Optimized mucoadhesive niosomal carriers for intranasal delivery of carvedilol: A quality by design approach.

Carvedilol (CV), a ß-blocker essential for treating cardiovascular diseases, faces bioavailability challenges due to poor water solubility and first-pass metabolism. This study developed and optimized chitosan (CS)-coated niosomes loaded with CV (CS/CV-NS) for intranasal (IN) delivery, aiming to enhance systemic bioavailability. Utilizing a Quality-by-Design (QbD) approach, the study investigated the effects of formulation variables, such as surfactant type, surfactant-to-cholesterol (CHOL) ratio, and CS concentration, on CS/CV-NS properties. The focus was to optimize specific characteristics including particle size (PS), polydispersity index (PDI), zeta potential (ZP), entrapment efficiency (EE%), and mucin binding efficiency (MBE%). The optimal formulation (Opt CS/CV-NS), achieved with a surfactant: CHOL ratio of 0.918 and a CS concentration of 0.062 g/100 mL, using Span 60 as the surfactant, exhibited a PS of 305 nm, PDI of 0.36, ZP of + 33 mV, EE% of 63 %, and MBE% of 57 %. Opt CS/CV-NS was characterized for its morphological and physicochemical properties, evaluated for stability under different storage conditions, and assessed for in vitro drug release profile. Opt CS/CV-NS demonstrated a 1.7-fold and 4.8-fold increase in in vitro CV release after 24 h, compared to uncoated CV-loaded niosomes (Opt CV-NS) and free CV, respectively. In vivo pharmacokinetic (PK) study, using a rat model, demonstrated that Opt CS/CV-NS achieved faster Tmax and higher Cmax compared to free CV suspension indicating enhanced absorption rate. Additionally, Opt CV-NS showed a 1.68-fold higher bioavailability compared to the control. These results underscore the potential of niosomal formulations in enhancing IN delivery of CV, offering an effective strategy for improving drug bioavailability and therapeutic efficacy.

Lauric acid-based thermosensitive delivery system for the treatment of head and neck squamous cell carcinoma.

Traditional treatments for head and neck squamous cell carcinoma (HNSCC) such as surgery, radiation therapy, and chemotherapy, often have severe side effects. Local delivery of chemotherapeutic agents can be a promising approach to minimise systemic toxicity and improve efficacy. Lauric acid (LA), was explored as a novel injectable thermosensitive drug reservoir as a depot for sustained release of anticancer drugs to treat HNSCC. LA was characterised in terms of melting temperature and gelation time. The efficacy of LA-based drug formulations was tested in vitro in a HNSCC cell line and in vivo in a mouse model of HNSCC. LA was modified to have a melting point of 38.5 °C and a gelation time of 40 s at 37.5 °C, rendering it suitable for injection at body temperature. LA- based doxorubicin (DOXO) formulation showed slow release with a maximum of 18% release after 3 days. The in vitro study showed that LA enhanced the cytotoxic effect of DOXO. LA combined with DOXO prevented tumour progression and LA alone significantly reduced the original tumour volume compared to the untreated control group. These findings confirmed that LA can function as practical carrier for the local delivery of chemotherapeutics and provides a safe and simple strategy for the delivery of hydrophobic anticancer drugs and warrant further testing in clinical trials.

Embedding patient safety in a scaffold of interprofessional education; a qualitative study with thematic analysis.

BACKGROUND: Regardless of a proliferation of interest in reducing unsafe practices in healthcare, threats to patient safety (PS) remain high. Moreover, little attention has been paid towards the role of interprofessional education (IPE) in enhancing PS. This qualitative study was conducted to unfold the insights of the senior medical, dental and health sciences students at the University of Sharjah (UoS) in the United Arab Emirates (UAE) about PS in an online IPE-based workshop. METHODS: This inductive thematic analysis study was conducted on senior medical and health students at the Colleges of Medicine, Dental Medicine, Health Sciences, and Pharmacy of UoS. During an online workshop, students discussed plausible solutions for four real practice-based clinical scenarios with elements of unsafe healthcare practices. During the breakout rooms, the students exhibited high level of articulation and proactively participated in discussions. The data from the online workshop were transcribed and then coding, categorizing, and labelling of recurrent themes were carried out. Multiple individual deliberations, consolidation, incorporation of the identified preliminary themes, and merging and reorganizing sub-themes led to a final thematic framework. RESULTS: This work delved into the perspectives of 248 students regarding teamwork, communication, problem-solving, and other aspects concerning PS in interprofessional settings in an online workshop. The iterative process of data transcription, curating and qualitative analysis surfaced 32 codes. Later, the inductive themaric analysis yielded five themes with distinct yet interconnected nested subthemes in the context of PS in IPE settings. These themes of information sharing and grounding (problem-solving, social skills), maintaining communication (clinical reasoning, shared mental model), executing interprofessional activities (collaborative practice, collaboration scripts), professional cognitive abilities (cognitive maturity, metacognition), and negotiating professional identities (systematic change, socio-economic scaffolding) emerged as fundamental pillars for enhancing PS in healthcare. CONCLUSION: Our study demonstrated the outcome of an innovative and team-based workshop which embedded PS within a scaffold of IPE environment. This research calls for incorporation of the emerging areas of clinical reasoning, problem solving, collaborative practice, and shared mental model into medical curricula for structured IPE in improving PS domains in medical education. These findings underscore the need for multifaceted dimensions of IPE imperatives for cultivating collaborative competence.

Exosomes Interactions with the Blood-Brain Barrier: Implications for Cerebral Disorders and Therapeutics.

The Blood-Brain Barrier (BBB) is a selective structural and functional barrier between the circulatory system and the cerebral environment, playing an essential role in maintaining cerebral homeostasis by limiting the passage of harmful molecules. Exosomes, nanovesicles secreted by virtually all cell types into body fluids, have emerged as a major mediator of intercellular communication. Notably, these vesicles can cross the BBB and regulate its physiological functions. However, the precise molecular mechanisms by which exosomes regulate the BBB remain unclear. Recent research studies focused on the effect of exosomes on the BBB, particularly in the context of their involvement in the onset and progression of various cerebral disorders, including solid and metastatic brain tumors, stroke, neurodegenerative, and neuroinflammatory diseases. This review focuses on discussing and summarizing the current knowledge about the role of exosomes in the physiological and pathological modulation of the BBB. A better understanding of this regulation will improve our understanding of the pathogenesis of cerebral diseases and will enable the design of effective treatment strategies.

Co-administration of amoxicillin-loaded chitosan nanoparticles and inulin: A novel strategy for mitigating antibiotic resistance and preserving microbiota balance in Helicobacter pylori treatment.

Helicobacter pylori (H. pylori) is a causative agent of various gastrointestinal diseases and eradication mainly relies on antibiotic treatment, with (AMX) being a key component. However, rising antibiotic resistance in H. pylori necessitates the use of antibiotics combination therapy, often disrupting gut microbiota equilibrium leading to further health complications. This study investigates a novel strategy utilizing AMX-loaded chitosan nanoparticles (AMX-CS NPs), co-administered with prebiotic inulin to counteract H. pylori infection while preserving microbiota health. Following microbroth dilution method, AMX displayed efficacy against H. pylori, with a MIC50 of 48.34 ± 3.3 ng/mL, albeit with a detrimental impact on Lactobacillus casei (L. casei). The co-administration of inulin (500 µg/mL) with AMX restored L. casei viability while retaining the lethal effect on H. pylori. Encapsulation of AMX in CS-NPs via ionic gelation method, resulted in particles of 157.8 ± 3.85 nm in size and an entrapment efficiency (EE) of 86.44 ± 2.19 %. Moreover, AMX-CS NPs showed a sustained drug release pattern over 72 h with no detectable toxicity on human dermal fibroblasts cell lines. Encapsulation of AMX into CS NPs also reduced its MIC50 against H. pylori, while its co-administration with inulin maintained L. casei viability. Interestingly, treatment with AMX-CS NPs also reduced the expression of the efflux pump gene hefA in H. pylori. This dual treatment strategy offers a promising approach for more selective antimicrobial treatment, minimizing disruption to healthy microbial communities while effectively addressing pathogenic threats.

Unmasking the enigma: An in-depth analysis of COVID-19 impact on the pediatric population.

OBJECTIVES: COVID-19, caused by the novel coronavirus, has had a profound and wide-reaching impact on individuals of all age groups across the globe, including children. This review article aims to provide a comprehensive analysis of COVID-19 in children, covering essential topics such as epidemiology, transmission, pathogenesis, clinical features, risk factors, diagnosis, treatment, vaccination, and others. By delving into the current understanding of the disease and addressing the challenges that lie ahead, this article seeks to shed light on the unique considerations surrounding COVID-19 in children and contribute to a deeper comprehension of this global health crisis affecting our youngest population. METHODS: A comprehensive literature search was conducted to gather the most recent and relevant information regarding COVID-19 in children. Multiple renowned databases, including MEDLINE, PubMed, Scopus, as well as authoritative sources such as the World Health Organization (WHO), the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the National Institutes of Health (NIH) websites and others were thoroughly searched. The search included articles, guidelines, reports, clinical trials results and expert opinions published within the past three years, ensuring the inclusion of the latest research findings on COVID-19 in children. Several relevant keywords, including "COVID-19," "SARS-CoV-2," "children," "pediatrics," and related terms were used to maximize the scope of the search and retrieve a comprehensive set of articles. RESULTS AND CONCLUSION: Three years since the onset of the COVID-19 pandemic, our understanding of its impact on children has evolved, but many questions remain unanswered. While SAR-CoV-2 generally leads to mild illness in children, the occurrence of severe cases and the potential for long-term effects cannot be overlooked. Efforts to comprehensively study COVID-19 in children must continue to improve preventive strategies, identify high-risk populations, and ensure optimal management. By unraveling the enigma surrounding COVID-19 in children, we can strive towards safeguarding their health and well-being in the face of future global health challenges.

Integrated multi-omics analysis reveals unique signatures of paclitaxel-loaded poly(lactide-co-glycolide) nanoparticles treatment of head and neck cancer cells.

The use of poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) as carriers for chemotherapeutic drugs is regarded as an actively targeted nano-therapy for the specific delivery of anti-cancer drugs to target cells. However, the exact mechanism by which PLGA NPs boost anticancer cytotoxicity at the molecular level remains largely unclear. This study employed different molecular approaches to define the response of carcinoma FaDu cells to different types of treatment, specifically: paclitaxel (PTX) alone, drug free PLGA NPs, and PTX-loaded PTX-PLGA NPs. Functional cell assays revealed that PTX-PLGA NPs treated cells had a higher level of apoptosis than PTX alone, whereas the complementary, UHPLC-MS/MS (TIMS-TOF) based multi-omics analyses revealed that PTX-PLGA NPs treatment resulted in increased abundance of proteins associated with tubulin, as well as metabolites such as 5-thymidylic acid, PC(18:1(9Z)/18:1(9Z0), vitamin D, and sphinganine among others. The multi-omics analyses revealed new insights about the molecular mechanisms underlying the action of novel anticancer NP therapies. In particular, PTX-loaded NPs appeared to exacerbate specific changes induced by both PLGA-NPs and PTX as a free drug. Hence, the PTX-PLGA NPs' molecular mode of action, seen in greater detail, depends on this synergy that ultimately accelerates the apoptotic process, resulting in cancer cell death.

Peptide-functionalized zinc oxide nanoparticles for the selective targeting of breast cancer expressing placenta-specific protein 1.

Functionalized metal oxide nanoparticles (NPs) have demonstrated specific binding affinity to antigens or receptors presented on the cancer cell surface, favouring selective targeting and minimizing side effects during the chemotherapy. Placenta-specific protein 1 (PLAC-1) is a small cell surface protein overexpressed in certain types of breast cancer (BC); therefore, it can be used as a therapeutic target. The objective of this study is to develop NPs that can bind PLAC-1 and hence can inhibit the progression and metastatic potential of BC cells. Zinc oxide (ZnO) NPs were coated with a peptide (GILGFVFTL), which possesses a strong binding ability to PLAC-1. The physical attachment of the peptide to ZnO NPs was verified through various physicochemical and morphological characterization techniques. The selective cytotoxicity of the designed NPs was investigated using PLAC-1-bearing MDA-MB 231 human BC cell line and compared to LS-180 cells that do not express PLAC-1. The anti-metastatic and pro-apoptotic effects of the functionalized NPs on MDA-MB 231 cells were examined. Confocal microscopy was used to investigate the mechanism of NPs uptake by MDA-MB 231 cells. Compared to non-functionalized NPs, peptide functionalization significantly improved the targeting and uptake of the designed NPs by PLAC-1-expressing cancer cells with significant pro-apoptotic and anti-metastatic effects. The uptake of peptide functionalized ZnO NPs (ZnO-P NPs) occurred via peptide-PLAC1 interaction-assisted clathrin-mediated endocytosis. These findings highlight the potential targeted therapy of ZnO-P NPs against PLAC-1-expressing breast cancer cells.

Peptide-functionalized graphene oxide quantum dots as colorectal cancer theranostics.

Colorectal cancer (CRC) accounts for approximately 10% of all new cancer cases worldwide with significant morbidity and mortality. The current imaging techniques are lacking diagnostic precision while traditional chemotherapeutic strategies are limited by their adverse side effects and poor response in advanced stages. Targeted nanoparticles (NPs) can specifically bind to surface antigens on cancer cells and provide effective delivery of diagnostic and chemotherapeutic agent. Placenta-specific protein 1 (PLAC-1) is overexpressed in CRC and can be used as a target for detection and treatment of the disease. The aim of this work was to develop a targeted nanotheranostic agent for early diagnosis and inhibition of the malignant progression and metastasis of CRC. Graphene oxide quantum dots (QD) were covalently labeled with a peptide (GILGFVFTL) having high affinity to PLAC-1. The covalent coupling between the QD and the peptide was confirmed using a series of physicochemical and morphological characterization techniques. Confocal microscopy was used to evaluate the uptake of QD and QD-P in HCT-29, HT-116 and LS-180 CRC cell lines. Selective targeting of antigen PLAC-1 overexpressed on HT-29 and HCT-116 cells was measured by immunofluorescence. Cell proliferation, cell invasion and extent of PLAC-1 expression in CRC cells after treatment with QD and QD-P were determined. The prepared QD-P showed a significant increase in targeting and specific uptake in cells expressing the antigen PLAC-1 compared to non-functionalized QD. Treatment with QD-P also increased the cell cytotoxicity, reduced the invasiveness of HT-29 and HCT-116 cells by 38% and 62%, respectively, and downregulated the expression of PLAC-1 by 53% and 33%, respectively. These results highlight the potential use of QD-P as a theranostic agent for the detection and treatment of CRC cells expressing the antigen PLAC-1.

Hyperthermia of Magnetically Soft-Soft Core-Shell Ferrite Nanoparticles.

Magnetically soft-soft MnFe2O4-Fe3O4 core-shell nanoparticles were synthesized through a seed-mediated method using the organometallic decomposition of metal acetyl acetonates. Two sets of core-shell nanoparticles (S1 and S2) of similar core sizes of 5.0 nm and different shell thicknesses (4.1 nm for S1 and 5.7 nm for S2) were obtained by changing the number of nucleating sites. Magnetic measurements were conducted on the nanoparticles at low and room temperatures to study the shell thickness and temperature dependence of the magnetic properties. Interestingly, both core-shell nanoparticles showed similar saturation magnetization, revealing the ineffective role of the shell thickness. In addition, the coercivity in both samples displayed similar temperature dependencies and magnitudes. Signatures of spin glass (SG) like behavior were observed from the field-cooled temperature-dependent magnetization measurements. It was suggested to be due to interface spin freezing. We observed a slight and non-monotonic temperature-dependent exchange bias in both samples with slightly higher values for S2. The effective magnetic anisotropy constant was calculated to be slightly larger in S2 than that in S1. The magnetothermal efficiency of the chitosan-coated nanoparticles was determined by measuring the specific absorption rate (SAR) under an alternating magnetic field (AMF) at 200-350 G field strengths and frequencies (495.25-167.30 kHz). The S2 nanoparticles displayed larger SAR values than the S1 nanoparticles at all field parameters. A maximum SAR value of 356.5 W/g was obtained for S2 at 495.25 kHz and 350 G for the 1 mg/mL nanoparticle concentration of ferrogel. We attributed this behavior to the larger interface SG regions in S2, which mediated the interaction between the core and shell and thus provided indirect exchange coupling between the core and shell phases. The SAR values of the core-shell nanoparticles roughly agreed with the predictions of the linear response theory. The concentration of the nanoparticles was found to affect heat conversion to a great extent. The in vitro treatment of the MDA-MB-231 human breast cancer cell line and HT-29 human colorectal cancer cell was conducted at selected frequencies and field strengths to evaluate the efficiency of the nanoparticles in killing cancer cells. The cellular cytotoxicity was estimated using flow cytometry and an MTT assay at 0 and 24 h after treatment with the AMF. The cells subjected to a 45 min treatment of the AMF (384.50 kHz and 350 G) showed a remarkable decrease in cell viability. The enhanced SAR values of the core-shell nanoparticles compared to the seeds with the most enhancement in S2 is an indication of the potential for tailoring nanoparticle structures and hence their magnetic properties for effective heat generation.

Graphene Oxide/Chitosan Injectable Composite Hydrogel for Controlled Release of Doxorubicin: An Approach for Enhanced Intratumoral Delivery.

Intratumoral (IT) injection of chemotherapeutics into needle-accessible solid tumors can directly localize the anticancer drug in the tumor site, thus increasing its local bioavailability and reducing its undesirable effects compared to systemic administration. In this study, graphene oxide (GO)-based chitosan/ß-glycerophosphate (CS/GP) thermosensitive injectable composite hydrogels (CH) were prepared and optimized for the localized controlled delivery of doxorubicin (DOX). A quality-by-design (QbD) approach was used to study the individual and combined effects of several formulation variables to produce optimal DOX-loaded GO/CS/GP CH with predetermined characteristics, including gelation time, injectability, porosity, and swelling capacity. The surface morphology of the optimal formulation (DOX/opt CH), chemical interaction between its ingredients and in vitro release of DOX in comparison to GO-free CS/GP CH were investigated. Cell viability and cellular uptake after treatment with DOX/opt CH were studied on MCF 7, MDB-MB-231 and FaDu cell lines. The statistical analysis of the measured responses revealed significant effects of the concentration of GO, the concentration of CS, and the CS:GP ratio on the physicochemical characteristics of the prepared GO/CS/GP CH. The optimization process showed that DOX-loaded GO/CS/GP CH prepared using 0.1% GO and 1.7% CS at a CS: GO ratio of 3:1 (v/v) had the highest desirability value. DOX/opt CH showed a porous microstructure and chemical compatibility between its ingredients. The incorporation of GO resulted in an increase in the ability of the CH matrices to control DOX release in vitro. Finally, cellular characterization showed a time-dependent increase in cytotoxicity and cellular uptake of DOX after treatment with DOX/opt CH. The proposed DOX/opt CH might be considered a promising injectable platform to control the release and increase the local bioavailability of chemotherapeutics in the treatment of solid tumors.

In Vivo Evaluation of Anti-Nociceptive Effects of Silver Nanoparticles.

Silver nanoparticles (AgNPs) are widely used commercially due to their antimicrobial effects. Little is known about the effect of AgNPs on neural transmission and pain response. The aim of this study was to assess the anti-nociceptive activity of AgNPs. AgNPs were prepared at 16 ug/mL, white albino rats were injected with various doses of AgNPs, and challenged using a hot-plate test and paw withdrawal latency (PWL) was measured. The chronic constriction injury (CCI) model was utilized to evaluate the pedal withdrawal reflex and tail withdrawal reflex. An electrophysiological study was conducted utilizing colon longitudinal muscle strips. AgNPs increased the latency of PWL in a dose-dependent matter over the duration of 6 h. The paw withdrawal threshold in animals with CCI significantly increased after AgNPs administration. In isolated colon longitudinal muscle strips, AgNPs significantly reduced the colonic migrating motor complexes (MMCs) and contraction. This action was completely reversed after removing the AgNPs and adding acetylcholine to the preparation. In this study, AgNPs showed significant anti-nociception properties. To our knowledge, this is the first report to describe this pharmacological action of AgNPs.

Radiofrequency thermoablation of the peripheral branches of trigeminal nerve versus the Gasserian ganglion for treating idiopathic trigeminal neuralgia: A systematic review and meta-analysis.

BACKGROUND: Trigeminal neuralgia is characterized by pain at the distribution of one or more of the trigeminal nerve branches and is usually treated with anti-epileptic medication. When first line treatment fails, patients receive other treatment modalities including radiofrequency thermoablation (RFT) of the Gasserian ganglion and peripheral branches of the trigeminal nerve. The aim of this study is to compare RFT of the Gasserian ganglion and peripheral branches of trigeminal nerve in terms of efficacy and rate of complications. METHODS: This was a systematic review and meta-analysis that searched Medline, Cochrane Central Register of Controlled Trials, and Embase using Medical Subject Headings and the references of the enrolled studies with no restriction on date. We included only RCTs that compared the RFT of the Gasserian ganglion and peripheral branches of trigeminal nerve with one of the following outcomes: pain scales, immediate effective rate, recurrence rate, and complications. RESULTS: Five articles were eligible for our review and showed that there was no difference between RFT of the peripheral nerves and the Gasserian ganglion in terms of pain scores. There was a non-significant trend for RFT of the peripheral nerve to have higher immediate effect rates and higher recurrence rates. RFT of the Gasserian ganglion group was associated with masticatory weakness, while the other group was associated with facial swelling and numbness of V2. CONCLUSION: RFT of the peripheral branches is a safe and effective method to treat idiopathic trigeminal neuralgia but leads to a higher recurrence rate when compared with RFT of the Gasserian ganglion.

Polymeric nanocarriers: A promising tool for early diagnosis and efficient treatment of colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is the third most prevalent type of cancer for incidence and second for mortality worldwide. Late diagnosis and inconvenient and expensive current diagnostic tools largely contribute to the progress of the disease. The use of chemotherapy in the management of CRC significantly reduces tumor growth, metastasis, and morbidity rates. However, poor solubility, low cellular uptake, nonspecific distribution, multiple drug resistance and unwanted adverse effects are still among the major drawbacks of chemotherapy that limit its clinical significance in the treatment of CRC. Owing to their remarkable advantages over conventional therapies, the use of nanotechnology-based delivery systems especially polymeric nanocarriers (PNCs) has revolutionized many fields including disease diagnosis and drug delivery. AIM OF REVIEW: In this review, we shed the light on the current status of using PNCs in the diagnosis and treatment of CRC with a special focus on targeting strategies, surface modifications and safety concerns for different types of PNCs in colonic cancer delivery. KEY SCIENTIFIC CONCEPTS OF REVIEW: The review explores the current progress on the use of PNCs in the diagnosis and treatment of CRC with a special focus on the role of PNCs in improvement of cellular uptake, drug targeting and co-delivery of chemotherapeutic agents. Possible toxicity and biocompatibility issues related to the use of PNCs and imitations and future recommendation for the use of those smart carriers in the diagnosis and treatment of CRC are also discussed.

Optimum inhibition of MCF-7 breast cancer cells by efficient targeting of the macropinocytosis using optimized paclitaxel-loaded nanoparticles.

AIMS: Breast cancer (BC) is the third leading cause of death among other cancer types. Worldwide, it is the most common harmful disease in women, representing 1/4 of all cancers. Treatment of BC remains an ongoing challenge to most researchers. Understanding how cancer cells differ from normal cells can enhance drug targeting and overall disease progression. Endocytosis is a major physiological process modified in cancer cells and affects the cellular uptake of chemotherapeutic agents. MCF-7 breast cancer cells exhibit constitutive macropinocytic activity in comparison to normal non-macropinocytic MCF-10A breast cells. Therefore, we hypothesized that blocking the macropinocytosis mechanism in MCF-7 cells may inhibit the cancer progression while maintaining the safety of normal cells. MAIN METHODS: Using nano-precipitation technique, paclitaxel-PLGA-NPs were successfully prepared in the size range and charge required to opt for macropinocytosis in MCF-7 cells. KEY FINDINGS: Uptake and endocytosis inhibitor assays indicated that the developed NPs acquired size and surface charges that efficiently target macropinocytosis of MCF-7 cells. Paclitaxel-loaded PLGA-NPs showed higher efficacy against MCF-7 cells, while providing no toxicity on normal MCF-10A cells. Metabolomics analysis indicated the nutrients deprivation because of occupying the macropinocytosis. However, treatment of fresh MCF-7 cancer cells by metabolites secreted from PLGA-NPs-treated MCF-7 cells showed a potential metastatic activity. Thus, co- administration with an anti-metastatic drug is advised. SIGNIFICANCE: Collectively, adjusting the size and surface characteristics of a drug can critically control its cellular uptake, affecting the efficacy of drugs and the microenvironment of cancer cells.

Thermosensitive injectable graphene oxide/chitosan-based nanocomposite hydrogels for controlling the in vivo release of bupivacaine hydrochloride.

Local anesthetics are commonly used for the management of intraoperative and postoperative acute and chronic pain caused by small invasive procedures. However, their short half-life and duration of action limit their clinical benefits. In this study, we proposed the incorporation of graphene oxide (GO) nanosheets to chitosan (CS)/ß-glycerophosphate (GP) thermosensitive hydrogel system to form an injectable nanocomposite hydrogel (NCH) with improved mechanical properties and better control over the release of bupivacaine hydrochloride (BH). The prepared NCHs were characterized for their gelation time, porosity, swelling ratio, injectability, mechanical strength and in vitro drug release. In vivo, the efficacy of the prepared NCH containing 0.5 % w/v BH was evaluated using a thermal nociceptive assay in a rat model. The incorporation of GO significantly enhanced the physicochemical and mechanical properties of the hydrogel scaffolds in a concentration-dependent manner. Inclusion of 0.1% w/v GO resulted in 84% reduction in gelation time and 16% and 40% decrease in the porosity and swelling ratio of the NCHs, respectively. The mechanical strength of the CS/GP hydrogel scaffolds was also significantly improved in presence of GO. BH was slowly released from the NCHs containing 0.1% w/v GO and resulted in a 55% and 86.43% drug release after 6 and 24 h, respectively. In vivo studies showed that BH-loaded NCH significantly prolonged the local anesthetic effect and resulted in a 6.5-fold increase in blocking the pain sensory reflex compared to BH solution. These results indicate that the incorporation of GO significantly improved the physical and mechanical properties of CS/GP thermosensitive hydrogels and successfully sustained the effect of local anesthesia for more effective pain management.

Nanomedicine Strategies for Management of Drug Resistance in Lung Cancer.

Lung cancer (LC) is one of the leading causes of cancer occurrence and mortality worldwide. Treatment of patients with advanced and metastatic LC presents a significant challenge, as malignant cells use different mechanisms to resist chemotherapy. Drug resistance (DR) is a complex process that occurs due to a variety of genetic and acquired factors. Identifying the mechanisms underlying DR in LC patients and possible therapeutic alternatives for more efficient therapy is a central goal of LC research. Advances in nanotechnology resulted in the development of targeted and multifunctional nanoscale drug constructs. The possible modulation of the components of nanomedicine, their surface functionalization, and the encapsulation of various active therapeutics provide promising tools to bypass crucial biological barriers. These attributes enhance the delivery of multiple therapeutic agents directly to the tumor microenvironment (TME), resulting in reversal of LC resistance to anticancer treatment. This review provides a broad framework for understanding the different molecular mechanisms of DR in lung cancer, presents novel nanomedicine therapeutics aimed at improving the efficacy of treatment of various forms of resistant LC; outlines current challenges in using nanotechnology for reversing DR; and discusses the future directions for the clinical application of nanomedicine in the management of LC resistance.

Ultrasound-Triggered Liposomes Encapsulating Quantum Dots as Safe Fluorescent Markers for Colorectal Cancer.

Quantum dots (QDs) are a promising tool to detect and monitor tumors. However, their small size allows them to accumulate in large quantities inside the healthy cells (in addition to the tumor cells), which increases their toxicity. In this study, we synthesized stealth liposomes encapsulating hydrophilic graphene quantum dots and triggered their release with ultrasound with the goal of developing a safer and well-controlled modality to deliver fluorescent markers to tumors. Our results confirmed the successful encapsulation of the QDs inside the core of the liposomes and showed no effect on the size or stability of the prepared liposomes. Our results also showed that low-frequency ultrasound is an effective method to release QDs encapsulated inside the liposomes in a spatially and temporally controlled manner to ensure the effective delivery of QDs to tumors while reducing their systemic toxicity.

Assessment of epinephrine sublingual stability and permeability pathways to enhance its permeability for the treatment of anaphylaxis.

Prompt epinephrine (Epi) injection using auto-injectors is the initial life-saving out-of-hospital treatment for anaphylaxis. However, patients and healthcare providers are eagerly awaiting a more convenient alternative dosage form that would overcome auto-injectors drawbacks. Previously, we extensively evaluated multiple alternative fast-disintegrating sublingual Epi tablet (FDSTs) formulations. However, the sublingual stability of Epi and effect of modifying the sublingual microenvironment pH on its stability and transport pathways were not yet fully investigated. Results depicted that Epi remained sufficiently stable at various pHs in human saliva and porcine sublingual tissue's extract. Epi permeability (EP) through excised porcine sublingual membrane was greatest at pH 8.0 (p < 0.05), 11-fold higher than the negative control (Epi at pH 6.8). Sodium carbonate (Na Carb) 0.75% was the most efficient buffer to modify Epi solution pH to 8.0. Both sodium dodecyl sulfate (SDS) 0.075% and palmitoyl-DL-carnitine chloride (PCC) 1.2% increased paracellular EP 10-fold and 3-fold, respectively; however, both demonstrated a delayed enhancement (>5 min). Meanwhile, Na Carb and SDS combination increased EP 23-fold without a delay. It is evident that pH-modifiers or their SDS combination showed promising potential to enhance Epi sublingual permeability and further reduce the required Epi dose using FDSTs as a feasible alternative to Epi auto-injectors.

Enhanced Anticancer Activity of Nanoformulation of Dasatinib against Triple-Negative Breast Cancer.

Triple negative breast cancer (TNBC) is the most aggressive breast cancer accounting for around 15% of identified breast cancer cases. TNBC lacks human epidermal growth factor receptor 2 (HER2) amplification, is hormone independent estrogen (ER) and progesterone receptors (PR) negative, and is not reactive to current targeted therapies. Existing treatment relies on chemotherapeutic treatment, but in spite of an initial response to chemotherapy, the inception of resistance and relapse is unfortunately common. Dasatinib is an approved second-generation inhibitor of multiple tyrosine kinases, and literature data strongly support its use in the management of TNBC. However, dasatinib binds to plasma proteins and undergoes extensive metabolism through oxidation and conjugation. To protect dasatinib from fast pharmacokinetic degradation and to prolong its activity, it was encapsulated on poly(styrene-co-maleic acid) (SMA) micelles. The obtained SMA-dasatinib nanoparticles (NPs) were evaluated for their physicochemical properties, in vitro antiproliferative activity in different TNBC cell lines, and in vivo anticancer activity in a syngeneic model of breast cancer. Obtained results showed that SMA-dasatinib is more potent against 4T1 TNBC tumor growth in vivo compared to free drug. This enhanced effect was ascribed to the encapsulation of the drug protecting it from a rapid metabolism. Our finding highlights the often-overlooked value of nanoformulations in protecting its cargo from degradation. Overall, results may provide an alternative therapeutic strategy for TNBC management.