Cervical cancer is the fourth most common malignancy among women. Compared to other types of cancer, therapeutic agents can be administrated locally at the mucosal vaginal membrane. Thermosensitive gels have been developed over the years for contraception or for the treatment of bacterial, fungal, and sexually transmitted infections. These formulations often carry therapeutic nanoparticles and are now being considered in the arsenal of tools for oncology. They can also be three-dimensionally (3D) printed for a better geometrical adjustment to the anatomy of the patient, thus enhancing the local delivery treatment. In this study, a localized delivery system composed of a Pluronic F127-alginate hydrogel with efficient nanoparticle (NP) release properties was prepared for intravaginal application procedures. The kinetics of hydrogel degradation and its NP releasing properties were demonstrated with ultrasmall gold nanoparticles (∼80% of encapsulated AuNPs released in 48 h). The mucoadhesive properties of the hydrogel formulation were assayed by the periodic acid/Schiff reagent staining, which revealed that 19% of mucins were adsorbed on the gel’s surface. The hydrogel formulation was tested for cytocompatibility in three cell lines (HeLa, CRL 2616, and BT-474; no sign of cytotoxicity revealed). The release of AuNPs from the hydrogel and their accumulation in vaginal membranes were quantitatively measured in vitro/ex vivo with positron emission tomography, a highly sensitive modality allowing real-time imaging of nanoparticle diffusion (lag time to start of permeation of 3.3 h, 47% of AuNPs accumulated in the mucosa after 42 h). Finally, the potential of the AuNP-containing Pluronic F127-alginate hydrogel for 3D printing was demonstrated, and the geometrical precision of the 3D printed systems was measured by magnetic resonance imaging (<0.5 mm precision; deviation from the design values <2.5%). In summary, this study demonstrates the potential of Pluronic F127-alginate formulations for the topical administration of NP-releasing gels applied to vaginal wall therapy. This technology could open new possibilities for photothermal and radiosensitizing oncology applications.
Cyclooxygenase type 2 (COX‐2) is an attractive biomarker for the visualization of neuroinflammation processes by positron emission tomography (PET). Neolignan 4’‐O‐methylhonokiol (MH) is known to have high anti‐inflammatory activity and inhibits the expression of COX‐2. We synthesized 4′‐[11C]methoxy‐5‐propyl‐1,1′‐biphenyl‐2‐ol ([11C]MPbP), a compound based on the MH structure and labeled with carbon‐11 (T1/2=20.4 min) and studied its distribution in rats treated with lipopolysaccharide (LPS). It was shown that the new ligand has significant inhibitory activity against COX‐2 (IC50=0.14 μM) and sufficient lipophilicity (logD7.4=2.46±0.12) for penetration the blood brain barrier (BBB). [11C]MPbP was obtained by 11C‐methylation using [11C]CH3I with decay‐corrected radiochemical yield of 20% based on [11C]CH3I with molar activity 10–15 GBq/μmol, high radiochemical purity (> 99%) and low level of chemical impurities (<1 μg/ml). The radioligand did not undergo any noticeable decomposition in human plasma for 40 min. The results of ex vivo biodistribution in rats demonstrated that [11C]MPbP crossed the BBB and the observed radioactivity uptake in brain of rats with LPS‐induced neuroinflammation was 4 times higher than in intact animals. Further studies of compounds with the MH scaffold are planned for their possible application in PET, including in vivo assessment in animal neuroinflammation models.
Neolignans honokiol and 4′-O-methylhonokiol (MH) and their derivatives have pronounced anti-inflammatory activity, as evidenced by numerous pharmacological studies. Literature data suggested that cyclooxygenase type 2 (COX-2) may be a target for these compounds in vitro and in vivo. Recent studies of [11C]MPbP (4′-[11C]methoxy-5-propyl-1,1′-biphenyl-2-ol) biodistribution in LPS (lipopolysaccharide)-treated rats have confirmed the high potential of MH derivatives for imaging neuroinflammation. Here, we report the synthesis of four structural analogs of honokiol, of which 4′-(2-fluoroethoxy)-2-hydroxy-5-propyl-1, 1′-biphenyl (F-IV) was selected for labeling with fluorine-18 (T1/2 = 109.8 min) due to its high anti-inflammatory activity confirmed by enzyme immunoassays (EIA) and neuromorphological studies. The high inhibitory potency of F-IV to COX-2 and its moderate lipophilicity and chemical stability are favorable factors for the preliminary evaluation of the radioligand [18F]F-IV in a rodent model of neuroinflammation. [18F]F-IV was prepared with good radiochemical yield and high molar activity and radiochemical purity by 18F-fluoroethylation of the precursor with Boc-protecting group (15) with [18F]2-fluoro-1-bromoethane ([18F]FEB). Ex vivo biodistribution studies revealed a small to moderate increase in radioligand uptake in the brain and peripheral organs of LPS-induced rats compared to control animals. Pretreatment with celecoxib resulted in significant blocking of radioactivity uptake in the brain (pons and medulla), heart, lungs, and kidneys, indicating that [18F]F-IV is likely to specifically bind to COX-2 in a rat model of neuroinflammation. However, in comparison with [11C]MPbP, the new radioligand showed decreased brain uptake in LPS rats and high retention in the blood pool, which apparently could be explained by its high plasma protein binding. We believe that the structure of [18F]F-IV can be optimized by replacing the substituents in the biphenyl core to eliminate these disadvantages and develop new radioligands for imaging activated microglia.
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