Novel inhaled andrographolide for treatment of lung cancer: In vitro assessment.

Andrographolide is a plant-based compound that showed promising activity against lung cancer. However, the compound's poor water solubility and low bioavailability limit its oral administration. Inhaled drug delivery of andrographolide is highly favourable as it delivers active ingredients directly into the affected lungs. In the current study, we compared in vitro aerosol performance, anti-cancer activity and storages stability of two (2) inhalable andrographolide formulations. Formulation 1 was prepared using precipitation and spray drying techniques, while Formulation 2 was prepared via direct spray drying technique. Drug morphology and physicochemical properties were confirmed using scanning electron microscopy (SEM) and X-ray diffraction (XRD) analysis. In vitro aerosol dispersion profile was evaluated using the next-generation impactor (NGI). Formulation 1 consisted of elongated crystals while Formulation 2 was made up of amorphous spherical particles. Both formulations had an inhalable fraction (<5 µm) of more than 40 %, making them suitable for pulmonary drug delivery. The formulations also showed an IC25 of less than 100 µg/mL against the human lung carcinoma cells (A549). Formulation 1 and 2 was stable in a vacuum condition at 30 °C for up to 6 and 3 months, respectively. Novel inhalable andrographolide dry powders were successfully produced with a good aerosol profile, potent anti-cancer activity and adequate storage stability, which deserve further in vivo investigations.

Revolutionizing Antiviral Therapeutics: Unveiling Innovative Approaches for Enhanced Drug Efficacy.

Since the beginning of the coronavirus pandemic in late 2019, viral infections have become one of the top three causes of mortality worldwide. Immunization and the use of immunomodulatory drugs are effective ways to prevent and treat viral infections. However, the primary therapy for managing viral infections remains antiviral and antiretroviral medication. Unfortunately, these drugs are often limited by physicochemical constraints such as low target selectivity and poor aqueous solubility. Although several modifications have been made to enhance the physicochemical characteristics and efficacy of these drugs, there are few published studies that summarize and compare these modifications. Our review systematically synthesized and discussed antiviral drug modification reports from publications indexed in Scopus, PubMed, and Google Scholar databases. We examined various approaches that were investigated to address physicochemical issues and increase activity, including liposomes, cocrystals, solid dispersions, salt modifications, and nanoparticle drug delivery systems. We were impressed by how well each strategy addressed physicochemical issues and improved antiviral activity. In conclusion, these modifications represent a promising way to improve the physicochemical characteristics, functionality, and effectiveness of antivirals in clinical therapy.

Review of inhalable nanoparticles for the pulmonary delivery of anti-tuberculosis drugs.

Tuberculosis is an airborne disease caused by the pathogen, Mycobacterium tuberculosis, which predominantly affects the lungs. World Health Organization (WHO) has reported that about 85% of TB patients are cured with the existing 6-month antibiotic regimen. However, the lengthy oral administration of high-dose anti-TB drugs is associated with significant side effects and leads to drug resistance cases. Alternatively, reformulating existing anti-tubercular drugs into inhalable nanoparticulate systems is a promising strategy to overcome the challenges associated with oral treatment as they could enhance drug retention in the pulmonary region to achieve an optimal drug concentration in the infected lungs. Hence, this review provides an overview of the literature on inhalable nano-formulations for the delivery of anti-TB drugs, including their formulation techniques and preclinical evaluations between the years 2000 and 2020, gathered from electronic journals via online search engines such as Google Scholar and PubMed. Previous in vitro and in vivo studies highlighted that the nano-size, low toxicity, and high efficacy were among the factors influencing the fate of nanoparticulate system upon deposition in the lungs. Although many preclinical studies have shown that inhalable nanoparticles increased therapeutic efficacy and minimised adverse drug reactions when delivered through the pulmonary route, none of them has progressed into clinical trials to date. This could be attributed to the high cost of inhaled regimes due to the expensive production and characterisation of the nanoparticles as well as the need for an inhalation device as compared to the oral treatment. Another barrier could be the lack of medical acceptance due to insufficient number of trained staff to educate the patients on the correct usage of the inhalation device. Hence, these barriers should be addressed satisfactorily to make the inhaled nanoparticles regimen a reality for the treatment of TB.

Eurycoma longifolia: an overview on the pharmacological properties for the treatment of common cancer.

Eurycoma longifolia plant, the so called Tongkat Ali in Malaysia, is a well grown prominent tree in all Southeast Asia. It is well known among traditional medicine practitioners as a curative plant for many diseases and health conditions. The major quassinoid from the plant is eurycomanone, which exhibits many prominent effects on various cancer cell lines. Numerous studies have shown that eurycomanone inhibits cancerous cell growth and encourages cell death both in vitro and in vivo test. Even though analyses of safety and toxicity have been conducted, there is still a substantial knowledge barrier when it comes to providing a scientific foundation for the molecular mechanism as well as intervention strategy in the living people cancer cell. In a way to offer adequate baseline data for future investigations based on molecular mechanism and intervention, the present work seeks to review the researches conducted to date on this herbal plant.

Dynorphin 1-17 biotransformation peptides: properties, challenges and solutions for future therapeutics development.

It is well established that endogenously produced dynorphin 1-17 (DYN 1-17) is susceptible to enzymatic degradation, producing a variety of unique fragments in different tissue matrices and disease pathologies. DYN 1-17 and its major biotransformation fragments have significant roles in neurological and inflammatory disorders upon interacting with opioid and non-opioid receptors at both central and peripheral levels, thus highlighting their potential as drug candidates. Nevertheless, their development as promising therapeutics is challenged by several issues. This review aims to provide the latest and comprehensive updates on DYN 1-17 biotransformed peptides, including their pharmacological roles, pharmacokinetic studies and relevant clinical trials. Challenges in their development as potential therapeutics and proposed solutions to overcome these limitations are also discussed.

This is a summary of published articles on the important roles of dynorphin 1-17 and its fragments in several disease pathologies, including neurological and inflammatory disorders. Dynorphin 1-17, which consists of 17 amino acids, is a substance produced in the human body that is easily degraded by the body's enzymes, producing a shorter chain of amino acids. For the past few decades, researchers have attempted to utilize these substances to treat the above-mentioned conditions. However, upon introduction, these substances are rapidly degraded by the enzymes, which hinder the molecules from reaching the site of action. Therefore, many studies have focused on addressing the degradation issue in order to benefit from the important role of dynorphin 1-17 and its fragments in treating respective diseases. Previous researchers have attempted structural modification of these substances by either changing the terminals of the amino acid chains or attaching them to other agents to increase the resistance of dynorphin 1-17 and its fragments toward enzymatic breakage. These substances were also incorporated into nano-sized delivery systems, which have been shown to protect the molecules while improving their delivery to different parts of the body. These results showed that the structurally modified dynorphin 1-17 and its fragments and their nano-sized delivery system could improve the stability of the molecules and allow them to be used to treat many conditions.

Conjugated ß-Cyclodextrin Enhances the Affinity of Folic Acid towards FRα: Molecular Dynamics Study.

Drug targeting is a progressive area of research with folate receptor alpha (FRα) receiving significant attention as a biological marker in cancer drug delivery. The binding affinity of folic acid (FA) to the FRα active site provides a basis for recognition of FRα. In this study, FA was conjugated to beta-cyclodextrin (ßCD) and subjected to in silico analysis (molecular docking and molecular dynamics (MD) simulation (100 ns)) to investigate the affinity and stability for the conjugated system compared to unconjugated and apo systems (ligand free). Docking studies revealed that the conjugated FA bound into the active site of FRα with a docking score (free binding energy < -15 kcal/mol), with a similar binding pose to that of unconjugated FA. Subsequent analyses from molecular dynamics (MD) simulations, root mean square deviation (RMSD), root mean square fluctuation (RMSF), and radius of gyration (Rg) demonstrated that FA and FA-ßCDs created more dynamically stable systems with FRα than the apo-FRα system. All systems reached equilibrium with stable RMSD values ranging from 1.9-2.4 Å and the average residual fluctuation values of the FRα backbone atoms for all residues (except for terminal residues ARG8, THR9, THR214, and LEU215) were less than 2.1 Å with a consistent Rg value of around 16.8 Å throughout the MD simulation time (0-100 ns). The conjugation with ßCD improved the stability and decreased the mobility of all the residues (except residues 149-151) compared to FA-FRα and apo-FRα systems. Further analysis of H-bonds, binding free energy (MM-PBSA), and per residue decomposition energy revealed that besides APS81, residues HIS20, TRP102, HIS135, TRP138, TRP140, and TRP171 were shown to have more favourable energy contributions in the holo systems than in the apo-FRα system, and these residues might have a direct role in increasing the stability of holo systems.

Pulmonary Delivery of Anticancer Drugs via Lipid-Based Nanocarriers for the Treatment of Lung Cancer: An Update.

Lung cancer (LC) is the leading cause of cancer-related deaths, responsible for approximately 18.4% of all cancer mortalities in both sexes combined. The use of systemic therapeutics remains one of the primary treatments for LC. However, the therapeutic efficacy of these agents is limited due to their associated severe adverse effects, systemic toxicity and poor selectivity. In contrast, pulmonary delivery of anticancer drugs can provide many advantages over conventional routes. The inhalation route allows the direct delivery of chemotherapeutic agents to the target LC cells with high local concertation that may enhance the antitumor activity and lead to lower dosing and fewer systemic toxicities. Nevertheless, this route faces by many physiological barriers and technological challenges that may significantly affect the lung deposition, retention, and efficacy of anticancer drugs. The use of lipid-based nanocarriers could potentially overcome these problems owing to their unique characteristics, such as the ability to entrap drugs with various physicochemical properties, and their enhanced permeability and retention (EPR) effect for passive targeting. Besides, they can be functionalized with different targeting moieties for active targeting. This article highlights the physiological, physicochemical, and technological considerations for efficient inhalable anticancer delivery using lipid-based nanocarriers and their cutting-edge role in LC treatment.

Advanced Nanoparticle-Based Drug Delivery Systems and Their Cellular Evaluation for Non-Small Cell Lung Cancer Treatment.

Lung cancers, the number one cancer killer, can be broadly divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), with NSCLC being the most commonly diagnosed type. Anticancer agents for NSCLC suffer from various limitations that can be partly overcome by the application of nanomedicines. Nanoparticles is a branch within nanomedicine that can improve the delivery of anticancer drugs, whilst ensuring the stability and sufficient bioavailability following administration. There are many publications available in the literature exploring different types of nanoparticles from different materials. The effectiveness of a treatment option needs to be validated in suitable in vitro and/or in vivo models. This includes the developed nanoparticles, to prove their safety and efficacy. Many researchers have turned towards in vitro models that use normal cells or specific cells from diseased tissues. However, in cellular works, the physiological dynamics that is available in the body could not be mimicked entirely, and hence, there is still possible development of false positive or false negative results from the in vitro models. This article provides an overview of NSCLC, the different nanoparticles available to date, and in vitro evaluation of the nanoparticles. Different types of cells suitable for in vitro study and the important precautions to limit the development of false results are also extensively discussed.

Heterocyclic Substitutions Greatly Improve Affinity and Stability of Folic Acid towards FRα. an In Silico Insight.

Folate receptor alpha (FRα) is known as a biological marker for many cancers due to its overexpression in cancerous epithelial tissue. The folic acid (FA) binding affinity to the FRα active site provides a basis for designing more specific targets for FRα. Heterocyclic rings have been shown to interact with many receptors and are important to the metabolism and biological processes within the body. Nineteen FA analogs with substitution with various heterocyclic rings were designed to have higher affinity toward FRα. Molecular docking was used to study the binding affinity of designed analogs compared to FA, methotrexate (MTX), and pemetrexed (PTX). Out of 19 FA analogs, analogs with a tetrazole ring (FOL03) and benzothiophene ring (FOL08) showed the most negative binding energy and were able to interact with ASP81 and SER174 through hydrogen bonds and hydrophobic interactions with amino acids of the active site. Hence, 100 ns molecular dynamics (MD) simulations were carried out for FOL03, FOL08 compared to FA, MTX, and PTX. The root mean square deviation (RMSD) and root mean square fluctuation (RMSF) of FOL03 and FOL08 showed an apparent convergence similar to that of FA, and both of them entered the binding pocket (active site) from the pteridine part, while the glutamic part was stuck at the FRα pocket entrance during the MD simulations. Molecular mechanics Poisson-Boltzmann surface accessible (MM-PBSA) and H-bond analysis revealed that FOL03 and FOL08 created more negative free binding and electrostatic energy compared to FA and PTX, and both formed stronger H-bond interactions with ASP81 than FA with excellent H-bond profiles that led them to become bound tightly in the pocket. In addition, pocket volume calculations showed that the volumes of active site for FOL03 and FOL08 inside the FRα pocket were smaller than the FA-FRα system, indicating strong interactions between the protein active site residues with these new FA analogs compared to FA during the MD simulations.

Advances in Nanocarriers for Effective Delivery of Docetaxel in the Treatment of Lung Cancer: An Overview.

Docetaxel (DCX) is a highly effective chemotherapeutic drug used in the treatment of different types of cancer, including non-small cell lung cancer (NSCLC). The drug is known to have low oral bioavailability due to its low aqueous solubility, poor membrane permeability and susceptibility to hepatic first-pass metabolism. To mitigate these problems, DCX is administered via the intravenous route. Currently, DCX is commercially available as a single vial that contains polysorbate 80 and ethanol to solubilize the poorly soluble drug. However, this formulation causes short- and long-term side effects, including hypersensitivity, febrile neutropenia, fatigue, fluid retention, and peripheral neuropathy. DCX is also a substrate to the drug efflux pump P-glycoprotein (P-gp) that would reduce its concentration within the vicinity of the cells and lead to the development of drug resistance. Hence, the incorporation of DCX into various nanocarrier systems has garnered a significant amount of attention in recent years to overcome these drawbacks. The surfaces of these drug-delivery systems indeed can be functionalized by modification with different ligands for smart targeting towards cancerous cells. This article provides an overview of the latest nanotechnological approaches and the delivery systems that were developed for passive and active delivery of DCX via different routes of administration for the treatment of lung cancer.

Design and development of dry powder sulfobutylether-ß-cyclodextrin complex for pulmonary delivery of fisetin.

This study has investigated complexation of fisetin, a natural flavonoid, with three types of cyclodextrins to improve its solubility. Sulfobutylether-ß-cyclodextrin (SBE-ß-CD) showed the highest complexation efficiency while maintaining the in vitro antioxidant activity of fisetin. Addition of 20%v/v ethanol in water improved the amount of solubilized fisetin in the complex 5.9-fold compared to the system containing water alone. Spray drying of fisetin-SBE-ß-CD complex solution in the presence of ethanol produced a dry powder with improved aerosolization properties when delivered from a dry powder inhaler, indicated by a 2-fold increase in the fine particle fraction (FPF) compared to the powder produced from the complex solution containing water alone. The pitted morphological surface of these particles suggested a more hollow internal structure, indicating a lighter and less dense powder. Incorporation of 20%w/w leucine improved the particle size distribution of the powder and further increased the FPF by 2.3-fold. This formulation also showed an EC50 value equivalent to fisetin alone in the A549 cell line. In conclusion, an inhalable dry powder containing fisetin-SBE-ß-CD complex was successfully engineered with an improved aqueous solubility of fisetin. The dry powder may be useful to deliver high amounts of fisetin to the deep lung region for therapeutic purposes.

Solid Lipid Nanoparticles of Atovaquone Based on 2(4) Full-Factorial Design.

Solid lipid nanoparticles of atovaquone (ATQ-SLN) were prepared by high shear homogenization method using tripalmitin, trilaurin, and Compritol 888 ATO as the lipid matrices and Phospholipon 90H, Tween 80, and poloxamer 188 as the surfactants. Optimization of the formulations was conducted using 6 sets of 2(4) full-factorial design based on four independent variables that were the number of homogenizing cycles, concentration of the lipid, concentration of the co-surfactant, and concentration of the main surfactant. The dependent variables were particle size and polydispersity index (PdI). The homogenizing cycles showed a negative influence on the dependent variables which reduced both the particle size and the PdI value. Moreover, a combination of certain percentages of the main surfactant and co-surfactant also showed a negative influence that reduced both the particle size and PdI value. Selected formulations from each design were further characterized for the entrapment efficiency and yield. The optimised formulation of ATQ-SLN consisted of trilaurin, Phospholipon 90H and Tween 80 with a particle size of 89.4 ± 0.2 nm and entrapment efficiency of 83.0 ± 1.7%. The in-vitro release evaluation of the formulation showed a complete and immediate release of ATQ from the SLN that could be a solution to improve the poor aqueous solubility and hence poor bioavailability of the drug.

Advanced drug delivery to the lymphatic system: lipid-based nanoformulations.

The delivery of drugs and bioactive compounds via the lymphatic system is complex and dependent on the physiological uniqueness of the system. The lymphatic route plays an important role in transporting extracellular fluid to maintain homeostasis and in transferring immune cells to injury sites, and is able to avoid first-pass metabolism, thus acting as a bypass route for compounds with lower bioavailability, ie, those undergoing more hepatic metabolism. The lymphatic route also provides an option for the delivery of therapeutic molecules, such as drugs to treat cancer and human immunodeficiency virus, which can travel through the lymphatic system. Lymphatic imaging is useful in evaluating disease states and treatment plans for progressive diseases of the lymph system. Novel lipid-based nanoformulations, such as solid lipid nanoparticles and nanostructured lipid carriers, have unique characteristics that make them promising candidates for lymphatic delivery. These formulations are superior to colloidal carrier systems because they have controlled release properties and provide better chemical stability for drug molecules. However, multiple factors regulate the lymphatic delivery of drugs. Prior to lymphatic uptake, lipid-based nanoformulations are required to undergo interstitial hindrance that modulates drug delivery. Therefore, uptake and distribution of lipid-based nanoformulations by the lymphatic system depends on factors such as particle size, surface charge, molecular weight, and hydrophobicity. Types of lipid and concentration of the emulsifier are also important factors affecting drug delivery via the lymphatic system. All of these factors can cause changes in intermolecular interactions between the lipid nanoparticle matrix and the incorporated drug, which in turn affects uptake of drug into the lymphatic system. Two lipid-based nanoformulations, ie, solid lipid nanoparticles and nanostructured lipid carriers, have been administered via multiple routes (subcutaneous, pulmonary, and intestinal) for targeting of the lymphatic system. This paper provides a detailed review of novel lipid-based nanoformulations and their lymphatic delivery via different routes, as well as the in vivo and in vitro models used to study drug transport in the lymphatic system. Physicochemical properties that influence lymphatic delivery as well as the advantages of lipid-based nanoformulations for lymphatic delivery are also discussed.