH
- Antibiotics, Antineoplastic * pharmacology chemistry MeSH
- Drug Screening Assays, Antitumor MeSH
- Temperature MeSH
- Materials Testing MeSH
- Drug Liberation MeSH
- Particle Size MeSH
- Cell Survival drug effects MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Biocompatible Materials * MeSH
- Doxorubicin * MeSH
- Polymers * MeSH
- Antibiotics, Antineoplastic * MeSH
