Biocompatible phospholipid-based nanovesicular drug delivery system of ketoprofen: Systematic development, optimization, and preclinical evaluation.

The present work involved development of phospholipid-based permeation enhancing nanovesicles (PENVs) for topical delivery of ketoprofen. Screening of phospholipids and process parameters was performed. Central composite design was used for optimization of factors, that is, amount (%, w/w) of phospholipid and ethanol at three levels. The optimized nanovesicles (NVs) were loaded with different terpenes and then incorporated into a gel base. Optimized NVs exhibited 69% entrapment efficiency, 51% transmittance, 328 nm mean vesicle size, and polydispersity index of 0.25. In vitro release kinetics evaluation indicated best fitting as per Korsemeyer-Peppa's model and drug release via Fickian-diffusion mechanism. The optimized NVs loaded with mint terpene showed minimal degree of deformability and maximal elasticity as compared with the conventional NVs and liposomes. Rheology and texture analysis indicated pseudoplastic flow and smooth texture of the vesicle gel formulation. Ex vivo permeation studies across Wistar rat skin indicated low penetration (0.43-fold decrease) and high skin retention (4.26-fold increase) of ketoprofen from the optimized PENVs gel vis-à-vis the conventional gel. Skin irritancy study indicated lower scores for PENVs gel construing its biocompatible nature. Stability studies confirmed cold storage is best suitable for vesicle gel, and optimized PENVs were found to be suitable for topical delivery of ketoprofen.

Novel therapeutic interventions in cancer treatment using protein and peptide-based targeted smart systems.

Cancer, being the most prevalent and resistant disease afflicting any gender, age or social status, is the ultimate challenge for the scientific community. The new generation therapeutics for cancer management has shifted the approach to personalized/precision medicine, making use of patient- and tumor-specific markers for specifying the targeted therapies for each patient. Peptides targeting these cancer-specific signatures hold enormous potential for cancer therapy and diagnosis. The rapid advancements in the combinatorial peptide libraries served as an impetus to the development of multifunctional peptide-based materials for targeted cancer therapy. The present review outlines benefits and shortcomings of peptides as cancer therapeutics and the potential of peptide modified nanomedicines for targeted delivery of anticancer agents.

EGF-functionalized lipid-polymer hybrid nanoparticles of 5-fluorouracil and sulforaphane with enhanced bioavailability and anticancer activity against colon carcinoma.

The present research work describes development of dual drug-loaded lipid-polymer hybrid nanoparticles (LPHNPs) of anticancer therapeutics for the management of colon cancer. The epidermal growth factor (EGF)-functionalized LPHNPs coloaded with 5-fluorouracil (FU) and sulforaphane (SFN) were prepared by one-step nanoprecipitation method. Box-Behnken design was applied for optimizing the material attributes and process parameters. The optimized LPHNPs revealed particle size 198 nm, polydispersity index 0.3, zeta potential -25.3 mV, and drug loading efficiency 19-20.3% for 5-FU and SFN, respectively. EGF functionalization on LPHNPs was confirmed from positive magnitude of zeta potential to 21.3 mV as compared with the plain LPHNPs. In vitro drug release performance indicated sustained and non-Fickian mechanism release nature of the drugs from LPHNPs. Anticancer activity evaluation in HCT-15 colon cancer cells showed significant reduction (p < 0.001) in the cell growth and cytotoxicity of the investigated drugs from various treatments in the order: EGF-functionalized LPHNPs > plain LPHNPs > free drug suspensions. Overall, the research work corroborated improved treatment efficacy of EGF-functionalized LPHNPs for delivering chemotherapeutic agents for the management of colon carcinoma.

Impact of highly phospholipid-containing lipid nanocarriers on oral bioavailability and pharmacodynamics performance of genistein.

Oxidative stress is a leading cause of different diseases. Genistein is a valuable bioflavonoid possessing antioxidant and anti-inflammatory activity but unfortunately, it suffers from low aqueous solubility, extremely poor bioavailability and first pass effect when used in its pure state. The aim of this work was to formulate and characterize genistein-loaded highly phospholipid-containing lipid nanocarriers to improve oral bioavailability and pharmacodynamic performance. Lipid nanocarriers were prepared by the emulsification/sonication technique. The influence of phospholipid percentage (1%-10%) on physicochemical properties, drug release and stability was investigated. The particle size, zeta potential and EE% were in ranges from 211.9 ± 21.6 to 342.3 ± 7.9 nm, -11.6 ± 1.7 to -19.4 ± 3.1 mV and 78.5 ± 4.7% to 92.2 ± 1.9%, respectively. Drug release was less predominant in the case of SLN formulations when compared to corresponding NLC formulations. High phospholipid percentage produced less stable formulations in terms of particle size growth, gelation and heterogeneous particle distributions. DSC, FT-IR and XRD tools revealed that genistein has existed in an amorphous form in NLC4. The bioavailability of NLC4 was approximately 2.6-fold greater than that of conventional suspension. Additionally, lipid peroxidation in liver homogenate and histopathological alterations in liver and kidney sections were particularly improved, providing a promising strategy for oral administration of genistein.

Nano lipidic carriers for codelivery of sorafenib and ganoderic acid for enhanced synergistic antitumor efficacy against hepatocellular carcinoma.

The current study focuses on the development and evaluation of nano lipidic carriers (NLCs) for codelivery of sorafenib (SRF) and ganoderic acid (GA) therapy in order to treat hepatocellular carcinoma (HCC). The dual drug-loaded NLCs were prepared by hot microemulsion technique, where SRF and GA as the drugs, Precirol ATO5, Capmul PG8 as the lipids, while Solutol HS15 and ethanol was used as surfactant and cosolvents. The optimized drug-loaded NLCs were extensively characterized through in vitro and in vivo studies. The optimized formulation had particle size 29.28 nm, entrapment efficiency 93.1%, and loading capacity 14.21%. In vitro drug release studies revealed>64% of the drug was released in the first 6 h. The enzymatic stability analysis revealed stable nature of NLCs in various gastric pH, while accelerated stability analysis at 25◦C/60% RH indicated the insignificant effect of studied condition on particle size, entrapment efficiency, and loading capacity of NLCs. The cytotoxicity performed on HepG2 cells indicated higher cytotoxicity of SRF and GA-loaded NLCs as compared to the free drugs (p < 0.05). Furthermore, the optimized formulation suppressed the development of hepatic nodules in the Wistar rats and significantly reduced the levels of hepatic enzymes and nonhepatic elements against DEN intoxication. The SRF and GA-loaded NLCs also showed a significant effect in suppressing the tumor growth and inflammatory cytokines in the experimental study. Further, histopathology study of rats treated SRF and GA-loaded NLCs and DEN showed absence of necrosis, apoptosis, and disorganized hepatic parenchyma, etc. over other treated groups of rats. Overall, the dual drug-loaded NLCs outperformed over the plain drugs in terms of chemoprotection, implying superior therapeutic action and most significantly eliminating the hepatic toxicity induced by DEN in Wistar rat model.

Sulfonamide-based 4-anilinoquinoline derivatives as novel dual Aurora kinase (AURKA/B) inhibitors: Synthesis, biological evaluation and in silico insights.

Aurora kinases (AURKs) were identified as promising druggable targets for targeted cancer therapy. Aiming at the development of novel chemotype of dual AURKA/B inhibitors, herein we report the design and synthesis of three series of 4-anilinoquinoline derivatives bearing a sulfonamide moiety (5a-d, 9a-d and 11a-d). The % inhibition of AURKA/B was determined for all target quinolines, then compounds showed more than 50% inhibition on either of the enzymes, were evaluated further for their IC50 on the corresponding enzyme. In particular, compound 9d displayed potent AURKA/B inhibitory activities with IC50 of 0.93 and 0.09 µM, respectively. Also, 9d emerged as the most efficient anti-proliferative analogue in the US-NCI anticancer assay toward the NCI 60 cell lines panel, with broad spectrum activity against different cell lines from diverse cancer subpanels. Docking studies, confirmed that, the sulfonamide SO2 oxygen was involved in a hydrogen bond with Lys162 and Lys122 in AURKA and AURKB, respectively, whereas, the sulfonamide NH could catch hydrogen bond interaction with the surrounding amino acid residues Lys141, Glu260, and Asn261 in AURKA and Lys101, Glu177, and Asp234 in AURKB. Furthermore, N1 nitrogen of the quinoline scaffold formed an essential hydrogen bond with the hinge region key amino acids Ala213 and Ala173 in AURKA and AURKB, respectively.

Brace-related Stress and Quality of Life Parameters between Chêneau and Boston Braces: A Cross-sectional Comparative Study on Adolescent Idiopathic Scoliosis in Saudi Arabia.

OBJECTIVE: Adolescent idiopathic scoliosis (AIS) is the most prevalent spinal deformity affecting healthy children. Although AIS typically lacks symptomatic manifestations, its resultant deformities can affect patients' quality of life (QoL). Evaluating QoL and stress levels is crucial in determining the optimal brace type for AIS patients; however, research comparing the effectiveness of different brace types in this regard is lacking. Therefore, this study aimed to evaluate the impact of Boston versus Chêneau braces on QoL and stress levels in AIS patients. METHODS: This cross-sectional study was conducted at a medical institution in Riyadh, Saudi Arabia, involving 52 eligible patients selected through stratified random sampling based on type of brace as the main stratum. The inclusion criteria were idiopathic scoliosis, age ≥ 10 years, bracing for at least 3 months, and no history of cancer. QoL was evaluated according to the revised Scoliosis Research Society 22-item questionnaire (SRS-22r) and stress levels according to the eight-item Bad Sobernheim stress questionnaire (BSSQ-Brace). Independent-sample t-tests were used to compare brace-related QoL and stress level according to participants' sex and brace type. RESULTS: Overall, 32 participants were treated with Boston braces (seven men and 25 women), with a median (IQR) age of 11.00 years (10.00-13.00), and 20 participants were treated with Chêneau braces (three men, 17 women), with a median (IQR) age of 12.50 years (10.00-14.25). The total SRS-22 score was not significantly different between the brace groups (p = 0.158). However, patients in the Boston brace group reported significantly higher satisfaction levels (median = 4.00, IQR = 3.50-4.50) than did those in the Chêneau brace group (median = 3.25, IQR = 2.38-4.13, p = 0.013, moderate effect size = 0.345, 95% CI = 0.060 to 0.590). Furthermore, the BSSQ-brace total score was significantly higher in the Boston brace group (median = 9.00, IQR = 8.00-12.00) than in the Chêneau brace group (median = 7.50, IQR = 4.75-10.00, p = 0.007, moderate effect size = 0.376, 95% CI = 0.130 to 0.590), indicating higher stress levels in the Chêneau brace group. CONCLUSION: The QoL in AIS patients undergoing brace treatment was comparable across groups. Nonetheless, patients who used Chêneau braces experienced higher stress levels and lower treatment satisfaction rates than did those who used Boston braces. These findings can inform clinical decisions regarding prescription of bracing types and highlight the need for further in-depth research.

A cross-sectional survey: The "Saudi guidelines for the prevention and management of obesity": Awareness and adaptation in Al-Qassim province.

Background: Obesity and overweight are major health problems in Saudi Arabia. In response, with reference to studies both local and from abroad, the Saudi Ministry of Health and the Saudi Arabian Society of Metabolic and Bariatric Surgery recently published the "Saudi Guidelines for the Prevention and Management of Obesity." Aims: We sought to investigate the awareness of and adherence to the "Guidelines" among health care professionals (HCPs) specializing in obesity in Al-Qassim province, Saudi Arabia. Settings and Design: Al-Qassim province, cross-sectional survey. Methods and Materials: In a cross-sectional survey, a three-part questionnaire (i.e., demographic background, information about obesity, and information about the "Guidelines") was distributed among HCPs in Al-Qassim province from January to April 2019. Data analysis was performed in Microsoft Excel. Statistical Analysis Used: Data analysis was performed in Microsoft Excel. Results: Among the 72 HCPs who completed and returned the survey, knowledge of the "Guidelines" was low (40.3%). Most were not even aware of the document's existence (59.7%), and most had not received any training regarding the Saudi obesity control program (55%). Conclusions: The survey's findings suggest that HCPs in Al-Qassim province have limited knowledge about the "Saudi Guidelines for the Prevention and Management of Obesity" and are mostly unaware of the document's existence. Even so, the overwhelming majority (82.8%) of HCPs who were aware have implemented the "Guidelines" in their clinical practice.

Systematic Development of Solid Lipid Nanoparticles of Abiraterone Acetate with Improved Oral Bioavailability and Anticancer Activity for Prostate Carcinoma Treatment.

In the present work, an attempt was undertaken to improve the oral bioavailability and anticancer activity of abiraterone acetate. Solid lipid nanoparticles (SLNs) were developed using the quality by design (QbD) principles and evaluated through in vitro, ex vivo, and in vivo studies. Solid lipid suitability was evaluated by equilibrium solubility study, while surfactant and cosurfactant were screened based on the ability to form microemulsion with the selected lipid. SLNs were prepared by emulsion/solvent evaporation method using glyceryl monostearate, Tween 80, and Poloxamer 407 as the solid lipid, surfactant, and cosurfactant, respectively. Box-Behnken design was applied for optimization of material attributes and evaluating their impact on particle size, polydispersity index, zeta potential, and entrapment efficiency of the SLNs. In vitro drug release study was evaluated in simulated gastric and intestinal fluids. Cell culture studies on PC-3 cells were performed to evaluate the cytotoxicity of the drug-loaded SLNs in comparison to the free drug suspension. Qualitative uptake was evaluated for Rhodamine B-loaded SLNs and compared with free dye solution. Ex vivo permeability was evaluated on Wistar rat intestine and in vivo pharmacokinetic evaluation on Wistar rats for SLNs and free drug suspension. Concisely, the SLNs showed potential for significant improvement in the biopharmaceutical performance of the selected drug candidate over the existing formulations of abiraterone acetate.

Hispolon-Loaded Liquid Crystalline Nanoparticles: Development, Stability, In Vitro Delivery Profile, and Assessment of Hepatoprotective Activity in Hepatocellular Carcinoma.

The present work describes the development and characterization of liquid crystalline nanoparticles of hispolon (HP-LCNPs) for treating hepatocellular carcinoma. HP-LCNPs were prepared by a top-down method utilizing GMO as the lipid and Pluronic F-127 as the polymeric stabilizer. The prepared formulations (HP1-HP8) were tested for long-term stability, where HP5 showed good stability with a particle size of 172.5 ± 0.3 nm, a polydispersity index (PDI) of 0.38 ± 0.31 nm, a zeta potential of -10.12 mV ± 0.05, an entrapment efficiency of 86.81 ± 2.5%, and a drug loading capacity of 12.51 ± 1.12%. Optical photomicrography and transmission electron microscopy images demonstrated a consistent, low degree of aggregation and a spherical shape of LCNPs. The effect of temperature and pH on the optimized formulation (HP5) indicated good stability at 45 °C and at pH between 2 and 5. In vitro gastrointestinal stability indicated no significant change in the particle size, PDI, and entrapment efficiency of the drug. The drug release study exhibited a biphasic pattern in simulated gastric fluid (pH 1.2) for 2 h and simulated intestinal fluid (pH 7.4) for up to 24 h, while the best fitting of the profile was observed with the Higuchi model, indicating the Fickian diffusion mechanism. The in vivo pharmacokinetic study demonstrated nearly 4.8-fold higher bioavailability from HP5 (AUC: 1774.3 ± 0.41 µg* h/mL) than from the HP suspension (AUC: 369.11 ± 0.11 µg* h/mL). The anticancer activity evaluation revealed a significant improvement in antioxidant parameters and serum hepatic biomarkers (SGOT, SGPT, ALP, total bilirubin, and GGT) in the diethyl nitrosamine-treated group of rats with the optimized LCNP formulation (HP5) vis-à-vis HP suspension.

Therapeutic potential of nanoemulsions as feasible wagons for targeting Alzheimer's disease.

Alzheimer's disease (AD) is an irreversible dementia state with characteristic clinical manifestations, including declining cognitive skills and loss of memory, which particularly affects the older population. Despite significant efforts in the field of nano-based drug delivery, there have been few successes achieved in the design of a rational drug therapy. Nanoemulsions (NEs) have potential for the delivery of AD therapeutics owing to their capability for brain drug delivery. Still, there is a long way to go before such therapeutics become a reality in the clinic. In this review, we highlight the preclinical assessment of NEs for AD and discuss the regulatory constraints to their clinical acceptance.

Mucoadhesive In Situ Rectal Gel Loaded with Rifampicin: Strategy to Improve Bioavailability and Alleviate Liver Toxicity.

Although it is a front-line in tuberculosis treatment, rifampicin (RF) exhibits poor oral bioavailability and hepatotoxicity. Rectal mucoadhesive and in situ rectal gels were developed to overcome drug drawbacks. A RF/polyethylene glycol 6000 co-precipitate was first prepared in different ratios. Based on the drug solubility, the selected ratio was investigated for drug/polymer interaction and then incorporated into in situ rectal gels using Pluronic F127 (15%) and Pluronic F68 (10%) as a gel base and mucoadhesive polymers (HPMC, sodium alginate and chitosan). The formulations were assessed for gelation temperature and gel strength. The selected formulation was investigated for in vivo assessments. The results showed that a 1:1 drug/polymer ratio exhibited satisfying solubility with the recorded drug/polymer interaction. Depending on their concentrations, adding mucoadhesive polymers shifted the gelation temperature to lower temperatures and improved the gel strength. The selected formulation (F4) did not exhibit any anal leakage or marked rectal irritation. Using a validated chromatographic analytical method, F4 exhibited higher drug absorption with a 3.38-fold and 1.74-fold higher bioavailability when compared to oral drug suspension and solid suppositories, respectively. Toxicity studies showed unnoticeable hepatic injury in terms of biochemical, histopathological and immunohistochemical examinations. Together, F4 showed a potential of enhanced performance and also offered lower hepatic toxicity, thus offering an encouraging therapeutic alternative.

Three 'D's: Design approach, dimensional printing, and drug delivery systems as promising tools in healthcare applications.

The development of pharmaceutical drug products is required for the treatment of disease, which has resulted in an increasing number of approvals by regulatory agencies across the globe. To establish a hassle-free manufacturing process, the systematic use of a quality-by-design (QbD) approach combined with process analytical technology (PAT) and printing techniques can revolutionize healthcare applications. Printing technology has been emerged in various dimensions, such as 3D, 4D, and 5D printing, with respect to their production capabilities, durability, and accuracy of pharmaceutical manufacturing, which can efficiently deliver novel patient-centric healthcare products with holistic characteristics. In this review, we provide current trends in pharmaceutical product development using a design approach and high-quality printing techniques.

Identification of N-phenyl-2-(phenylsulfonyl)acetamides/propanamides as new SLC-0111 analogues: Synthesis and evaluation of the carbonic anhydrase inhibitory activities.

As a front-runner selective CA IX inhibitor currently in Phase Ib/II clinical trials, SLC-0111 has been herein exploited as a lead molecule for development of new different sets of N-phenyl-2-(phenylsulfonyl)acetamides/propanamides incorporating different functionalities; primary sulfonamide (5a-f), free carboxylic (8a, 8d), ethyl ester (8b, 8e), acetyl (8c, 8f) and nitro (10a, 10b), as potential carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. All the prepared analogues have been examined for their CA inhibitory activities towards four human (h) isoenzymes, hCA I, II, IX and XII. Interestingly, replacement of SLC-0111 ureido linker with the flexible sulfonyl acetamide linker, as well as linker branching and elongation strategies successfully enhanced the inhibitory action toward hCA IX isoform, such as in sulfones 5a-d and 5f which displayed better activity than SLC-0111. Furthermore, sulfonamide-based sulfone (5f) and carboxylic acid-based sulfones (8a and 8d) demonstrated interesting selectivity toward the tumor-related hCA IX isoform over both hCA I and hCA II, which suggests them as promising candidates for further development as potential anticancer candidates. Thereafter, the anti-proliferative action for sulfones 5f, 8a and 8d was examined against breast (MCF-7) and colon (HCT-116) cancer cell lines. Also, sulfone 5f was further assessed for its impact on the cell cycle progression and apoptosis in HCT-116 cells.

Lipid/polymer-based nanocomplexes in nucleic acid delivery as cancer vaccines.

Cancer vaccines consist of nucleic acid derivatives such as plasmid DNA, small interfering RNA and mRNA, and can be customized according to the patient's needs. Nanomedicines have proven to be exceptionally good as miniaturized drug carriers, and thus they offer great advantages for delivering cancer vaccines. This review provides an overview of the literature on cancer vaccines, from their inception to current developments in the field.

Evaluation of Ligustrazine-Based Synthetic Compounds for their Antiproliferative Effects.

BACKGROUND: Ligustrazine and chalcones have been reported previously for various biological activities including anticancer effects. OBJECTIVES: Based on the multitargeted biological activities approach of ligustrazine-based chalcones, in the current study 18 synthetic ligustrazine-containing α, ß-unsaturated carbonyl-based 1, 3- Diphenyl-2-propen-1-one derivatives were evaluated for their inhibitory effects on the growth of five different types of cancer cells. METHODS: All the compounds were evaluated for anticancer effects on various cancer cell lines by propidium iodide fluorescence assay and various other assays were performed for mechanistic studies. RESULTS: A majority of compounds exhibited strong inhibition of cancer cells, especially synthetic compounds 4a and 4b, bearing 1-Pyridin-3-yl-ethanone as a ketone moiety in the main structural backbone were found to be most powerful inhibitors of cancer cell growth. Nine most active compounds among the whole series were selected for further studies related to different cancer targets, including EGFR TK kinases, tubulin polymerization, KAF and BRAFV600E. CONCLUSION: Synthetic derivatives, including 4a-b and 5a-b showed a multitarget approach and strong inhibitory effects on EGFR, FAK and BRAF while three compounds, including 3e bearing methoxy substitution, 4a and 4b with 1-pyridin-3-yl-ethanone moiety showed the inhibition of tubulin polymerization.

Superbranched polyglycerol nanostructures as drug delivery and theranostics tools for cancer treatment.

Hyperbranched polymers (HBPs), such as hyperbranched polyglycerols (HPGs) with a dendritic configuration, have been recognized for their excellent biocompatibility and multifunctionalization. HPGs have been studied for use in the delivery diagnostic, imaging and therapeutic molecules in the area of nanobiomedicine. They show superior characteristics to linear polymers and dendrimers, such as compact structure, a simple manufacturing process with easy functionalization ability, low viscosity, and high stability. Owing to these advantages, HPGs are now considered promising carriers for drug delivery, diagnostics, imaging, and theranostics applications for cancer treatment. In this review, we also discuss safety aspects of HPG-based nanoformulations in various animal models and the clinical translation status of such polymers for real-time applications.

Nanocarriers-loaded with natural actives as newer therapeutic interventions for treatment of hepatocellular carcinoma.

Introduction: Cancer has always been a menace for the society. Hepatocellular carcinoma (HCC) is one of the most lethal and 3rdlargest causes of deaths around the world.Area covered: The emergence of natural actives is considered as the greatest boon for fighting cancer. The natural actives take precedence over the traditional chemotherapeutic drugs in terms of their multi-target, multi-level and coordinated effects in the treatment of HCC. Literature reports have indicated the tremendous potential of bioactive natural products in inhibiting the HCC via molecular drug targeting, augmented bioavailability, and the ability for both passive or active targeting and stimulus-responsive drug release characteristics. This review provides a newer treatment approaches involved in the mechanism of action of different natural actives used for the HCC treatment via different molecular pathways. Besides, the promising advantage of natural bioactive-loaded nanocarriers in HCC treatment has also been also presented in this review. Expert opinion: The remarkable outcomes have been observed with therapeutic efficacy of the nanocarriers of natural actives in the treatment of HCC.Furthermore, it requires a thorough assessment of the safety and efficacy evaluation of the nanocarriers for the delivery of targeted natural active ingredients in HCC.].

Nucleic acid-loaded lipid-polymer nanohybrids as novel nanotherapeutics in anticancer therapy.

INTRODUCTION: Since decades, cancer is a major public health problem worldwide. The increasing knowledge of molecular and tumor biology has significantly changed the cancer treatment paradigms during the past few years. AREA COVERED: Conventionally, the first-line treatment of solid tumors is their surgical removal followed by chemotherapy and/or radiation treatment. Unfortunately, these approaches often fail, and the patient may discontinue the treatment before the complete eradication of tumors due to therapeutic and toxicological limitations. In this regard, the nucleic acid-based treatment therapy has been widely used in the management of cancer. However, nucleic acid delivery to the target sites is highly challenging because of their molecular size, difficulties to pass cellular membranes, and susceptibility toward enzymatic and/or chemical degradation. EXPERT OPINION: Researchers have now overcome many problems associated with delivering nucleic acids to the target tissues by preventing them from off-target side effects and overcoming rapid degradation and clearance in the bloodstream using the lipid-polymer hybrid nanoparticles (LPHNs). The present review, therefore, aims to provide an overview account on LPNHs, their preparation, characterization, application with special emphasis on intracellular delivery/transfection of nucleic acids in the management of cancer, and key aspects of challenges in its delivery and clinical transition.

Inhibition of Bruton tyrosine kinase by acalabrutinib dampens lipopolysaccharide/galactosamine-induced hepatic damage.

Bruton tyrosine kinase (BTK) sits at the crossroads of adaptive and innate immunities. Nevertheless, the detailed role of BTK activation in hepatic inflammatory disorders is still elusive to date. Accordingly, we investigated the impact of blocking BTK activation by acalabrutinib (ACB) on lipopolysaccharide/galactosamine (LPS/D-GaIN)-induced deleterious manifestations in the liver. This was achieved by pretreating mice with ACB (6, 12 or 24 mg/kg, oral) 2 h before challenge with LPS/D-GaIN (70 µg/kg and 700 mg/kg, respectively, i.p.) for 6 h. The results showed that ACB (6 and 12 mg/kg) (i) curbed LPS/D-GaIN-induced rise in biochemical (serum ALT, AST and LDH) and histological (necrosis, degeneration and congestion scores) indices of hepatocellular injury; (ii) attenuated LPS/D-GaIN-induced elevation in parameters of hepatocellular apoptosis (cleaved caspase 3) and proliferation (PCNA); and (iii) importantly, mitigated LPS/D-GaIN-induced recruitment and infiltration of the inflammatory cells to the liver evidenced by lowering elevated serum MCP-1 concentration and hepatic F4/80 immunostaining. These effects were linked to ACB dose-dependent inhibition of NF-κB nuclear translocation that subsequently reduced LPS/D-GaIN-mediated release of TNF-α, IL-1ß and IL-22 in the blood circulation. However, a dose of 12 mg/kg of ACB elevated the hepatic TNF-α, IL-1ß and IL-22 concentrations that arose from a compensatory activation of ERK and JNK. Inhibition of BTK also attenuated LPS/D-GaIN-induced overexpression of CD98, which is another contributor alongside cytokines for monocyte recruitment. Therapeutically, targeting BTK by ACB is an efficient approach for hitting multiple points with one agent that can dampen hepatocellular injury, death, immune cell recruitment and inflammation cascade.