Dual ligand-targeted Pluronic P123 polymeric micelles enhance the therapeutic effect of breast cancer with bone metastases.

Bone metastasis secondary to breast cancer negatively impacts patient quality of life and survival. The treatment of bone metastases is challenging since many anticancer drugs are not effectively delivered to the bone to exert a therapeutic effect. To improve the treatment efficacy, we developed Pluronic P123 (P123)-based polymeric micelles dually decorated with alendronate (ALN) and cancer-specific phage protein DMPGTVLP (DP-8) for targeted drug delivery to breast cancer bone metastases. Doxorubicin (DOX) was selected as the anticancer drug and was encapsulated into the hydrophobic core of the micelles with a high drug loading capacity (3.44%). The DOX-loaded polymeric micelles were spherical, 123 nm in diameter on average, and exhibited a narrow size distribution. The in vitro experiments demonstrated that a pH decrease from 7.4 to 5.0 markedly accelerated DOX release. The micelles were well internalized by cultured breast cancer cells and the cell death rate of micelle-treated breast cancer cells was increased compared to that of free DOX-treated cells. Rapid binding of the micelles to hydroxyapatite (HA) microparticles indicated their high affinity for bone. P123-ALN/DP-8@DOX inhibited tumor growth and reduced bone resorption in a 3D cancer bone metastasis model. In vivo experiments using a breast cancer bone metastasis nude model demonstrated increased accumulation of the micelles in the tumor region and considerable antitumor activity with no organ-specific histological damage and minimal systemic toxicity. In conclusion, our study provided strong evidence that these pH-sensitive dual ligand-targeted polymeric micelles may be a successful treatment strategy for breast cancer bone metastasis.

Application of electron paramagnetic resonance spectroscopy for determining the relative nanoenvironment fluidity of polymeric micelles.

Polymeric micelles are nanocarriers for drug, protein and gene delivery due to their unique core/shell structure, which encapsulates and protects therapeutic cargos with diverse physicochemical properties. However, information regarding the micellar nanoenvironment's fluidity can provide unique insight into their makeup. In this study, we used electron paramagnetic resonance (EPR) spectroscopy to study free radical spin probe (5-doxylstearate methyl ester, 5-MDS, and 16-doxylstearic acid, 16-DS) behaviour in methoxy-poly(ethylene oxide)-poly(α-benzyl carboxylate-ε-caprolactone) (PEO-PBCL) and methoxy-poly(ethylene oxide)-poly(ε-caprolactone) (PEO-PCL) polymeric micelles. Spin probes provided information about the spectroscopic rotational correlation time (τ, s) and the spectroscopic partition parameter F. We hypothesized that spin probes would partition into the polymeric micelles, and these parameters would be calculated. The results showed that both 5-MDS and 16-DS spectra were modulated in the presence of polymeric micelles. Based on τ values, 5-MDS revealed that PEO-PCL (τ = 3.92 ± 0.26 × 10-8 s) was more fluid than PEO-PBCL (τ = 7.15 ± 0.63 × 10-8 s). The F parameter, however, could not be calculated due to the rotational hindrance of the probe within the micelles. With 16-DS, more probe rotation was observed, and although the F parameter could be calculated, it was not helpful to distinguish the micelles' fluidity. Also, doxorubicin-loading interfered with the spin probes, particularly for 16-DS. However, using simulations, we could distinguish the hydrophilic and hydrophobic components of the 16-DS probe. The findings suggest that EPR spectroscopy is a valuable method for determining core fluidity in polymeric micelles.

Assessing the structural stability and drug encapsulation efficiency of poly(ethylene glycol)-poly(L-lactic acid) nanoparticles loaded with atorvastatin calcium: Based on dissipative particle dynamics.

Block polymer micelles have been proven highly biocompatible and effective in improving drug utilization for delivering atorvastatin calcium. Therefore, it is of great significance to measure the stability of drug-loading nano micelles from the perspective of block polymer molecular sequence design, which would provide theoretical guidance for subsequent clinical applications. This study aims to investigate the structural stability of drug-loading micelles formed by two diblock/triblock polymers with various block sequences through coarse-grained dissipative particle dynamics (DPD) simulations. From the perspectives of the binding strength of poly(L-lactic acid) (PLLA) and polyethylene glycol (PEG) in nanoparticles, hydrophilic bead surface coverage, and the morphological alteration of nanoparticles induced by shear force, the ratio of hydrophilic/hydrophobic sequence length has been observed to affect the stability of nanoparticles. We have found that for diblock polymers, PEG3kda-PLLA2kda has the best stability (corresponding hydrophilic coverage ratio is 0.832), while PEG4kda-PLLA5kda has the worst (coverage ratio 0.578). For triblock polymers, PEG4kda-PLLA2kda-PEG4kda has the best stability (0.838), while PEG4kda-PLLA5kda-PEG4kda possesses the worst performance (0.731), and the average performance on stability is better than nanoparticles composed of diblock polymers.

Polymeric micelle gel with luliconazole: in vivo efficacy against cutaneous candidiasis in Wistar rats.

The objective of this research was focused on the design and development of luliconazole-loaded polymeric micelle hydrogel (LUL-PM-CHG) using quality by design (QbD) principle to improve the penetration and retention of LUL in the skin. The optimization of the formulation involved the utilization of a Box-Behnken design with three factors and three levels. The impact of specific formulation variables, namely the ratio of poloxamer P123 and F127, sonication time, and the quantity of drug, was investigated in terms of particle size, micellar incorporation efficiency, and polydispersity index. The LUL-loaded P123/F127 mixed micelles involved the thin film hydration method for thin preparation. The characteristics of optimized formulation include a particle size of 226 ± 8.52 nm, a polydispersity index (PDI) of 0.153 ± 0.002, a zeta potential (ZP) of 30.15 ± 2.32 mV, and a micellar incorporation efficiency (MIE) of 88.38 ± 3.84%. In vitro release studies indicated a sustained release of LUL-PM-CHG for a duration of up to 8 h. The MIC, GI50, and GI90 of different formulations on Candida albicans were determined using both the microtiter broth dilution method and the plate method and showed that LUL-PM-CHG exhibited the highest antifungal activity compared to the other formulations, with MIC values of 3.25 ± 0.19 ng/mL, GI50 values of 37.11 ± 2.89, and GI90 values of 94.98 ± 3.41 The study also measured the % of inhibition activity and the generation of intracellular reactive oxygen species (ROS) using flow cytometry. LUL-PM-CHG showed the highest percentage of inhibition (75.5%) and ROS production (MFI-140951), indicating its enhanced activity compared to LUL-CHG and LUL. Fungal infection was induced in Wistar rats using immunosuppressant's treatment followed by exposure to C. albicans. Finally, in vivo fungal scaling and histopathological studies indicated a reduction in fungal infection in Wistar rat skin after treatment. The obtained results suggested that LUL-PM can serve as a promising formulation to enhance luliconazole antifungal activity and increase patient compliance.

Fluorescence lifetime imaging and phasor analysis of intracellular porphyrinic photosensitizers applied with different polymeric formulations.

The fluorescence lifetime of a porphyrinic photosensitizer (PS) is an important parameter to assess the aggregation state of the PS even in complex biological environments. Aggregation-induced quenching of the PS can significantly reduce the yield of singlet oxygen generation and thus its efficiency as a medical drug in photodynamic therapy (PDT) of diseased tissues. Hydrophobicity and the tendency to form aggregates pose challenges on the development of efficient PSs and often require carrier systems. A systematic study was performed to probe the impact of PS structure and encapsulation into polymeric carriers on the fluorescence lifetime in solution and in the intracellular environment. Five different porphyrinic PSs including chlorin e6 (Ce6) derivatives and tetrakis(m-hydroxyphenyl)-porphyrin and -chlorin were studied in free form and combined with polyvinylpyrrolidone (PVP) or micelles composed of triblock-copolymers or Cremophor. Following incubation of HeLa cells with these systems, fluorescence lifetime imaging combined with phasor analysis and image segmentation was applied to study the lifetime distribution in the intracellular surrounding. The data suggest that for free PSs, the structure-dependent cell uptake pathways determine their state and emission lifetimes. PS localization in the plasma membrane yielded mostly monomers with long fluorescence lifetimes whereas the endocytic pathway with subsequent lysosomal deposition adds a short-lived component for hydrophilic anionic PSs. Prolonged incubation times led to increasing contributions from short-lived components that derive from aggregates mainly localized in the cytoplasm. Encapsulation of PSs into polymeric carriers led to monomerization and mostly fluorescence emission decays with long fluorescence lifetimes in solution. However, the efficiency depended on the binding strength that was most pronounced for PVP. In the cellular environment, PVP was able to maintain monomeric long-lived species over prolonged incubation times. This was most pronounced for Ce6 derivatives with a logP value around 4.5. Micellar encapsulation led to faster release of the PSs resulting in multiple components with long and short fluorescence lifetimes. The hydrophilic hardly aggregating PS exhibited a mostly stable invariant lifetime distribution over time with both carriers. The presented data are expected to contribute to optimized PDT treatment protocols and improved PS-carrier design for preventing intracellular fluorescence quenching. In conclusion, amphiphilic and concurrent hydrophobic PSs with high membrane affinity as well as strong binding to the carrier have best prospects to maintain their photophysical properties in vivo and serve thus as efficient photodynamic diagnosis and PDT drugs.

Amphiphilic, lauric acid-coupled pluronic-based nano-micellar system for efficient glipizide delivery.

Glipizide; an insulin secretagogue belonging to the sulfonylurea class, is a widely used antidiabetic drug for managing type 2 diabetes. However, the need for life-long administration and repeated doses poses challenges in maintaining optimal blood glucose levels. In this regard, orally active sustained-release nano-formulations can be a better alternative to traditional antidiabetic formulations. The present study explored an innovative approach by formulating orally active sustained-release nano-micelles using the amphiphilic lauric acid-conjugated-F127 (LAF127) block copolymer. LAF127 block copolymer was synthesized through esterification and thoroughly characterized before being employed to develop glipizide-loaded nano-micelles (GNM) via the thin-film hydration technique. The optimized formulation exhibited mean particle size of 341.40 ± 3.21 nm and depicted homogeneous particle size distribution with a polydispersity index (PDI) < 0.2. The formulation revealed a surface charge of -17.11 ± 6.23 mV. The in vitro release studies of glipizide from developed formulation depicted a sustained release profile. Drug loaded micelles exhibited a substantial reduction in blood glucose levels in diabetic rats for a duration of up to 24 h. Notably, neither the blank nano-micelles of LAF127 nor the drug loaded micelles manifested any indications of toxicity in healthy rats. This study provides an insight on suitability of synthesized LAF127 block copolymer for development of effective oral drug delivery systems for anti-diabetic activity without any significant adverse effects.

Ordered mesoporous nanofibers mimicking vascular bundles for lithium metal batteries.

Hierarchical self-assembly with long-range order above centimeters widely exists in nature. Mimicking similar structures to promote reaction kinetics of electrochemical energy devices is of immense interest, yet remains challenging. Here, we report a bottom-up self-assembly approach to constructing ordered mesoporous nanofibers with a structure resembling vascular bundles via electrospinning. The synthesis involves self-assembling polystyrene (PS) homopolymer, amphiphilic diblock copolymer, and precursors into supramolecular micelles. Elongational dynamics of viscoelastic micelle solution together with fast solvent evaporation during electrospinning cause simultaneous close packing and uniaxial stretching of micelles, consequently producing polymer nanofibers consisting of oriented micelles. The method is versatile for the fabrication of large-scale ordered mesoporous nanofibers with adjustable pore diameter and various compositions such as carbon, SiO2, TiO2 and WO3. The aligned longitudinal mesopores connected side-by-side by tiny pores offer highly exposed active sites and expedite electron/ion transport. The assembled electrodes deliver outstanding performance for lithium metal batteries.

A Remarkable Impact of pH on the Thermo-Responsive Properties of Alginate-Based Composite Hydrogels Incorporating P2VP-PEO Micellar Nanoparticles.

A heterograft copolymer with an alginate backbone, hetero-grafted by polymer pendant chains displaying different lower critical solution temperatures (LCSTs), combined with a pH-responsive poly(2-vinyl pyridine)-b-poly(ethylene oxide) (P2VP-b-PEO) diblock copolymer forming micellar nanoparticles, was investigated in aqueous media at various pHs. Due to its thermo-responsive side chains, the copolymer forms hydrogels with a thermo-induced sol-gel transition, above a critical temperature, Tgel (thermo-thickening). However, by lowering the pH of the medium in an acidic regime, a remarkable increase in the elasticity of the formulation was observed. This effect was more pronounced in low temperatures (below Tgel), suggesting secondary physical crosslinking, which induces significant changes in the hydrogel thermo-responsiveness, transforming the sol-gel transition to soft gel-strong gel. Moreover, the onset of thermo-thickening shifted to lower temperatures followed by the broadening of the transition zone, implying intermolecular interactions between the uncharged alginate backbone with the PNIPAM side chains, likely through H-bonding. The shear-thinning behavior of the soft gel in low temperatures provides injectability, which allows potential applications for 3D printing. Furthermore, the heterograft copolymer/nanoparticles composite hydrogel, encapsulating a model hydrophobic drug in the hydrophobic cores of the nanoparticles, was evaluated as a pH-responsive drug delivery system. The presented tunable drug delivery system might be useful for biomedical potential applications.

Structures and interactions forming stable shellac-casein nanocomplexes with a pH-cycle.

Casein forms diverse structures with functionalities tunable by complexation with surfactants, and shellac is an emerging surfactant. In the present work, molecular and mesoscopic structures of shellac and micellar casein and the underlying interactions after treatment with a pH-cycle were investigated. Dispersions with 0.5 % w/v shellac and various shellac:casein mass ratios were prepared at pH 12.0 to dissolve shellac and dissociate casein micelles, followed by neutralization to pH 7.0 to form complexes. Both covalent and non-covalent (hydrogen bonding, electrostatic, and hydrophobic) interactions contributed to the complex formation. The formed complexes had an average diameter of ~80 nm. The complexation of shellac and casein prevented the precipitation of protonated shellac during neutralization, and dispersions with casein:shellac mass ratios of 2:1 and above were absent of precipitates at pH 7.0. The formed nanocomplexes may have applications for preparing novel colloidal systems and loading lipophilic bioactive compounds.

Dendritic polymer prodrug-based unimolecular micelles for pH-responsive co-delivery of doxorubicin and camptothecin with synergistic controlled drug release effect.

Combination chemotherapy has been recognized as a more powerful strategy for tumor treatment rather than the single chemotherapy. However, the interactive mechanism of the two hydrophobic chemotherapeutic drugs has not been explored by now. Aiming for a better synergistic effect, such interactive mechanism was investigated in the present work, by designing CPT@DOX-DPUTEA-PEG nanomedicine with encapsulated camptothecin (CPT) and conjugated doxorubicin (DOX). The synergistic controlled drug release effect was found for the two drugs loaded on the different sites of the dendritic polyurethane core. Synergism was achieved on the HepG2 cells with a combination index (CI) of 0.58 in the in vitro cellular experiments. The results demonstrated the promising application of the unimolecular micelles-based nanomedicine with independently loading of two hydrophobic chemotherapeutic drugs.

Direct radiolabeling of methotrexate and methotrexate micelles with Tc-99m using QbD approach.

The aim of the work presented in this manuscript was to radiolabel methotrexate and prepare radiolabeled methotrexate micelles, an antifolate drug with Tc-99m using QbD approach. The radiolabeling was executed using the experimental design and the radiolabeled drug was further encapsulated in micelles. The authors are of the view that the radiolabeled MTX could be used to target the folate receptor overexpressing cancers such as the kidney, colorectal, breast, brain etc thereby opening newer possibilities to the theranostic applications of the formed conjugate.

Wheat germ agglutinin modified mixed micelles overcome the dual barrier of mucus/enterocytes for effective oral absorption of shikonin and gefitinib.

The combination of shikonin (SKN) and gefitinib (GFB) can reverse the drug resistance of lung cancer cells by affecting energy metabolism. However, the poor solubility of SKN and GFB limits their clinical application because of low bioavailability. Wheat germ agglutinin (WGA) can selectively bind to sialic acid and N-acetylglucosamine on the surfaces of microfold cells and enterocytes, and is a targeted biocompatible material. Therefore, we created a co-delivery micelle system called SKN/GFB@WGA-micelles with the intestinal targeting functions to enhance the oral absorption of SKN and GFB by promoting mucus penetration for nanoparticles via oral administration. In this study, Caco-2/HT29-MTX-E12 co-cultured cells were used to simulate a mucus/enterocyte dual-barrier environment, and HCC827/GR cells were used as a model of drug-resistant lung cancer. We aimed to evaluate the oral bioavailability and anti-tumor effect of SKN and GFB using the SKN/GFB@WGA-micelles system. In vitro and in vivo experimental results showed that WGA promoted the mucus penetration ability of micelles, significantly enhanced the uptake efficiency of enterocytes, improved the oral bioavailability of SKN and GFB, and exhibited good anti-tumor effects by reversing drug resistance. The SKN/GFB@WGA-micelles were stable in the gastrointestinal tract and provided a novel safe and effective drug delivery strategy.

Current approaches in smart nano-inspired drug delivery: A narrative review.

Background and Aim: The traditional drug delivery approach involves systemic administration of a drug that could be nonspecific in targeting, low on efficacy, and with severe side-effects. To address such challenges, the field of smart drug delivery has emerged aiming at designing and developing delivery systems that can target specific cells, tissues, and organs and have minimal off-target side-effects. Methods: A literature search was done to collate papers and reports about the currently available various strategies for smart nano-inspired drug delivery. The databases searched were PubMed, Scopus, and Google Scholar. Based on selection criteria, the most pertinent and recent items were included. Results: Smart drug delivery is a cutting-edge revolutionary intervention in modern medicines to ensure effective and safe administration of therapeutics to target sites. These hold great promise for targeted and controlled delivery of therapeutic agents to improve the efficacy with reduced side-effects as compared to the conventional drug delivery approaches. Current smart drug delivery approaches include nanoparticles, liposomes, micelles, and hydrogels, each with its own advantages and limitations. The success of these delivery systems lies in engineering and designing them, and optimizing their pharmacokinetics and pharmacodynamics properties. Conclusion: Development of drug delivery systems that can get beyond various physiological and clinical barriers, as observed in conventionally administered chemotherapeutics, has been possible through recent advancements. Using multifunctional targeting methodologies, smart drug delivery tries to localize therapy to the target location, reduces cytotoxicity, and improves the therapeutic index. Rapid advancements in research and development in smart drug delivery provide wider and more promising avenues to guarantee a better healthcare system, improve patient outcomes, and achieve higher levels of effective medical interventions like personalized medicine.

Inhibiting the cGAS-STING Pathway in Ulcerative Colitis with Programmable Micelles.

Ulcerative colitis is a chronic condition in which a dysregulated immune response contributes to the acute intestinal inflammation of the colon. Current clinical therapies often exhibit limited efficacy and undesirable side effects. Here, programmable nanomicelles were designed for colitis treatment and loaded with RU.521, an inhibitor of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. STING-inhibiting micelles (SIMs) comprise hyaluronic acid-stearic acid conjugates and include a reactive oxygen species (ROS)-responsive thioketal linker. SIMs were designed to selectively accumulate at the site of inflammation and trigger drug release in the presence of ROS. Our in vitro studies in macrophages and in vivo studies in a murine model of colitis demonstrated that SIMs leverage HA-CD44 binding to target sites of inflammation. Oral delivery of SIMs to mice in both preventive and delayed therapeutic models ameliorated colitis's severity by reducing STING expression, suppressing the secretion of proinflammatory cytokines, enabling bodyweight recovery, protecting mice from colon shortening, and restoring colonic epithelium. In vivo end points combined with metabolomics identified key metabolites with a therapeutic role in reducing intestinal and mucosal inflammation. Our findings highlight the significance of programmable delivery platforms that downregulate inflammatory pathways at the intestinal mucosa for managing inflammatory bowel diseases.

Tumor-Targeted Perfluorinated Micelles as Efficient Theranostic Agents Combining Positron Emission Tomography and Radiosensitization.

We report the synthesis of biocompatible perfluorinated micelles designed to improve radiotherapeutic efficacy in a radioresistant tumor environment. In vitro and in vivo behaviors of perfluorinated micelles were assessed at both cellular and tissular levels. The micellar platform offers key advantages as theranostic tool: (i) small size, allowing deep tissue penetration; (ii) oxygen transport to hypoxic tissues; (iii) negligible toxicity in the absence of ionizing radiation; (iv) internalization into cancer cells; (v) potent radiosensitizing effect; and (vi) excellent tumor-targeting properties, as monitored by positron emission tomography. We have demonstrated strong in vitro radiosensitizing effects of the micelle and in vivo tumor targeting, making this nanometric carrier a promising tool for the potentiation of focused radiotherapy.

Enhancing breast cancer treatment: Comprehensive study of gefitinib-loaded poloxamer 407/TPGS mixed micelles through design, development, in-silico modelling, In-Vitro testing, and Ex-Vivo characterization.

Breast cancer continues to pose a substantial global health challenge, emphasizing the critical need for the advancement of novel therapeutic approaches. Key players in the regulation of apoptosis, a fundamental process in cell death, are the B-cell lymphoma 2 (Bcl-2) family proteins, namely Bcl-2 and Bax. These proteins have garnered attention as highly promising targets for the treatment of breast cancer. Targeting the overexpressed anti-apoptotic Bcl-2 protein in breast cancer, Gefitinib (GEF), an EGFR (Epidermal Growth Factor Receptor) inhibitor, emerges as a potential solution. This study focuses on designing Gefitinib-loaded polymeric mixed micelles (GPMM) using poloxamer 407 and TPGS (D-alpha tocopherol PEG1000 succinate) for breast cancer therapy. In silico analyses unveil strong interactions between GEF- Bcl-2 and TPGS-Pgp-2 receptors, indicating efficacy against breast cancer. Molecular dynamics simulations offer insights into GEF and TPGS interactions within the micelles. Formulation optimization via Design of Experiment ensures particle size and entrapment efficiency within acceptable ranges. Characterization tools such as zeta sizer, ATR-FTIR, XRD, TEM, AFM, NMR, TGA, and DSC confirms particle size, structure, functional groups, and thermodynamic events. The optimized micelles exhibit a particle size of 22.34 ±â€¯0.18 nm, PDI of 0.038 ±â€¯0.009, and zeta potential of -0.772 ±â€¯0.12 mV. HPLC determines 95.67 ±â€¯0.34 % entrapment efficiency and 1.05 ±â€¯0.12 % drug loading capacity. In-vitro studies with MDA-MB-231 cell lines demonstrate enhanced cytotoxicity of GPMM compared to free GEF, suggesting its potential in breast cancer therapy. Cell cycle analysis reveals apoptosis induction through key apoptotic proteins. Western blot results confirm GPMM's ability to trigger apoptosis in MDA-MB-231 cells by activating caspase-3, Bax, Bcl-2, and Parp. In conclusion, these polymeric mixed micelles show promise in selectively targeting cancer cells, warranting future in-vivo studies for optimized clinical application against breast cancer.

Multi-functional Chitosan Polymeric Micelles for improving the oral bioavailability of Paclitaxel based on synergistic effect.

A novel multi-functional micelle delivery system was developed for enhancing the oral absorption of paclitaxel (PTX). The delivery carriers were constructed by modifying chitosan-stearic acid (CS-SA) micelles with L-carnitine (LC) and co-encapsulating quercetin (Que), and the PTX-loaded micelles were prepared by film-sonication dispersing technique. The as-prepared micelles showed homogeneous spherical shapes with a small particle size of 148.3 ± 1.7 nm, high drug loading of 7.05% and low critical micelle concentration (CMC) of 16.89 µg/ml. Compared to the in-house PTX formulation similar to the commercial injection Taxol™, the target PTX-loaded micelles had obvious sustained-release effects and exhibited an oral relative bioavailability of 168.08%. The cellular uptake studies of Caco-2 cells confirmed the micellar modification of LC and the co-loading of Que played important roles in promoting the absorption of drug loaded in micelles. The CYP3A4 enzyme test demonstrated the micelles had an inhibitory effect on the metabolic enzyme due to the presence of Que. These findings confirmed the potential of the multi-functional chitosan polymeric micelles based on synergistic effect as an effective oral delivery system.

Lipase and pH-responsive diblock copolymers featuring fluorocarbon and carboxyl betaine for methicillin-resistant staphylococcus aureus infections.

The emergence of multidrug-resistant bacteria along with their resilient biofilms necessitates the development of creative antimicrobial remedies. We designed versatile fluorinated polymer micelles with surface-charge-switchable properties, demonstrating enhanced efficacy against Methicillin-Resistant Staphylococcus Aureus (MRSA) in planktonic and biofilm states. Polymethacrylate diblock copolymers with pendant fluorocarbon chains and carboxyl betaine groups were prepared using reversible addition-fragmentation chain transfer polymerization. Amphiphilic fluorinated copolymers self-assembled into micelles, encapsulating ciprofloxacin in their cores (CIP@FCBMs) for antibacterial and antibiofilm applications. As a control, fluorine-free copolymer micelles loaded with ciprofloxacin (CIP@BCBMs) were prepared. Although both CIP@FCBMs and CIP@BCBMs exhibited pH-responsive surface charges and lipase-triggered drug release, CIP@FCBMs exhibited powerful antimicrobial and antibiofilm activities in vitro and in vivo, attributed to superior serum stability, higher drug loading, enhanced fluorination-facilitated cellular uptake, and lipase-triggered drug release. Collectively, reversing surface charge, on-demand antibiotic release, and fluorination-mediated nanoparticles hold promise for treating bacterial infections and biofilms.

A normalized parameter for comparison of biofilm dispersants in vitro.

Dispersal of infectious biofilms increases bacterial concentrations in blood. To prevent sepsis, the strength of a dispersant should be limited to allow the immune system to remove dispersed bacteria from blood, preferably without antibiotic administration. Biofilm bacteria are held together by extracellular polymeric substances that can be degraded by dispersants. Currently, comparison of the strength of dispersants is not possible by lack of a suitable comparison parameter. Here, a biofilm dispersal parameter is proposed that accounts for differences in initial biofilm properties, dispersant concentration and exposure time by using PBS as a control and normalizing outcomes with respect to concentration and time. The parameter yielded near-identical values based on dispersant-induced reductions in biomass or biofilm colony-forming-units and appeared strain-dependent across pathogens. The parameter as proposed is largely independent of experimental methods and conditions and suitable for comparing different dispersants with respect to different causative strains in particular types of infection.

Preparation, Characterization, and Hepatoprotective Activity Evaluation of Quercetin-loaded Pluronic® F127/Chitosan-Myristic Acid Mixed Micelles.

BACKGROUND: Quercetin (QTN) is a flavonol antioxidant found in foods, medicinal plants, fruits, vegetables, and beverages. QTN oral consumption produces several biological effects, including antioxidant, cardioprotective, anti-apoptotic, anti-cancer, neuroprotection, anti-hypertensive, and chemo preventive. OBJECTIVE: The study aimed to prepare Pluronic®F127/chitosan-myristic acid copolymer (PF127/C-MAc)-based mixed micelles (QTN MM) to improve the biopharmaceutical and hepatoprotective potential of QTN. METHODS: QTN MM was developed employing thin-film hydration and optimized using full factorial design (FFD). Optimized QTN MM was analyzed using scanning electron microscopy (SEM), differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FT-IR), powder x-ray diffractometry (PXRD), in vitro dissolution, ex vivo permeation, and in vivo antioxidant activity in carbon tetrachloride (CCL4)-induced albino rats. RESULTS: PF127/C-MAc ratio (1:1) with CMC value ~ 5 µg/mL showed the suitability for MM. Characterization supported the formation of MM. QTN MM revealed prominent encapsulation efficiency and drug loading of about ~ 95.10% and ~ 12.28% w/w, respectively. MM spherical shape of QTN with a smaller particle size of ~ 34.08 nm and a higher zeta potential of ~ 36.24 nm indicated excellent physical stability. Dissolution and ex vivo permeation results revealed higher dissolution and permeation of QTN MM compared to QTN and PM. In vivo antioxidant activity suggested that QTN MM at (~ 20 mg/kg, p.o.) restored the enhanced marker enzyme level compared to QTN. CONCLUSION: The findings demonstrate that developed QTN MM could be used as an alternative nanocarrier to increase the biopharmaceutical and hepatoprotective potential of QTN and other flavonoids.