Although nitric oxide (NO) is a bactericidal component of the macrophage’s innate response to intracellular infections such as tuberculosis (TB), prolonged inhalation of NO gas has little benefit in ...chemotherapy of TB. The impact of controlled release of NO through intracellular delivery of NO donors to macrophages infected in vitro with Mycobacterium tuberculosis (Mtb) was investigated. Inhalable microparticles (MP) were prepared by spray-drying. Isosorbide mononitrate (ISMN), sodium nitroprusside (SNP), and diethylenetriamine nitric oxide adduct (DETA/NO) were incorporated in poly(lactic-co-glycolic acid) (PLGA) with encapsulation efficiencies of >90% to obtain MP yields of ∼70%. The mass median aerodynamic diameter (MMAD) of the MP was 2.2–2.4 μm within geometric standard deviations (GSD) of ≤0.1 μm. MP were phagocytosed by THP-1 derived macrophages in culture and significantly (P < 0.05) sustained NO secretion into culture supernatant from 6 to 72 h in comparison to equivalent amounts of drugs in solution. Significantly (P < 0.05) higher dose-dependent killing of intracellular Mtb by MP compared to equivalent amounts of drugs in solution was observed on estimation of colony forming units (CFU) surviving 24 h after exposure to drugs or MP. The cytotoxicity of MP toward macrophages was lower than that of dissolved drugs. It was concluded that inhalable MP can target NO donors to the macrophage, control NO release in the macrophage cytosol, and reduce Mtb CFU by up to 3-log in 24 h, at doses that are much lower than those required for cardiovascular effects.
Flavonoids represent a major group of polyphenolic compounds. Their capacity to inhibit tumor proliferation, cell cycle, angiogenesis, migration and invasion is substantially responsible for their ...chemotherapeutic activity against lung cancer. However, their clinical application is limited due to poor aqueous solubility, low permeability and quick blood clearance, which leads to their low bioavailability. Nanoengineered systems such as liposomes, nanoparticles, micelles, dendrimers and nanotubes can considerably enhance the targeted action of the flavonoids with improved efficacy and pharmacokinetic properties, and flavonoids can be successfully translated from bench to bedside through various nanoengineering approaches. This review addresses the therapeutic potential of various flavonoids and highlights the cutting-edge progress in the nanoengineered systems that incorporate flavonoids for treating lung cancer.
This study aimed to formulate a self-nanoemulsifying drug delivery system (SNEDDS) for enhanced pharmacokinetic (PK) behavior of rifampicin and isoniazid using excipients holding innate ...anti-mycobacterial activity followed with in vivo – in silico predictions using GastroPlus™. The optimized formulations of rifampicin (RIF-OF1) and isoniazid (INH-OF1) were characterized for drug loading efficiency, viscosity, optical clarity, particle size, zeta potential, morphological assessment and in vitro drug release. The oral bioavailability of RIF-OF1 and INH-OF1 was estimated in rats using validated UPLC MS/MS. The results of in vitro studies showed better drug loading, Newtonian rheological behavior and nanosized globular morphology of SNEDDS. In vitro drug release of both drugs was found to be higher at pH 1.2 and 6.8 as compared to their respective suspensions. The AUC and C max values of RIF-OF1 were increased by 3.72 and 5.22 fold compared to the RIF suspension, respectively, whereas INH-OF1 has shown that these values increased by 1.604 and 2.69 times compared to the INH suspension, respectively. Parameter sensitivity analysis predicted the considerable effect of solubility and permeability on main PK profiles. GastroPlus predicted maximum compartmental absorption of RIF-OF1 from proximal and distal portions of intestine whereas INH-OF1 was mainly absorbed from the duodenum and jejunum portions followed with improved PK parameters. The MIC value of the optimized formulation was reduced as compared to the pure drug indicating drugs acting in tandem in the explored carrier. The study suggested that the explored strategy could be a suitable alternative to conventional delivery systems for improved oral bioavailability of anti-tubercular drugs working in tandem.
Lung cancer is the second leading cause of cancer-related mortality globally, and non-small-cell lung cancer accounts for most lung cancer cases. Nanotechnology-based drug-delivery systems have ...exhibited immense potential in lung cancer therapy due to their fascinating physicochemical characteristics,
stability, bioavailability, prolonged and targeted delivery, gastrointestinal absorption and therapeutic efficiency of their numerous chemotherapeutic agents. However, traditional chemotherapeutics have systemic toxicity issues; therefore, dietary polyphenols might potentially replace them in lung cancer treatment. Polyphenol-based targeted nanotherapeutics have demonstrated interaction with a multitude of protein targets and cellular signaling pathways that affect major cellular processes. This review summarizes the various molecular mechanisms and targeted therapeutic potentials of nanoengineered dietary polyphenols in the effective management of lung cancer.
Nicotinamide (NIC), also called vitamin B-3, is commonly known as a pellagra-preventive drug. Citric acid (CA) is a weak tribasic acid, generally used as a flavouring and chelating agent. Herein, a ...combined experimental and quantum chemical approach was adopted to study the structural properties and spectroscopic signatures of nicotinamide-citric acid (NIC-CA) cocrystals using monomer (2NIC + CA) and cluster (4NIC + CA) models. In the cluster model, two additional NIC molecules were attached to cover the nearest possible interactions to understand the complete molecular geometries and hydrogen bonding interactions present in the cocrystal. In addition to this, our strategy was to calculate and analyse the physicochemical properties of NIC and CA along with improved properties after NIC-CA cocrystal formation. The observed red shift in the stretching modes of C&z.dbd;O and N-H of the NH
2
groups of NIC and the C&z.dbd;O and O-H groups of CA along with the elongation in bond lengths in the cluster model of NIC-CA indicated the presence of hydrogen bonding interactions as well as the formation of cocrystals. Moreover, natural bond orbital (NBO) analysis was performed to obtain information about the interactions that were responsible for the stability and formation of the NIC-CA cocrystal. The 'quantum theory of atoms in molecules' (QTAIM) calculations revealed that all the intra- and intermolecular hydrogen bonding interactions present in the NIC-CA (monomer) and NIC-CA (cluster) model were partially covalent in nature. The molecular electrostatic potential (MESP) map of NIC and CA shows that the carbonyl (C&z.dbd;O) group and C-N of the pyridine ring in NIC are prone to electrophilic attack, and the hydroxyl (O-H) group of CA is prone to nucleophilic attack. The chemical reactivity parameters calculated using both models show that the NIC-CA cocrystal is more reactive and softer than NIC (API) and CA (co-former) since the band gap of the cocrystal is less than that of both NIC and CA.
The hydrogen bond interactions in the cocrystal lead to spatial arrangements enhancing the physicochemical properties.
The pharmaceutical cocrystal of caffeine-citric acid (CAF-CA, Form II) has been studied to explore the presence of hydrogen bonding interactions and structure-reactivity-property relationship between ...the two constituents CAF and Citric acid. The cocrystal was prepared by slurry crystallization. Powder X-ray diffraction (PXRD) analysis was done to characterize CAF-CA cocrystal. Also, differential scanning calorimetry (DSC) confirmed the existence of CAF-CA cocrystal. The vibrational spectroscopic (FT-IR and FT-Raman) signatures and quantum chemical approach have been used as a strategy to get insights into structural and spectral features of CAF-CA cocrystal. There was a good correlation among the experimental and theoretical results of dimer of cocrystal, as this model is capable of covering all nearest possible interactions present in the crystal structure of cocrystal. The spectroscopic results confirmed that (O33-H34) mode forms an intramolecular (C25 = O28∙∙∙H34-O33), while (O26-H27) (O39-H40) and (O43-H44) groups form intermolecular hydrogen bonding (O26-H27∙∙∙N24-C22, O39-H40∙∙∙O52 = C51 and O43-H44∙∙∙O86 = C83) in cocrystal due to red shifting and increment in bond length. The quantum theory of atoms in molecules (QTAIM) analysis revealed (O88-H89∙∙∙O41) as strongest intermolecular hydrogen bonding interaction with interaction energy -12.4247 kcal mol
in CAF-CA cocrystal. The natural bond orbital analysis of the second-order theory of the Fock matrix highlighted the presence of strong interactions (N∙∙∙H and O∙∙∙H) in cocrystal. The HOMO-LUMO energy gap value shows that the CAF-CA cocrystal is more reactive, less stable and softer than CAF active pharmaceutical ingredients. The electrophilic and nucleophilic reactivities of atomic sites involved in intermolecular hydrogen bond interactions in cocrystal have been demonstrated by mapping electron density isosurfaces over electrostatic potential i.e. plotting molecular electrostatic potential (MESP) map. The molar refractivity value of cocrystal lies within the set range by Lipinski and hence it may be used as orally active form. The results show that the physicochemical properties of CAF-CA cocrystal are enhanced in comparison to CAF (API).
Pseudomonas aeruginosa
has been implicated in a broad range of infections and shown to acquire rapid resistance to anti-microbial agents. In the present, study we have used particular amalgamation of ...specific lipids that hold innate antibacterial activities, which can be transformed into cationized and non-cationized nanoemulsions. The anti-
Pseudomonas
activities were then elucidated by transmission/scanning electron microscopy, and atomic force microscopy. The microscopic studies revealed the cell lysis due to the formation of blebs, exudation of essential cellular contents and loss of characteristics contour of the cells. The microscopic studies were then corroborated by zone of inhibition, cytoplasmic release studies, time dependent killing and MIC determination. Conclusively, it can be inferred that the delivery issues of antibiotics could be reassessed by using certain excipients that possess inherent antibacterial properties. This will not only avoid unnecessary introduction of inactive excipients in the body, but will also reduce the dose of antibiotics because of synergistic effects of excipients and drug acting together.
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