Correction: Al Khatib et al. Inhaled Medicines for Targeting Non-Small Cell Lung Cancer. Pharmaceutics 2024, 15, 2777.

In the original publication [...].

A comprehensive review of PRAME and BAP1 in melanoma: Genomic instability and immunotherapy targets.

In a thorough review of the literature, the complex roles of PRAME (preferentially expressed Antigen of Melanoma) and BAP1 (BRCA1-associated protein 1) have been investigated in uveal melanoma (UM) and cutaneous melanoma. High PRAME expression in UM is associated with poor outcomes and correlated with extraocular extension and chromosome 8q alterations. BAP1 mutations in the UM indicate genomic instability and a poor prognosis. Combining PRAME and BAP1 immunohistochemical staining facilitates effective risk stratification. Mechanistically, both genes are associated with genomic instability, making them promising targets for cancer immunotherapy. Hypomethylation of PRAME, specifically in its promoter regions, is critical for UM progression and contributes to epigenetic reprogramming. Additionally, miR-211 regulation is crucial in melanoma and has therapeutic potential. The way PRAME changes signaling pathways provides clues about the cause of cancer due to genomic instability related to modifications in DNA repair. Inhibition of poly(ADP-ribose) polymerase-1 (PARP-1) and PARP-2 in cells expressing PRAME could lead to potential therapeutic applications. Pathway enrichment analysis underscores the significance of PRAME and BAP1 in melanoma pathogenesis.

Tirzepatide: unveiling a new dawn in dual-targeted diabetes and obesity management.

INTRODUCTION: Incretin-based therapies have emerged as effective treatments for type 2 diabetes (T2D) and obesity. However, not all patients achieve optimal outcomes with existing treatments, highlighting the need for more effective solutions. AREAS COVERED: We present a comprehensive evaluation of Tirzepatide (TZP), a novel dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 (GIP/GLP-1) receptor agonist, for managing obesity and T2D. We conducted a systematic search of Cochrane, PubMed, Scopus, and Web of Science databases from inception to April 2024. The focus of the review is on the development and therapeutic potential of TZP, with detailed exploration on pharmacodynamics, pharmacokinetics, clinical efficacy, and safety. Furthermore, it reviews TZP's impacts on glycemic control, weight management, and its potential cardiovascular (CV) benefits. EXPERT OPINION: TZP represents a significant advancement in the dual-targeted approach to treating T2D and obesity. Its unique mechanism of action offers superior efficacy in reducing glycemic levels and body weight compared to existing therapies. New data suggesting improvements in CV outcomes indicate that TZP could set a new standard in the treatment paradigm. While long-term data on efficacy and safety are still forthcoming, current evidence positions TZP as a promising option for patients who have not reached their therapeutic goals with existing treatments.

Metabolic vulnerabilities in cancer: A new therapeutic strategy.

Cancer metabolism is now a key area for therapeutic intervention, targeting unique metabolic reprogramming crucial for tumor growth and survival. This article reviews the therapeutic potential of addressing metabolic vulnerabilities through glycolysis and glutaminase inhibitors, which disrupt cancer cell metabolism. Challenges such as tumor heterogeneity and adaptive resistance are discussed, with strategies including personalized medicine and predictive biomarkers to enhance treatment efficacy. Additionally, integrating diet and lifestyle changes with metabolic targeting underscores a holistic approach to improving therapy outcomes. The article also examines the benefits of incorporating these strategies into standard care, highlighting the potential for more tailored, safer treatments. In conclusion, exploiting metabolic vulnerabilities promises a new era in oncology, positioning metabolic targeting at the forefront of personalized cancer therapy and transforming patient care.

The Complex Connection between Obesity and Cancer: Signaling Pathways and Therapeutic Implications.

Obesity has emerged as an important global health challenge, significantly influencing the incidence and progression of various cancers. This comprehensive review elucidates the complex relationship between obesity and oncogenesis, focusing particularly on the role of dysregulated signaling pathways as central mediators of this association. We delve into the contributions of obesity-induced alterations in key signaling cascades, including PI3K/AKT/mTOR, JAK/STAT, NF-κB, and Wnt/ß-catenin to carcinogenesis. These alterations facilitate unchecked cellular proliferation, chronic inflammation and apoptosis resistance. Epidemiological evidence links obesity with increased cancer susceptibility and adverse prognostic outcomes, with pronounced risks for specific cancers such as breast, colorectal, endometrial and hepatic malignancies. This review synthesizes data from both animal and clinical studies to underscore the pivotal role of disrupted signaling pathways in shaping innovative therapeutic strategies. We highlight the critical importance of lifestyle modifications in obesity management and cancer risk mitigation, stressing the benefits of dietary changes, physical activity, and behavioral interventions. Moreover, we examine targeted pharmacological strategies addressing aberrant pathways in obesity-related tumors and discuss the integration of cutting-edge treatments, including immunotherapy and precision medicine, into clinical practice.

Nanomaterial-Driven Precision Immunomodulation: A New Paradigm in Therapeutic Interventions.

Immunotherapy is a rapidly advancing field of research in the treatment of conditions such as cancer and autoimmunity. Nanomaterials can be designed for immune system manipulation, with precise targeted delivery and improved immunomodulatory efficacy. Here, we elaborate on various strategies using nanomaterials, including liposomes, polymers, and inorganic NPs, and discuss their detailed design intricacies, mechanisms, and applications, including the current regulatory issues. This type of nanomaterial design for targeting specific immune cells or tissues and controlling release kinetics could push current technological frontiers and provide new and innovative solutions for immune-related disorders and diseases without off-target effects. These materials enable targeted interactions with immune cells, thereby enhancing the effectiveness of checkpoint inhibitors, cancer vaccines, and adoptive cell therapies. Moreover, they allow for fine-tuning of immune responses while minimizing side effects. At the intersection of nanotechnology and immunology, nanomaterial-based platforms have immense potential to revolutionize patient-centered immunotherapy and reshape disease management. By prioritizing safety, customization, and compliance with regulatory standards, these systems can make significant contributions to precision medicine, thereby significantly impacting the healthcare landscape.

Evaluation of Solubility, Dissolution Rate, and Oral Bioavailability of ß-Cyclodextrin and Hydroxypropyl ß-Cyclodextrin as Inclusion Complexes of the Tyrosine Kinase Inhibitor, Alectinib.

This study aims to improve the solubility and dissolution rate of alectinib (ALB), a tyrosine kinase inhibitor commonly used for treating non-small-cell carcinoma (NSCLC). Given ALB's low solubility and bioavailability, complexation with ß-cyclodextrin (ßCD) and hydroxy propyl ß-cyclodextrin (HPßCD) was evaluated. Some of the different preparation methods used with varying ALB-to-CD ratios led to the formation of complexes that were characterized using Fourier-Transform Infrared (FTIR) techniques and Differential Scanning Calorimetry (DSC) to prove complex formation. The encapsulation efficiency was also determined. The simulations were carried out for ALB's interactions with ßCD and HPßCD. This study identified the most soluble complex (ALB-HPßCD; 1:2 ratio) and evaluated its dissolution. The bioavailability of the ALB-HPßCD complex was evaluated in Wistar rats relative to free ALB. Pharmacokinetic profiles revealed increased Cmax (240 ± 26.95 ng/mL to 474 ± 50.07 ng/mL) and AUC0-48 (5946.75 ± 265 ng.h/mL to 10520 ± 310 ng.h/mL) with no change in the elimination rate constant. In conclusion, the complexation of ALB-HPßCD manages to increase in vitro solubility, the dissolution rate, and oral bioavailability, providing a favorable approach to improving ALB administration.

Advances in glioblastoma multiforme: Integrating therapy and pathology perspectives.

Glioblastoma, a highly lethal form of brain cancer, is characterized by its aggressive growth and resistance to conventional treatments, often resulting in limited survival. The response to therapy is notably influenced by various patient-specific genetic factors, underscoring the disease's complexity. Despite the utilization of diverse treatment modalities such as surgery, radiation, and chemotherapy, many patients experience local relapse, emphasizing the critical need for improved therapeutic strategies to effectively target these formidable tumors. Recent years have witnessed a surge in interest in natural products derived from plants, particularly alkaloids, for their potential anticancer effects. Alkaloids have shown promise in cancer chemotherapy by selectively targeting crucial signaling pathways implicated in tumor progression and survival. Specifically, they modulate the NF-κB and MAPK pathways, resulting in reduced tumor growth and altered gene expression across various cancer types. Additionally, alkaloids exhibit the capacity to induce cell cycle arrest, further impeding tumor proliferation in several malignancies. This review aims to delineate recent advances in understanding the pathology of glioblastoma multiforme (GBM) and to explore the potential therapeutic implications of alkaloids in managing this deadly disease. By segregating discussions on GBM pathology from those on alkaloid-based therapies, we provide a structured overview of the current challenges in GBM treatment and the promising opportunities presented by alkaloid-based interventions. Furthermore, we briefly discuss potential future directions in GBM research and therapy beyond alkaloids, including emerging treatment modalities or areas of investigation that hold promise for improving patient outcomes. In conclusion, our efforts offer hope for enhanced outcomes and improved quality of life for GBM patients through alkaloid-based therapies. By integrating insights from pathology and therapeutic perspectives, we underscore the significance of a comprehensive approach in addressing this devastating disease.

Unraveling the tumor microenvironment: Insights into cancer metastasis and therapeutic strategies.

This comprehensive review delves into the pivotal role of the tumor microenvironment (TME) in cancer metastasis and therapeutic response, offering fresh insights into the intricate interplay between cancer cells and their surrounding milieu. The TME, a dynamic ecosystem comprising diverse cellular and acellular elements, not only fosters tumor progression but also profoundly affects the efficacy of conventional and emerging cancer therapies. Through nuanced exploration, this review illuminates the multifaceted nature of the TME, elucidating its capacity to engender drug resistance via mechanisms such as hypoxia, immune evasion, and the establishment of physical barriers to drug delivery. Moreover, it investigates innovative therapeutic approaches aimed at targeting the TME, including stromal reprogramming, immune microenvironment modulation, extracellular matrix (ECM)-targeting agents, and personalized medicine strategies, highlighting their potential to augment treatment outcomes. Furthermore, this review critically evaluates the challenges posed by the complexity and heterogeneity of the TME, which contribute to variable therapeutic responses and potentially unintended consequences. This underscores the need to identify robust biomarkers and advance predictive models to anticipate treatment outcomes, as well as advocate for combination therapies that address multiple facets of the TME. Finally, the review emphasizes the necessity of an interdisciplinary approach and the integration of cutting-edge technologies to unravel the intricacies of the TME, thereby facilitating the development of more effective, adaptable, and personalized cancer treatments. By providing critical insights into the current state of TME research and its implications for the future of oncology, this review highlights the dynamic and evolving landscape of this field.

Doxorubicin conjugates: a practical approach for its cardiotoxicity alleviation.

INTRODUCTION: Doxorubicin (DOX) emerges as a cornerstone in the arsenal of potent chemotherapeutic agents. Yet, the clinical deployment of DOX is tarnished by its proclivity to induce severe cardiotoxic effects, culminating in heart failure and other consequential morbidities. In response, a panoply of strategies has undergone rigorous exploration over recent decades, all aimed at attenuating DOX's cardiotoxic impact. The advent of encapsulating DOX within lipidic or polymeric nanocarriers has yielded a dual triumph, augmenting DOX's therapeutic efficacy while mitigating its deleterious side effects. AREAS COVERED: Recent strides have spotlighted the emergence of DOX conjugates as particularly auspicious avenues for ameliorating DOX-induced cardiotoxicity. These conjugates entail the fusion of DOX through physical or chemical bonds with diminutive natural or synthetic moieties, polymers, biomolecules, and nanoparticles. This spectrum encompasses interventions that impinge upon DOX's cardiotoxic mechanism, modulate cellular uptake and localization, confer antioxidative properties, or refine cellular targeting. EXPERT OPINION: The endorsement of DOX conjugates as a compelling stratagem to mitigate DOX-induced cardiotoxicity resounds from this exegesis, amplifying safety margins and the therapeutic profile of this venerated chemotherapeutic agent. Within this ambit, DOX conjugates stand as a beacon of promise in the perpetual pursuit of refining chemotherapy-induced cardiac compromise.

In vivo evaluation of mebendazole and Ran GTPase inhibition in breast cancer model system.

Aim: To investigate the therapeutic potential of mebendazole (MBZ)-loaded nanostructured lipid carriers (NLCs). Methodology: NLC-MBZ was prepared and characterized to evaluate the in vitro and in vivo anticancer effects and the inhibitory effect on RanGTP and its potential as an antimetastatic treatment in vivo. Results: NLC-MBZ exhibited a size and charge of 155 ± 20 nm and -27 ± 0.5 mV, respectively, with 90.7% encapsulation. Free MBZ and NLC-MBZ had a 50% inhibitory concentration of 610 and 305 nM, respectively, against MDA-MB-231 cell lines. NLC-MBZ decreased tumor size, suppressed tumor lung metastases, and lowered the expression of CDC25A, SKP2, RbX1 and Cullin1 while boosting the Rb proteins. Conclusion: NLC-MBZ displayed antiangiogenic potential and resulted in a reduced rate of lung metastasis in vivo.

[Box: see text].

In vitro dissolution equivalence of Jordanian sildenafil generics via validated, stability-indicating HPLC method.

This study was conducted to compare dissolution profiles of four Jordanian registered sildenafil (SDF) products to the originator. Dissolution samples were analyzed utilizing a validated and stability-indicating HPLC method in human plasma. Validation was performed for specificity, linearity, limit of detection, lower limit of quantification, precision, trueness and stability. SDF was extracted from plasma samples using liquid-liquid extraction. The analysis was performed utilizing isocratic elution on C18 column with 1.0 ml/min flow rate. The regression value was ∼0.999 over 3 days with drug recovery between 86.6 to 89.8%with 10 ng/ml lower limit of quantitation. This method displayed a good selectivity of SDF with improved stability under various conditions. The method was used for SDF quantification in dissolution medium. Similarity factors for local products varied according to the used mediums, but all SDF local products passed the dissolution in vitro test since all of them showed a released of >85% after 60 min at the dissolution mediums.

[Box: see text].

Dual-loaded liposomal carriers to combat chemotherapeutic resistance in breast cancer.

INTRODUCTION: The resistance to chemotherapy is a significant hurdle in breast cancer treatment, prompting the exploration of innovative strategies. This review discusses the potential of dual-loaded liposomal carriers to combat chemoresistance and improve outcomes for breast cancer patients. AREAS COVERED: This review discusses breast cancer chemotherapy resistance and dual-loaded liposomal carriers. Drug efflux pumps, DNA repair pathways, and signaling alterations are discussed as chemoresistance mechanisms. Liposomes can encapsulate several medicines and cargo kinds, according to the review. It examines how these carriers improve medication delivery, cancer cell targeting, and tumor microenvironment regulation. Also examined are dual-loaded liposomal carrier improvement challenges and techniques. EXPERT OPINION: The use of dual-loaded liposomal carriers represents a promising and innovative strategy in the battle against chemotherapy resistance in breast cancer. This article has explored the various mechanisms of chemoresistance in breast cancer, emphasizing the potential of dual-loaded liposomal carriers to overcome these challenges. These carriers offer versatility, enabling the encapsulation and precise targeting of multiple drugs with different modes of action, a crucial advantage when dealing with the complexity of breast cancer treatment.

Non-coding RNAs as Key Regulators of the Notch Signaling Pathway in Glioblastoma: Diagnostic, Prognostic, and Therapeutic Targets.

Glioblastoma multiforme (GBM) is a highly invasive brain malignancy originating from astrocytes, accounting for approximately 30% of central nervous system malignancies. Despite advancements in therapeutic strategies including surgery, chemotherapy, and radiopharmaceutical drugs, the prognosis for GBM patients remains dismal. The aggressive nature of GBM necessitates the identification of molecular targets and the exploration of effective treatments to inhibit its proliferation. The Notch signaling pathway, which plays a critical role in cellular homeostasis, becomes deregulated in GBM, leading to increased expression of pathway target genes such as MYC, Hes1, and Hey1, thereby promoting cellular proliferation and differentiation. Recent research has highlighted the regulatory role of non-coding RNAs (ncRNAs) in modulating Notch signaling by targeting critical mRNA expression at the post-transcriptional or transcriptional levels. Specifically, various types of ncRNAs, including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), have been shown to control multiple target genes and significantly contribute to the carcinogenesis of GBM. Furthermore, these ncRNAs hold promise as prognostic and predictive markers for GBM. This review aims to summarize the latest studies investigating the regulatory effects of ncRNAs on the Notch signaling pathway in GBM.

The impact of the BCR-ABL oncogene in the pathology and treatment of chronic myeloid leukemia.

Chronic Myeloid Leukemia (CML) is characterized by chromosomal aberrations involving the fusion of the BCR and ABL genes on chromosome 22, resulting from a reciprocal translocation between chromosomes 9 and 22. This fusion gives rise to the oncogenic BCR-ABL, an aberrant tyrosine kinase identified as Abl protein. The Abl protein intricately regulates the cell cycle by phosphorylating protein tyrosine residues through diverse signaling pathways. In CML, the BCR-ABL fusion protein disrupts the first exon of Abl, leading to sustained activation of tyrosine kinase and resistance to deactivation mechanisms. Pharmacological interventions, such as imatinib, effectively target BCR-ABL's tyrosine kinase activity by binding near the active site, disrupting ATP binding, and inhibiting downstream protein phosphorylation. Nevertheless, the emergence of resistance, often attributed to cap structure mutations, poses a challenge to imatinib efficacy. Current research endeavours are directed towards overcoming resistance and investigating innovative therapeutic strategies. This article offers a comprehensive analysis of the structural attributes of BCR-ABL, emphasizing its pivotal role as a biomarker and therapeutic target in CML. It underscores the imperative for ongoing research to refine treatment modalities and enhance overall outcomes in managing CML.

The role of the gut microbiome in gastrointestinal cancers.

The gut microbiota present in the human digestive system is incredibly varied and is home to trillions of microorganisms. The gut microbiome is shaped at birth, while numerous genetic, dietary, and environmental variables primarily influence the microbiome composition. The importance of gut microbiota on host health is becoming more widely acknowledged. Digestion, intestinal permeability, and immunological and metabolism responses can all be affected by changes in the composition and function of the gut microbiota. There is mounting evidence that the microbial population's complex traits are important biomarkers and indicators of patient outcomes in cancer and its therapies. Numerous studies have demonstrated that changed commensal gut microorganisms contribute to the development and spread of cancer through various routes. Despite the ongoing controversy surrounding the gut microbiome and gastrointestinal cancer, accumulating evidence points to a potentially far more intricate connection than a simple cause-and-effect relationship. SIMPLE SUMMARY: Due to their high frequency and fatality rate, gastrointestinal cancers are regarded as a severe public health issue with complex medical and economic burdens. The gut microbiota may directly or indirectly interact with existing therapies like immunotherapy and chemotherapy, affecting how well a treatment works. The gut microbiome influences the immune response's activity, function, and development. Generally, certain gut bacteria impact the antitumor actions during cancer by creating particular metabolites or triggering T-cell responses. Yet, certain bacterial species have been found to promote cellular proliferation and metastasis in cancer, and comprehending these interactions in the context of cancer may help identify possible treatment targets. Notwithstanding the improvements in the field, additional research is still required to comprehend the underlying processes, examine the effects on existing therapies, and pinpoint certain bacteria and immune cells that can cause this interaction.

Cellular signaling in the hypoxic cancer microenvironment: Implications for drug resistance and therapeutic targeting.

The rewiring of cellular metabolism is a defining characteristic of cancer, as tumor cells adapt to acquire essential nutrients from a nutrient-poor environment to sustain their viability and biomass. While hypoxia has been identified as a major factor depriving cancer cells of nutrients, recent studies have revealed that cancer cells distant from supporting blood vessels also face nutrient limitations. To overcome this challenge, hypoxic cancer cells, which heavily rely on glucose as an energy source, employ alternative pathways such as glycogen metabolism and reductive carboxylation of glutamine to meet their energy requirements for survival. Our preliminary studies, alongside others in the field, have shown that under glucose-deficient conditions, hypoxic cells can utilize mannose and maltose as alternative energy sources. This review aims to comprehensively examine the hypoxic cancer microenvironment, its association with drug resistance, and potential therapeutic strategies for targeting this unique niche. Furthermore, we will critically evaluate the current literature on hypoxic cancer microenvironments and explore state-of-the-art techniques used to analyze alternate carbohydrates, specifically mannose and maltose, in complex biological fluids. We will also propose the most effective analytical methods for quantifying mannose and maltose in such biological samples. By gaining a deeper understanding of the hypoxic cancer cell microenvironment and its role in drug resistance, novel therapeutic approaches can be developed to exploit this knowledge.

Preparation, Optimization and In vitro Evaluation of Doxorubicin-loaded into Hyaluronic Acid Coated Niosomes Against Breast Cancer.

Doxorubicin (DOX) is widely used against solid tumors. Niosomes are self-assembled nanocarriers of non-ionic surfactants. DOX loaded into cationic niosomes (DOX-Nio) was prepared via thin film hydration method. DOX-Nio was then decorated with a hyaluronic acid (DOX-HA-Nio) via electrostatic interaction. DOX-Nio and DOX-HA-Nio displayed a particle size of 120.0±1.02 and 182.9±2.3 nm, and charge of + 35.5±0.15 and -15.6±0.25 mV, respectively, with PDI < 0.3. DOX-HA-Nio showed a good stability regarding size and charge over 4 weeks at 4 °C and maintain their integrity after lyophilization. HPLC results showed a 94.1±4.2 % encapsulation efficiency of DOX with good entrapment and slow, prolonged DOX release even after 48 hrs. Cell viability assay showed an IC50 of 14.26 nM for the DOX-HA-Nio against MCF-7 cell line with micromolar IC50 results against CD-44 negative cell lines (NIH/3T3). DOX-HA-Nio was proven to be an effective, targeted nanocarrier for DOX against MCF-7 cell line.

Inhaled Medicines for Targeting Non-Small Cell Lung Cancer.

Throughout the years, considerable progress has been made in methods for delivering drugs directly to the lungs, which offers enhanced precision in targeting specific lung regions. Currently, for treatment of lung cancer, the prevalent routes for drug administration are oral and parenteral. These methods, while effective, often come with side effects including hair loss, nausea, vomiting, susceptibility to infections, and bleeding. Direct drug delivery to the lungs presents a range of advantages. Notably, it can significantly reduce or even eliminate these side effects and provide more accurate targeting of malignancies. This approach is especially beneficial for treating conditions like lung cancer and various respiratory diseases. However, the journey towards perfecting inhaled drug delivery systems has not been without its challenges, primarily due to the complex structure and functions of the respiratory tract. This comprehensive review will investigate delivery strategies that target lung cancer, specifically focusing on non-small-cell lung cancer (NSCLC)-a predominant variant of lung cancer. Within the scope of this review, active and passive targeting techniques are covered which highlight the roles of advanced tools like nanoparticles and lipid carriers. Furthermore, this review will shed light on the potential synergies of combining inhalation therapy with other treatment approaches, such as chemotherapy and immunotherapy. The goal is to determine how these combinations might amplify therapeutic results, optimizing patient outcomes and overall well-being.

Development and validation of reversed-phase-HPLC method for simultaneous quantification of fulvestrant and disulfiram in liposomes.

This study aims to develop and validate an HPLC technique for the determination of fulvestrant and disulfiram in liposomes. Encapsulation of both drugs into liposomes may improve their anticancer potential. Validation was performed following the International Conference on Harmonization guidelines for specificity, linearity, limit of detection, limit of quantification, precision, accuracy and robustness. Method specificity displayed no interference and linearity over 25-200 and 12.5-100 µg/ml for fulvestrant and disulfiram, respectively. Precision and accuracy exhibited a low relative standard deviation (<1.70%) and appropriate recovery. The validated method could be designated as a proper method for the simultaneous determination of fulvestrant and disulfiram in liposomes. The liposomes displayed 148.5 ± 5.1 nm size. The encapsulation efficiencies were 73.52 and 50.50% for fulvestrant and disulfiram, respectively.