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Molecules (Basel, Switzerland) May 2024The synergistic effect of drug and gene delivery is expected to significantly improve cancer therapy. However, it is still challenging to design suitable nanocarriers...
The synergistic effect of drug and gene delivery is expected to significantly improve cancer therapy. However, it is still challenging to design suitable nanocarriers that are able to load simultaneously anticancer drugs and nucleic acids due to their different physico-chemical properties. In the present work, an amphiphilic block copolymer comprising a biocompatible poly(ethylene glycol) (PEG) block and a multi-alkyne-functional biodegradable polycarbonate (PC) block was modified with a number of poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) side chains applying the highly efficient azide-alkyne "click" chemistry reaction. The resulting cationic amphiphilic copolymer with block and graft architecture (MPEG--(PC--PDMAEMA)) self-associated in aqueous media into nanosized micelles which were loaded with the antioxidant, anti-inflammatory, and anticancer drug quercetin. The drug-loaded nanoparticles were further used to form micelleplexes in aqueous media through electrostatic interactions with DNA. The obtained nanoaggregates-empty and drug-loaded micelles as well as the micelleplexes intended for simultaneous DNA and drug codelivery-were physico-chemically characterized. Additionally, initial in vitro evaluations were performed, indicating the potential application of the novel polymer nanocarriers as drug delivery systems.
Topics: Micelles; Quercetin; Methacrylates; DNA; Nylons; Drug Carriers; Humans; Polyethylene Glycols; Nanoparticles; Polymers
PubMed: 38893415
DOI: 10.3390/molecules29112540 -
Nutrients May 2024The aim of this pilot study was to evaluate and compare bioavailability and safety of two Vitamin D formulations (softgels) in healthy adults, at single daily doses of... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
The aim of this pilot study was to evaluate and compare bioavailability and safety of two Vitamin D formulations (softgels) in healthy adults, at single daily doses of 1000 and 2500 IU, over a 60-day period. A total of 69 participants were initially screened for eligibility in a double-blind randomized study with a four-arm parallel design; 35 participants were randomized to treatment groups: (1) standard Vitamin D 1000 IU (STD1000), (2) micellar Vitamin D 1000 IU (LMD1000), (3) standard Vitamin D 2500 IU (STD2500), and (4) micellar Vitamin D 2500 IU (LMD2500). Serum Vitamin D concentrations were determined through calcifediol [25(OH)D] at baseline (=before treatment), at day 5, 10, and 15 (=during treatment), at day 30 (=end of treatment), and at day 45 and 60 (=during follow-up/post treatment). Safety markers and minerals were evaluated at baseline and at day 30 and day 60. The pharmacokinetic parameters with respect to iAUC were found to be significantly different between LMD1000 vs. STD1000: iAUC(5-60): 992 ± 260 vs. 177 ± 140 nmol day/L; < 0.05, suggesting up to 6 times higher Vitamin D absorption of LMD when measured incrementally. During follow-up, participants in the LMD1000 treatment group showed approx. 7 times higher Vitamin D concentrations than the STD1000 group (iAUC(30-60): 680 ± 190 vs. 104 ± 91 nmol day/L; < 0.05). However, no significant differences were found between the pharmacokinetics of the higher dosing groups STD2500 and LMD2500. No significant changes in serum 1,25(OH)D concentrations or other biochemical safety markers were detected at day 60; no excess risks of hypercalcemia (i.e., total serum calcium > 2.63 mmol/L) or other adverse events were identified. LMD, a micellar delivery vehicle for microencapsulating Vitamin D (LipoMicel), proved to be safe and only showed superior bioavailability when compared to standard Vitamin D at the lower dose of 1000 IU. This study has clinical trial registration: NCT05209425.
Topics: Humans; Pilot Projects; Cholecalciferol; Male; Female; Double-Blind Method; Adult; Dietary Supplements; Micelles; Biological Availability; Administration, Oral; Middle Aged; Young Adult; Calcifediol; Vitamin D
PubMed: 38892507
DOI: 10.3390/nu16111573 -
International Journal of Molecular... Jun 2024Many different types of nanoparticles have been suggested for tumor-targeted theranosis. However, most systems were prepared through a series of complicated processes...
Many different types of nanoparticles have been suggested for tumor-targeted theranosis. However, most systems were prepared through a series of complicated processes and could not even overcome the blood-immune barriers. For the accurate diagnosis and effective treatment of cancers, herein we suggested the lipid micellar structure capturing quantum dot (QD) for cancer theranosis. The QD/lipid micelles (QDMs) were prepared using a simple self-assembly procedure and then conjugated with anti-epidermal growth factor receptor (EGFR) antibodies for tumor targeting. As a therapeutic agent, Bcl2 siRNA-cholesterol conjugates were loaded on the surface of QDMs. The EGFR-directed QDMs containing Bcl2 siRNA, so-called immuno-QDM/siBcl2 (iQDM/siBcl2), exhibited the more effective delivery of QDs and siBcl2 to target human colorectal cancer cells in cultures as well as in mouse xenografts. The effective in vivo targeting of iQDM/siBcl2 resulted in a more enhanced therapeutic efficacy of siBcl2 to the target cancer in mice. Based on the results, anti-EGFR QDM capturing therapeutic siRNA could be suggested as an alternative modality for tumor-targeted theranosis.
Topics: Quantum Dots; Animals; ErbB Receptors; Humans; RNA, Small Interfering; Proto-Oncogene Proteins c-bcl-2; Mice; Cell Line, Tumor; Nanoparticles; Lipids; Theranostic Nanomedicine; Xenograft Model Antitumor Assays; Micelles
PubMed: 38892434
DOI: 10.3390/ijms25116246 -
International Journal of Molecular... May 2024We investigated the pharmacokinetic pathway of berberine and its metabolites in vitro, in Caco-2 cells, and in human participants following the administration of...
We investigated the pharmacokinetic pathway of berberine and its metabolites in vitro, in Caco-2 cells, and in human participants following the administration of dihydroberberine (DHB) and micellar berberine (LipoMicel, LMB) formulations. A pilot trial involving nine healthy volunteers was conducted over a 24 h period; blood samples were collected and subjected to Ultra High-Performance Liquid Chromatography-High Resolution Mass Spectrometry (UHPLC-HRMS) analyses to quantify the concentrations of berberine and its metabolites. Pharmacokinetic correlations indicated that berberrubine and thalifendine follow distinct metabolic pathways. Additionally, jatrorrhizine sulfate appeared to undergo metabolism differently compared to the other sulfated metabolites. Moreover, berberrubine glucuronide likely has a unique metabolic pathway distinct from other glucuronides. The human trial revealed significantly higher blood concentrations of berberine metabolites in participants of the DHB treatment group compared to the LMB treatment group-except for berberrubine glucuronide, which was only detected in the LMB treatment group. Similarly, results from in vitro investigations showed significant differences in berberine metabolite profiles between DHB and LMB. Dihydroberberine, dihydroxy-berberrubine/thalifendine and jatrorrhizine sulfate were detected in LMB-treated cells, but not in DHB-treated cells; thalifendine and jatrorrhizine-glucuronide were detected in DHB-treated cells only. While DHB treatment provided higher blood concentrations of berberine and most berberine metabolites, both in vitro (Caco-2 cells) and in vivo human studies showed that treatment with LMB resulted in a higher proportion of unmetabolized berberine compared to DHB. These findings suggest potential clinical implications that merit further investigation in future large-scale trials.
Topics: Humans; Berberine; Caco-2 Cells; Pilot Projects; Male; Micelles; Adult; Female; Chromatography, High Pressure Liquid
PubMed: 38891813
DOI: 10.3390/ijms25115625 -
Polymers May 2024A series of stimuli-responsive fluorescent hydrogels were successfully synthesized via micelle radical copolymerization of hydrophilic acrylamide (AM), hydrophobic...
A series of stimuli-responsive fluorescent hydrogels were successfully synthesized via micelle radical copolymerization of hydrophilic acrylamide (AM), hydrophobic chromophore terpyridine-based monomer (TPY), and -isopropylacrylamide (NIPAM). These hydrogels presented blue emissions (423-440 nm) under room temperature, which is caused by the π-π* transition of the conjugated structures. Once the ambient temperature was increased to 55 °C, the fluorescence color changed from blue (430 nm) to pink (575 nm) within 10 min, subsequently to yellow (535 nm), and eventually back to pink. The thermal-responsive properties are attributed to the transition of the TPY units from unimer to dimer aggregation via the intermolecular charge transfer complex at high temperatures. The hydrogels showed pH-responsive properties. The emission peak of the hydrogel exhibited a blue shift of ~54 nm from neuter conditions to acidic conditions, while a 6 nm red shift to an alkaline environment was observed. The hydrogels demonstrated an obvious change in fluorescence intensity and wavelength upon adding different metal ions, which is caused by the coordination between the terpyridine units incorporated on the backbones and the metal ions. As a consequence, the hydrogels presented a sharp quenching fluorescence interaction with Fe, Fe, Cu, Hg, Ni, and Co, while it exhibited an enhanced fluorescence intensity interaction with Sn, Cd, and Zn. The microstructural, mechanical, and rheological properties of these luminescent hydrogels have been systematically investigated.
PubMed: 38891465
DOI: 10.3390/polym16111519 -
Foods (Basel, Switzerland) Jun 2024Curcumin, a hydrophobic polyphenol extracted from the rhizome of , is now considered a candidate drug for the treatment of neurological diseases, including Parkinson's... (Review)
Review
Curcumin, a hydrophobic polyphenol extracted from the rhizome of , is now considered a candidate drug for the treatment of neurological diseases, including Parkinson's Disease (PD), Alzheimer's Disease (AD), Huntington's Disease (HD), Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), and prion disease, due to its potent anti-inflammatory, antioxidant potential, anticancerous, immunomodulatory, neuroprotective, antiproliferative, and antibacterial activities. Traditionally, curcumin has been used for medicinal and dietary purposes in Asia, India, and China. However, low water solubility, poor stability in the blood, high rate of metabolism, limited bioavailability, and little capability to cross the blood-brain barrier (BBB) have limited the clinical application of curcumin, despite the important pharmacological activities of this drug. A variety of nanocarriers, including liposomes, micelles, dendrimers, cubosome nanoparticles, polymer nanoparticles, and solid lipid nanoparticles have been developed with great success to effectively deliver the active drug to brain cells. Functionalization on the surface of nanoparticles with brain-specific ligands makes them target-specific, which should significantly improve bioavailability and reduce harmful effects. The aim of this review is to summarize the studies on curcumin and/or nanoparticles containing curcumin in the most common neurodegenerative diseases, highlighting the high neuroprotective potential of this nutraceutical.
PubMed: 38891002
DOI: 10.3390/foods13111774 -
Foods (Basel, Switzerland) May 2024Micellar calcium phosphate (MCP) plays an important role in maintaining the structure and stability of the casein micelle and its properties during processing. The...
Micellar calcium phosphate (MCP) plays an important role in maintaining the structure and stability of the casein micelle and its properties during processing. The objective of this study was to investigate how heating (10 min at 80 or 90 °C) at different pH levels (6.3, 6.6, 6.9, or 7.2) impacted the acid-induced gelation of MCP-adjusted milk, containing 67 (MCP), 100 (MCP), or 113 (MCP) % of the original MCP content. The unheated sample MCP at pH 6.6 was considered the control. pH acidification to pH 4.5 at 30 °C was achieved with glucono delta-lactone while monitoring viscoelastic behaviour by small-amplitude oscillatory rheology. The partitioning of calcium and proteins between colloidal and soluble phases was also examined. In MCP-depleted skim milk samples, the concentrations of non-sedimentable caseins and whey proteins were higher compared to the control and MCP-enriched skim milk samples. The influence of MCP adjustment on gelation was dependent on pH. Acid gels from sample MCP exhibited the highest storage modulus (G'). At other pH levels, MCP resulted in the greatest G'. The pH of MCP-adjusted skim milk also impacted the gel properties after heating. Overall, this study highlights the substantial impact of MCP content on the acid gelation of milk, with a pronounced dependency of the MCP adjustment effect on pH variations.
PubMed: 38890952
DOI: 10.3390/foods13111724 -
Scientific Reports Jun 2024The balance between the low and high temperature performance of asphalt materials is important to avoid either rutting deformation or low temperature cracking resistance...
The balance between the low and high temperature performance of asphalt materials is important to avoid either rutting deformation or low temperature cracking resistance of asphalt pavement. This is beneficial for improving the asphalt pavement comprehensive performance. Considering the excellent high temperature performance of Ethylene-vinyl acetate (EVA) modified asphalt, this study first modified it with Waste Biological Oil (WBO) to prepare WBO/EVA composite modified asphalt (WEMA) with different dosages. Then the samples were evaluated by the traditional physical properties, low and high temperature rheological properties. Finally, the micro mechanism of WBO on EVA modified asphalt were explored by gel permeation chromatography (GPC) test and atomic force microscope (AFM) experiments. The experimental results reveal that WBO has a softening effect on EVA modified asphalt, reducing its stiffness and improving its stretching performance and flowability. In addition, WBO can reduce the high-temperature deformation resistance of EMA modified asphalt, but it significantly enhances the low-temperature property of EVA modified asphalt. When the WBO content ranges from 1.5 to 2.5%, the high-temperature performance of WEMA is inferior to that of EVA-modified asphalt, however, its low-temperature performance is significantly better than that of EVA-modified asphalt. Importantly, within this WBO content range, the comprehensive performance of WEMA is superior to that of pure asphalt. Mechanism investigation showed that WBO reduces the content of macromolecular micelles and average molecular weight in EVA modified asphalt, and it also diluts the asphaltene components in the asphalt system, resulting in a slight weakening of the performance of WEMA at high temperatures and a significant performance enhancement at low temperatures. Ultimately, the utilization of WBO/EVA composite modified asphalt has a better comprehensive performance.
PubMed: 38890504
DOI: 10.1038/s41598-024-64816-9 -
Journal of Structural Biology: X Jun 2024NMR spectroscopy has played a pivotal role in fragment-based drug discovery by coupling detection of weak ligand-target binding with structural mapping of the binding...
NMR spectroscopy has played a pivotal role in fragment-based drug discovery by coupling detection of weak ligand-target binding with structural mapping of the binding site. Fragment-based screening by NMR has been successfully applied to many soluble protein targets, but only to a limited number of membrane proteins, despite the fact that many drug targets are membrane proteins. This is partly because of difficulties preparing membrane proteins for NMR-especially human membrane proteins-and because of the inherent complexity associated with solution NMR spectroscopy on membrane protein samples, which require the inclusion of membrane-mimetic agents such as micelles, nanodiscs, or bicelles. Here, we developed a generalizable protocol for fragment-based screening of membrane proteins using NMR. We employed two human membrane protein targets, both in fully protonated detergent micelles: the single-pass C-terminal domain of the amyloid precursor protein, C99, and the tetraspan peripheral myelin protein 22 (PMP22). For both we determined the optimal NMR acquisition parameters, protein concentration, protein-to-micelle ratio, and upper limit to the concentration of D-DMSO in screening samples. Furthermore, we conducted preliminary screens of a plate-format molecular fragment mixture library using our optimized conditions and were able to identify hit compounds that selectively bound to the respective target proteins. It is hoped that the approaches presented here will be useful in complementing existing methods for discovering lead compounds that target membrane proteins.
PubMed: 38883400
DOI: 10.1016/j.yjsbx.2024.100100 -
International Journal of Nanomedicine 2024This review article discusses the potential of nanomaterials in targeted therapy and immunomodulation for stroke-induced immunosuppression. Although nanomaterials have... (Review)
Review
This review article discusses the potential of nanomaterials in targeted therapy and immunomodulation for stroke-induced immunosuppression. Although nanomaterials have been extensively studied in various biomedical applications, their specific use in studying and addressing immunosuppression after stroke remains limited. Stroke-induced neuroinflammation is characterized by T-cell-mediated immunodepression, which leads to increased morbidity and mortality. Key observations related to immunodepression after stroke, including lymphopenia, T-cell dysfunction, regulatory T-cell imbalance, and cytokine dysregulation, are discussed. Nanomaterials, such as liposomes, micelles, polymeric nanoparticles, and dendrimers, offer advantages in the precise delivery of drugs to T cells, enabling enhanced targeting and controlled release of immunomodulatory agents. These nanomaterials have the potential to modulate T-cell function, promote neuroregeneration, and restore immune responses, providing new avenues for stroke treatment. However, challenges related to biocompatibility, stability, scalability, and clinical translation need to be addressed. Future research efforts should focus on comprehensive studies to validate the efficacy and safety of nanomaterial-based interventions targeting T cells in stroke-induced immunosuppression. Collaborative interdisciplinary approaches are necessary to advance the field and translate these innovative strategies into clinical practice, ultimately improving stroke outcomes and patient care.
Topics: Animals; Humans; Cytokines; Nanomedicine; Nanoparticles; Nanostructures; Stroke; T-Lymphocytes
PubMed: 38882535
DOI: 10.2147/IJN.S456632