This study describes the comparison between the interaction of a series of peptide-functionalized chitosan-based nanocapsules and liposomes with two cell lines, i.e., mouse macrophages RAW 264.7 and ...human endothelial cells EA.hy926. Both types of nanocarriers are loaded with magnetic nanoparticles and designed for anti-inflammatory therapy. The choice of these magnetic nanostructures is argued based on their advantages in terms of size, morphology, chemical composition, and the multiple possibilities of modifying their surface. Moreover, active targeting might be ensured by using an external magnetic field. To explore the impact of chitosan-based nanocapsules and liposomes on cell cytophysiology, the cell viability, using the MTT assay, and cell morphology were investigated. The results revealed low to moderate cytotoxicity of free nanocapsules and significant cytotoxicity induced by chitosan-coated liposomes loaded with dexamethasone, confirming its release from the delivery system. Thus, after 48 h of treatment with nanocapsules, the viability of RAW 264.7 cells varied between 88.18% (OCNPM-1I, 3.125 µg/mL) and 76.37% (OCNPM-1, 25 µg/mL). In the same conditions, EA.hy926 cell viability was between 99.91% (OCNPM-3, 3.125 µg/mL) and 75.15% (OCNPM-3, 25 µg/mL) at the highest dose (25 µg/mL), the values being comparable for both cell lines. Referring to the cell reactivity after dexamethasone-loaded liposome application, the lowest viability of RAW 264.7 cells was 41.25% (CLDM5CP-1, 25 µg/mL) and 58.20% (CLDMM2CP-1 1.25 µg/mL) in the endothelial cell line, proving a selective character of action of nanocarriers. The cell morphology test, performed to support and confirm the results obtained by the MTT test, revealed a differentiated response for the two types of nano-carriers. As expected, an intense cytotoxic effect in the case of dexamethasone-loaded liposomes and a lack of cytotoxicity for drug-free nanocapsules were noticed. Therefore, our study demonstrated the biocompatible feature of the studied nanocarriers, which highlights them for future research as potential drug delivery systems for pharmacological applications, including anti-inflammatory therapy.
Electrospinning (ES) is a versatile and diverse technique to fabricate nano and micro fibers that could be utilized as drug delivery systems. The aim of this research was the fabrication and ...characterization of drug loaded nanofibrous scaffold produced by single-needle ES using poly(Ɛ-caprolactone) (PCL) and poly(ethylene glycol-400) (PEG) and to investigate the potential of this material as a drug delivery system. A model drug, Ibuprofen (IBU), was used. Ibuprofen is a medicine that is a non-steroidal, anti-inflammatory drug (NSAID). Two concentrations of IBU, 5 wt% and 7 wt%, were incorporated for the ES of PCL and PCL/PEG nanofibers. Characterization of nanofibers was done by using Scanning Electron Microscopy (SEM), Differential Scanning Calorimeter (DSC), Thermogravimetric Analysis (TGA), and Water Contact Angle Measurements. The impact of IBU on nanofibers’ properties such as morphology, diameters, hydrophilicity, and tensile strength was investigated. Finally, the drug release kinetics of IBU from nanofibers was analyzed and their percentage release efficiency of IBU (RE%) was determined by UV-vis spectroscopy during 24 h.
Patient-derived organoids (PDOs) have recently emerged as robust preclinical models; however, their potential to predict clinical outcomes in patients has remained unclear. We report on a living ...biobank of PDOs from metastatic, heavily pretreated colorectal and gastroesophageal cancer patients recruited in phase 1/2 clinical trials. Phenotypic and genotypic profiling of PDOs showed a high degree of similarity to the original patient tumors. Molecular profiling of tumor organoids was matched to drug-screening results, suggesting that PDOs could complement existing approaches in defining cancer vulnerabilities and improving treatment responses. We compared responses to anticancer agents ex vivo in organoids and PDO-based orthotopic mouse tumor xenograft models with the responses of the patients in clinical trials. Our data suggest that PDOs can recapitulate patient responses in the clinic and could be implemented in personalized medicine programs.
This study reports the preparation of novel polymeric nanocapsules based on a natural polymer, chitosan and a synthetic one, poly(
N
-vinylpyrrolidone-
alt
-itaconic anhydride) (poly(NVPAI) using an ...interfacial condensation technique. The infrared spectroscopy studies confirmed the crosslinking through the presence of amide bonds, formed between the two polymers chains. The diameter of nanocapsules was found in the range of 126–214 nm and it was determined by dynamic light scattering method. Morphological characterization demonstrated their nano size, the spherical shape of the nanocapsules and the formation of hollow particles. The nanocapsules presented good swelling capacity in aqueous solutions. 5-Fluorouracil (5-FU) loading and release capacity was studied, the processes being controlled by the drug diffusion through the polymeric membrane. The obtained results were encouraging, showing that 5-FU-loaded nanocapsules had 70 % higher apoptotic effect on A549 tumour cells than the drug in free state or mixed with the nanocapsules.
Objectives:
To assess the repeatability of quantitative multiparametric whole-body MRI (mpWB-MRI) parameters in advanced prostate cancer (APC) bone metastases.
Methods:
1.5T MRI was performed twice ...on the same day in 10 APC patients. MpWB-MRI-included diffusion weighted imaging (DWI) and T
1
-weighted gradient-echo 2-point Dixon sequences. ADC and relative fat-fraction percentage (rFF%) maps were calculated, respectively. A radiologist delineated up to 10 target bone metastases per study. Means of ADC, b900 signal intensity(SI), normalised b900 SI, rFF% and maximum diameter (MD) for each target lesion and overall parameter averages across all targets per patient were recorded. The total disease volume (tDV in ml) was manually delineated on b900 images and mean global (g)ADC was derived. Bland-Altman analyses were performed with calculation of 95% repeatability coefficients (RC).
Results:
Seventy-three individual targets (median MD 26 mm) were included. Lesion mean ADC RC was 12.5%, mean b900 SI RC 137%, normalised mean b900 SI RC 110%, rFF% RC 3.2 and target MD RC 5.5 mm (16.3%). Patient target lesion average mean ADC RC was 6.4%, b900 SI RC 104% and normalised mean b900 SI RC 39.6%. Target average rFF% RC was 1.8, average MD RC 1.3 mm (4.8%). tDV segmentation RC was 6.4% and mean gADC RC 5.3%.
Conclusions:
APC bone metastases’ ADC, rFF% and maximum diameter, tDV and gADC show good repeatability.
Advances in knowledge:
APC bone metastases’ mean ADC and rFF% measurements of single lesions and global disease volumes are repeatable, supporting their potential role as quantitative biomarkers in metastatic bone disease.
Inhibition of monocarboxylate transporter (MCT) 1-mediated lactate transport may have cytostatic and/or cytotoxic effects on tumor cells. We report results from the dose-escalation part of a ...first-in-human trial of AZD3965, a first-in-class MCT1 inhibitor, in advanced cancer.
This multicentre, phase I, dose-escalation and dose-expansion trial enrolled patients with advanced solid tumors or lymphoma and no standard therapy options. Exclusion criteria included history of retinal and/or cardiac disease, due to MCT1 expression in the eye and heart. Patients received daily oral AZD3965 according to a 3+3 then rolling six design. Primary objectives were to assess safety and determine the MTD and/or recommended phase II dose (RP2D). Secondary objectives for dose escalation included measurement of pharmacokinetic and pharmacodynamic activity. Exploratory biomarkers included tumor expression of MCT1 and MCT4, functional imaging of biological impact, and metabolomics.
During dose escalation, 40 patients received AZD3965 at 5-30 mg once daily or 10 or 15 mg twice daily. Treatment-emergent adverse events were primarily grade 1 and/or 2, most commonly electroretinogram changes (retinopathy), fatigue, anorexia, and constipation. Seven patients receiving ≥20 mg daily experienced dose-limiting toxicities (DLT): grade 3 cardiac troponin rise (n = 1), asymptomatic ocular DLTs (n = 5), and grade 3 acidosis (n = 1). Plasma pharmacokinetics demonstrated attainment of target concentrations; pharmacodynamic measurements indicated on-target activity.
AZD3965 is tolerated at doses that produce target engagement. DLTs were on-target and primarily dose-dependent, asymptomatic, reversible ocular changes. An RP2D of 10 mg twice daily was established for use in dose expansion in cancers that generally express high MCT1/low MCT4).
Display omitted
•Dexamethasone-loaded carboxylated chitosan/PVA based microcapsules were prepared.•Controlled and sustained Dexamethasone release was observed.•BSA adsorption on microcapsules was ...influenced by the presence of PVA in the system.•Microcapsules were biodegradable and hemocompatibles.
Polymeric microcapsules are extensively investigated as drug delivery systems for a broad range of applications. In the present study, Dexamethasone-loaded carboxylated chitosan (CCS)/poly (vinyl alcohol) (PVA)-based microcapsules were prepared in view of their potential administration by inhalation for the treatment of lung diseases. The crosslinking between PVA and CCS was activated by 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM) and the FTIR results proved the formation of ester bonds between the two polymers. The sizes of the obtained microcapsules are influenced by the ratio between the polymers but also by the concentration of the DMT-MM activator. Moreover, the amount of PVA in the system has an important influence on swelling degree, encapsulation efficiency, drug release degree, biodegradation and protein adsorption. The sample with the highest amount of PVA has the highest crosslinking density and thus the lowest swelling degree and encapsulation efficiency. However, an encapsulation degree of 61.3% was obtained for the sample MCP-6 with the lowest PVA content. The same sample showed the lowest BSA adsorption. A controlled and sustained Dexamethasone release of around 90% was observed in PBS at pH 7.4 and 37 °C during 24 h. All the obtained samples were hemocompatibles and thus can be used as efficient drug delivery systems.
Nanocapsules with diameter around 100 nm based on a natural polymer (chitosan) and a synthetic polymer poly(vinyl acetate-
alt
-maleic anhydride) poly(MAVA) by interfacial condensation method were ...prepared. The present study proposes a new type of biocompatible nanocapsules based on poly(vinyl acetate-
alt
-maleic anhydride-chitosan) (MCS) able to become a reliable support for inclusion and release of drugs. The spherical shape of the nanocapsules was evidenced by scanning electron microscopy. Nanocapsules presented a good Norfloxacin loading and release capacity. Haemocompatibility tests have demonstrated that the nanocapsules present a low toxicity and a good compatibility with sanguine medium. The biocompatibility properties of the nanocapsules after their intraperitoneal administration in rats were evidenced by histopathological examination of different organs (brain, liver, kidney, and lung). The results are encouraging and the nanocapsules can be used as controlled drug delivery systems.
Objectives
Diffusion-weighted imaging (DWI) with simultaneous multi-slice (SMS) acquisition and advanced processing can accelerate acquisition time and improve MR image quality. This study evaluated ...the image quality and apparent diffusion coefficient (ADC) measurements of free-breathing DWI acquired from patients with liver metastases using a prototype SMS-DWI acquisition (with/without an advanced processing option) and conventional DWI.
Methods
Four DWI schemes were compared in a pilot 5-patient cohort; three DWI schemes were further assessed in a 24-patient cohort. Two readers scored image quality of all
b
-value images and ADC maps across the three methods. ADC measurements were performed, for all three methods, in left and right liver parenchyma, spleen, and liver metastases. The Friedman non-parametric test (post-hoc Wilcoxon test with Bonferroni correction) was used to compare image quality scoring;
t
-test was used for ADC comparisons.
Results
SMS-DWI was faster (by 24%) than conventional DWI. Both readers scored the SMS-DWI with advanced processing as having the best image quality for highest
b
-value images (b750) and ADC maps; Cohen’s kappa inter-reader agreement was 0.6 for b750 image and 0.56 for ADC maps. The prototype SMS-DWI sequence with advanced processing allowed a better visualization of the left lobe of the liver. ADC measured in liver parenchyma, spleen, and liver metastases using the SMS-DWI with advanced processing option showed lower values than those derived from the SMS-DWI method alone (
t
-test,
p
< 0.0001;
p
< 0.0001;
p
= 0.002).
Conclusions
Free-breathing SMS-DWI with advanced processing was faster and demonstrated better image quality versus a conventional DWI protocol in liver patients.
Clinical relevance statement
Free-breathing simultaneous multi-slice- diffusion-weighted imaging (DWI) with advanced processing was faster and demonstrated better image quality versus a conventional DWI protocol in liver patients.
Key Points
• Diffusion-weighted imaging (DWI) with simultaneous multi-slice (SMS) can accelerate acquisition time and improve image quality.
• Apparent diffusion coefficients (ADC) measured in liver parenchyma, spleen, and liver metastases using the simultaneous multi-slice DWI with advanced processing were significantly lower than those derived from the simultaneous multi-slice DWI method alone.
• Simultaneous multi-slice DWI sequence with inline advanced processing was faster and demonstrated better image quality in liver patients.
Objectives
Pharmacokinetic (PK) modelling of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) data requires a reliable measure of the arterial input function (AIF) to robustly ...characterise tumour vascular properties. This study compared repeatability and treatment-response effects of DCE-MRI-derived PK parameters using a population-averaged AIF and three patient-specific AIFs derived from pre-bolus MRI, DCE-MRI and dynamic contrast computed tomography (DC-CT) data.
Methods
The four approaches were compared in 13 patients with abdominal metastases. Baseline repeatability Bland-Altman statistics; coefficient of variation (CoV), cohort percentage change and
p
value (paired
t
test) and number of patients with significant DCE-MRI parameter change post-treatment (limits of agreement) were assessed.
Results
Individual AIFs were obtained for all 13 patients with pre-bolus MRI and DC-CT-derived AIFs, but only 10/13 patients had AIFs measurable from DCE-MRI data. The best CoV (7.5 %) of the transfer coefficient between blood plasma and extravascular extracellular space (
K
trans
) was obtained using a population-averaged AIF. All four AIF methods detected significant treatment changes: the most significant was the DC-CT-derived AIF. The population-based AIF was similar to or better than the pre-bolus and DCE-MRI-derived AIFs.
Conclusions
A population-based AIF is the recommended approach for measuring cohort and individual effects since it has the best repeatability and none of the PK parameters derived using measured AIFs demonstrated an improvement in treatment sensitivity.
Key Points
•
Pharmacokinetic modelling of DCE-MRI data requires a reliable measure of AIF
.
•
Individual MRI-DCE-derived AIFs cannot reliably be extracted from patients
.
•
All four AIF methods detected significant K
trans
changes after treatment
.
•
A population-based AIF can be recommended for measuring cohort treatment responses in trials
.
PDF
