Intranasal Delivery of Carvedilol- and Quercetin-Encapsulated Cationic Nanoliposomes for Cardiovascular Targeting: Formulation and In Vitro and Ex Vivo Studies.

Carvedilol (CVD), an adrenoreceptor blocker, is a hydrophobic Biopharmaceutics Classification System class II drug with poor oral bioavailability due to which frequent dosing is essential to attain pharmacological effects. Quercetin (QC), a polyphenolic compound, is a potent natural antioxidant, but its oral dosing is restricted due to poor aqueous solubility and low oral bioavailability. To overcome the common limitations of both drugs and to attain synergistic cardioprotective effects, we formulated CVD- and QC-encapsulated cationic nanoliposomes (NLPs) in situ gel (CVD/QC-L.O.F.) for intranasal administration. We designed CVD- and QC-loaded cationic nanoliposomal (NLPs) in situ gel (CVD/QC-L.O.F.) for intranasal administration. In vitro drug release studies of CVD/QC-L.O.F. (16.25%) exhibited 18.78 ± 0.57% of QC release and 91.38 ± 0.93% of CVD release for 120 h. Ex vivo nasal permeation studies of CVD/QC-L.O.F. demonstrated better permeation of QC (within 96 h), i.e., 75.09% compared to in vitro drug release, whereas CVD permeates within 48 h, indicating the better interaction between cationic NLPs and the negatively charged biological membrane. The developed nasal gel showed a sufficient mucoadhesive property, good spreadability, higher firmness, consistency, and cohesiveness, indicating suitability for membrane application and intranasal administration. CVD-NLPs, QC-NLPs, and CVD/QC-NLPs were evaluated for in vitro cytotoxicity, in vitro ROS-induced cell viability assessment, and a cellular uptake study using H9c2 rat cardiomyocytes. The highest in vitro cellular uptake of CVD/QC-cationic NLPs by H9c2 cells implies the benefit of QC loading within the CVD nanoliposomal carrier system and gives evidence for better interaction of NLPs carrying positive charges with the negatively charged biological cells. The in vitro H2O2-induced oxidative stress cell viability assessment of H9c2 cells established the intracellular antioxidant activity and cardioprotective effect of CVD/QC-cationic NLPs with low cytotoxicity. These findings suggest the potential of cationic NLPs as a suitable drug delivery carrier for CVD and QC combination for the intranasal route in the treatment of various cardiovascular diseases like hypertension, angina pectoris, etc. and for treating neurodegenerative disorders.

Therapeutic Implications of Dietary Polyphenols-Loaded Nanoemulsions in Cancer Therapy.

Cancer is one of the major causes of death worldwide, even the second foremost cause related to non-communicable diseases. Cancer cells typically possess several cellular and biological processes including, persistence, propagation, differentiation, cellular death, and expression of cellular-type specific functions. The molecular picture of carcinogenesis and progression is unwinding, and it appears to be a tangled combination of processes occurring within and between cancer cells and their surrounding tissue matrix. Polyphenols are plant secondary metabolites abundant in fruits, vegetables, cereals, and other natural plant sources. Natural polyphenols have implicated potential anticancer activity by various mechanisms involved in their antitumor action, including modulation of signaling pathways majorly related to cellular proliferation, differentiation, relocation, angiogenesis, metastatic processes, and cell death. The applications of polyphenols have been limited due to the hydrophobic nature and lower oral bioavailability that could be possibly overcome through encapsulating them into nanocarrier-mediated delivery systems, leading to improved anticancer activity. Nanoemulsions (NEs) possess diverse feasible properties, including greater surface area, modifiable surficial charge, higher half-life, site-specific targeting, and formulation imaging capability necessary to create a practical therapeutic impact, and have drawn increased attention in cancer therapy research. This review has summarized and discussed the basic concepts, classification, delivery approaches, and anticancer mechanism of various polyphenols and polyphenols-encapsulated nanoemulsions with improved cancer therapy.

Characterization and Exploration of Placket-Burman-Designed Porous Calcium Carbonate (Vaterite) Microparticles.

The objective of the research was to identify significant variables that impact the porosity-related properties of CaCO3 particles. The Placket-Burman design was employed to screen multiple variables, including pH, molar concentrations of calcium chloride and sodium carbonate, temperature, concentration of Gelucire 44/14, Cremophor RH40, Solutol HS15, Labrasol, mixing rate, reaction time, and order of addition. The response variables were surface area, pore radius, and pore volume. Influential methodologies such as XRD, FTIR, Raman spectroscopy, and TGA were utilized to validate the precipitate type. The BET surface area ranged from 1.5 to 16.14 m2/g, while the pore radius varied from 2.62 to 6.68 nm, and the pore volume exhibited a range of 2.43 to 37.97 cc/gm. Vaterite structures with spherical mesoporous characteristics were observed at high pH, whereas calcite formations occurred at low pH. The order of addition impacted the surface area but did not affect the pore volume. To maximize the surface area, a lower reaction time and molar concentrations of sodium carbonate were found to be advantageous. The pore radius was influenced by the pH, surfactants, and reaction conditions. The sediments were categorized based on the percentage of vaterite formation. The instrumental techniques effectively characterized the precipitates and provided a valuable complementary analysis.

Recent Advances in the Carotenoids Added to Food Packaging Films: A Review.

Food spoilage is one of the key concerns in the food industry. One approach is the improvement of the shelf life of the food by introducing active packaging, and another is intelligent packaging. Detecting packed food spoilage in real-time is key to stopping outbreaks caused by food-borne diseases. Using active materials in packaging can improve shelf life, while the nonharmful color indicator can be useful to trace the quality of the food through simple color detection. Recently, bio-derived active and intelligent packaging has gained a lot of interest from researchers and consumers. For this, the biopolymers and the bioactive natural ingredient are used as indicators to fabricate active packaging material and color-changing sensors that can improve the shelf life and detect the freshness of food in real-time, respectively. Among natural bioactive components, carotenoids are known for their good antimicrobial, antioxidant, and pH-responsive color-indicating properties. Carotenoids are rich in fruits and vegetables and fat-soluble pigments. Including carotenoids in the packaging system improves the film's physical and functional performance. The recent progress on carotenoid pigment-based packaging (active and intelligent) is discussed in this review. The sources and biological activity of the carotenoids are briefly discussed, and then the fabrication and application of carotenoid-activated packaging film are reviewed. The carotenoids-based packaging film can enhance packaged food's shelf life and indicate the freshness of meat and vegetables in real-time. Therefore, incorporating carotenoid-based pigment into the polymer matrix could be promising for developing novel packaging materials.

Biopolymer-Capped Pyrazinamide-Loaded Colloidosomes: In Vitro Characterization and Bioavailability Studies.

This study aimed to prepare colloidosome particles loaded with pyrazinamide (PZA). These drug-loaded colloidosomes were prepared using an in situ gelation technique using a central composite design with a shell made of calcium carbonate (CaCO3) particles. Optimal amounts of 150 mg of CaCO3, sodium alginate (2%), and 400 mg of poly(3-hydroxybutyrate-co-3-hydroxy valerate) (PHBV) concentration resulted in the maximum drug loading and efficient release profile. Field emission scanning electron microscopy results showed spherical porous particles with a good coating of the PHBV polymer. Additionally, Fourier transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC), thermogravimetric and differential thermal analysis (TGA-DTA), and X-ray diffraction (XRD) analysis showed good compatibility between the drug and excipients. The pharmacokinetic studies demonstrated that the drug-loaded colloidosomes resulted in 4.26 times higher plasma drug concentrations with Cmax values of 32.386 ± 2.744 mcg/mL (PZA solution) and 115.868 ± 53.581 mcg/mL (PZA-loaded colloidosomes) and AUC0-t values of 61.24 mcg-h/mL (PZA solution) and 260.9 mcg-h/mL (PZA-loaded colloidosomes), indicating that colloidosomes have the potential to be effective drug carriers for delivering PZA to the target site.

Cannabidiol-Loaded Nanocarriers and Their Therapeutic Applications.

Cannabidiol (CBD), one of the most promising constituents isolated from Cannabis sativa, exhibits diverse pharmacological actions. However, the applications of CBD are restricted mainly due to its poor oral bioavailability. Therefore, researchers are focusing on the development of novel strategies for the effective delivery of CBD with improved oral bioavailability. In this context, researchers have designed nanocarriers to overcome limitations associated with CBD. The CBD-loaded nanocarriers assist in improving the therapeutic efficacy, targetability, and controlled biodistribution of CBD with negligible toxicity for treating various disease conditions. In this review, we have summarized and discussed various molecular targets, targeting mechanisms and types of nanocarrier-based delivery systems associated with CBD for the effective management of various disease conditions. This strategic information will help researchers in the establishment of novel nanotechnology interventions for targeting CBD.

Liquid Chromatography-Electrospray Ionization Tandem Mass Spectrometry Estimation of Quercetin-Loaded Nanoemulsion in Rabbit Plasma: In Vivo-In Silico Pharmacokinetic Analysis Using GastroPlus.

In the present study, we developed and validated a rapid, specific, sensitive, and reproducible liquid chromatography-electrospray ionization tandem mass spectrometry method for quantifying quercetin (QT) in rabbit plasma using hydrochlorothiazide as the internal standard. Animals were orally administered with optimized QT-loaded nanoemulsion (QTNE) and QT suspension (QTS), equivalent to 30 mg/kg, to the test and control group, respectively. The blood samples were collected at pre-determined time points up to 48 h. The linearity range was from 5 to 5000 ng mL-1 with R 2 = 0.995. Further, we analyzed the various pharmacokinetic parameters and established the in vitro-in vivo correlation (IVIVC) of QTNE using GastroPlus software. The method was successfully developed and validated, and when applied for the determination of QT in rabbit plasma, it exhibited an increase in C max from 122.56 ng mL-1 (QTS) to 286.51 ng mL-1 (QTNE) (2.34-fold) and AUC0-48 from 976 ng h mL-1 (QTS) to 4249 ng h mL-1 (QTNE) (4.35-fold), indicating improved oral bioavailability QT when administered as QTNE. Statistical analysis revealed that the Loo-Riegelman method (two-compartmental method) best fitted the deconvolution approach (R 2 = 0.998, SEP = 4.537, MAE = 2.759, and AIC = 42.38) for establishing the IVIVC. In conclusion, the established bioanalytical method and IVIVC studies revealed that QTNE is a potential carrier for the effective delivery of QT with enhanced oral bioavailability.

Oral Brincidofovir Therapy for Monkeypox Outbreak: A Focused Review on the Therapeutic Potential, Clinical Studies, Patent Literature, and Prospects.

The monkeypox disease (MPX) outbreak of 2022 has been reported in more than one hundred countries and is becoming a global concern. Unfortunately, only a few treatments, such as tecovirimat (TCV), are available against MPX. Brincidofovir (BCV) is a United States Food and Drug Administration (USFDA)-approved antiviral against smallpox. This article reviews the potential of BCV for treating MPX and other Orthopoxvirus (OPXVs) diseases. The literature for this review was collected from PubMed, authentic websites (USFDA, Chimerix), and freely available patent databases (USPTO, Espacenet, and Patentscope). BCV (a lipophilic derivative of cidofovir) has been discovered and developed by Chimerix Incorporation, USA. Besides smallpox, BCV has also been tested clinically for various viral infections (adenovirus, cytomegalovirus, ebola virus, herpes simplex virus, and double-stranded DNA virus). Many health agencies and reports have recommended using BCV for MPX. However, no health agency has yet approved BCV for MPX. Accordingly, the off-label use of BCV is anticipated for MPX and various viral diseases. The patent literature revealed some important antiviral compositions of BCV. The authors believe there is a huge opportunity to create novel, inventive, and patentable BCV-based antiviral therapies (new combinations with existing antivirals) for OPXVs illnesses (MPX, smallpox, cowpox, camelpox, and vaccinia). It is also advised to conduct drug interaction (food, drug, and disease interaction) and drug resistance investigations on BCV while developing its combinations with other medications. The BCV-based drug repurposing options are also open for further exploration. BCV offers a promising opportunity for biosecurity against OPXV-based bioterrorism attacks and to control the MPX outbreak of 2022.

Curcumin-loaded alginate hydrogels for cancer therapy and wound healing applications: A review.

Hydrogels have emerged as a versatile platform for a numerous biomedical application due to their ability to absorb a huge quantity of biofluids. In order to design hydrogels, natural polymers are an attractive option owing to their biocompatibility and biodegradability. Due to abundance in occurrence, cost effectiveness, and facile crosslinking approaches, alginate has been extensively investigated to fabricate hydrogel matrix. Management of cancer and chronic wounds have always been a challenge for pharmaceutical and healthcare sector. In both cases, curcumin have been shown significant improvement and effectiveness. However, the innate restraints like poor bioavailability, hydrophobicity, and rapid systemic clearance associated with curcumin have restricted its clinical translations. The current review explores the cascade of research around curcumin encapsulated alginate hydrogel matrix for wound healing and cancer therapy. The focus of the review is to emphasize the mechanistic effects of curcumin with its fate inside the cells. Further, the review discusses different approaches to designed curcumin loaded alginate hydrogels along with the parameters that regulates their release behavior. Finally, the review is concluded with emphasize on some key aspect on increasing the efficacy of these hydrogels along with novel strategies to further develop curcumin loaded alginate hydrogel matrix with multifacet applications.

Neuroprotective Role of Quercetin against Alpha-Synuclein-Associated Hallmarks in Parkinson's Disease.

Quercetin, a natural antioxidant, exhibits potential neuroprotective effects by efficiently downregulating α-synuclein protein aggregation and associated neurological hallmarks, responsible for the progression of Parkinson's Disease.

Neuropharmacological interventions of quercetin and its derivatives in neurological and psychological disorders.

Quercetin is a naturally occurring bioactive flavonoid abundant in many plants and fruits. Quercetin and its derivatives have shown an array of pharmacological activities in preclinical tests against various illnesses and ailments. Owing to its protective role against oxidative stress and neuroinflammation, quercetin is a possible therapeutic choice for the treatment of neurological disorders. Quercetin and its derivatives can modulate a variety of signal transductions, including neuroreceptor, neuroinflammatory receptor, and redox signaling events. The research on quercetin and its derivatives in neurology-related illnesses mainly focused on the targets, such as redox stress, neuroinflammation, and signaling pathways; however, the function of quercetin and its derivatives on specific molecular targets, such as nuclear receptors and proinflammatory mediators are yet to be explored. Findings showed that various molecular targets of quercetin and its derivatives have therapeutic potential against psychological and neurodegenerative disorders.

Quantum dots: The cutting-edge nanotheranostics in brain cancer management.

Quantum dots (QDs) are semiconductor nanocrystals possessing unique optoelectrical properties in that they can emit light energy of specific tunable wavelengths when excited by photons. They are gaining attention nowadays owing to their all-around ability to allow high-quality bio-imaging along with targeted drug delivery. The most lethal central nervous system (CNS) disorders are brain cancers or malignant brain tumors. CNS is guarded by the blood-brain barrier which poses a selective blockade toward drug delivery into the brain. QDs have displayed strong potential to deliver therapeutic agents into the brain successfully. Their bio-imaging capability due to photoluminescence and specific targeting ability through the attachment of ligand biomolecules make them preferable clinical tools for coming times. Biocompatible QDs are emerging as nanotheranostic tools to identify/diagnose and selectively kill cancer cells. The current review focuses on QDs and associated nanoformulations as potential futuristic clinical aids in the continuous battle against brain cancer.

Therapeutic Potential of Quercetin-Loaded Nanoemulsion against Experimental Visceral Leishmaniasis: In Vitro/Ex Vivo Studies and Mechanistic Insights.

Visceral leishmaniasis (VL) is one of the most fatal and neglected tropical diseases caused by Leishmania donovani (L. donovani). The applications of currently available chemotherapy (amphotericin B, miltefosine, and others) in VL treatment have been limited due to their poor bioavailability, unfavorable toxicity profile, and prolonged parenteral dosing. Quercetin (QT), a potent natural antioxidant, is a prominent target when conducting investigations on alternative therapies against L. donovani infections. However, the therapeutic applications of QT have been restricted due to its low solubility and bioavailability. In the present study, we developed and evaluated the antileishmanial activity (ALA) of quercetin-loaded nanoemulsion (QTNE) against L. donovani clinical strains. In vitro anti-promastigote assay results demonstrated that QTNE (IC50 6.6 µM, 48 h) significantly inhibited the growth of parasites more efficiently than the pure QT suspension in a dose- and time-dependent manner. Results of the anti-amastigote assay revealed that the infected macrophages (%) of QTNE were significantly more than those of the pure QT suspension at all concentrations (6.6, 26.4, and 52.8 µM; p < 0.05, p < 0.01 compared to the control). Moreover, the results of in vitro and ex vivo studies assisted in determining the mechanistic insights associated with the ALA of QTNE. The overall findings suggested that QTNE exhibited potential ALA by enhancing the intracellular ROS and nitric oxide levels, inducing distortion of membrane integrity and phosphatidylserine release (AV/PI), rupturing the parasite DNA (late apoptosis/necrosis process), and upregulating the immunomodulatory effects (IFN-γ and IL-10 levels). Additionally, QTNE showed superior biocompatibility against all of the treated healthy cells (PBMCs, PECs, and BMCs) as compared to the control. In conclusion, QTNE acts as a potential antileishmanial agent targeting both promastigote and intracellular amastigote forms of L. donovani, which thus opens a new avenue for the use of QTNE in VL therapy.

Food-Grade Quercetin-Loaded Nanoemulsion Ameliorates Effects Associated with Parkinson's Disease and Cancer: Studies Employing a Transgenic C. elegans Model and Human Cancer Cell Lines.

A nanosized food-grade quercetin-loaded nanoemulsion (QNE) system comprising capmul MCM NF (oil) and cremophor RH 40 (surfactant) was developed using a high-speed homogenization technique. The developed QNE was studied for its significant neuroprotective (anti-Parkinsonism) and cytotoxicity (anticancer) effects against Caenorhabditis elegans (C. elegans) strains and human cancer cells, respectively. HR-TEM studies revealed that the QNE was spherical with a mean globule size of ~50 nm. Selected area electron diffraction (SAED) studies results demonstrated that QNE was amorphous. In vivo results show that QNE potentially reduced the α-Syn aggregation, increased mitochondrial and fat content, and improved the lifespan in transgenic C. elegans strain NL5901. QNE significantly downregulated the reactive oxygen species (ROS) levels in wild-type C. elegans strain N2. In vitro results of the MTT assay show that QNE significantly exhibited chemotherapeutic effects in all treated human cancer cells in an order of cytotoxicity: HeLa cells > A549 cells > MIA PaCa-2 cells, based on the IC50 values at 24 h. Conclusively, the QNE showed improved solubility, targetability, and neuroprotective effects against the PD-induced C. elegans model, and also cytotoxicity against human cancer cells and could be potentially used as an anti-Parkinson's or anticancer agent.

Mechanistic role of HPV-associated early proteins in cervical cancer: Molecular pathways and targeted therapeutic strategies.

PURPOSE: Cervical cancer (CC), one of the major causes of death of women throughout the world is primarily caused due to Human Papilloma Virus (HPV) 16 and 18. The early region (E) oncoproteins of HPV are associated with the etiopathogenesis and contribute to the progression of cancer. The present article comprehensively discussed the structural organization and biological functions of all E proteins of HPV and their contribution to progression of CC with an intent to decipher the pathological hallmarks and their relationship. Additionally, the role of E proteins in reference to therapeutics will also be presented. METHODS: A systematic search has been carried out for articles published in PubMed database by using combinations of different keywords with Boolean operators (AND, OR, NOT) including cervical cancer, HPV, E proteins, and signaling. RESULTS: From the analysis of literature review, its apparent that E proteins are the major contributor to disease progression. E1, E2, and E4 forms are mainly associated with viral integration, replication, and transcription whereas E6 and E7 act as an oncoprotein and are associated with the progression of cancer. E5 regulates cell proliferation, apoptosis, and facilitates the activity of E6 and E7. Additionally, E proteins were observed associated with numerous cell signaling pathways including PI3K/AKT, Wnt, Notch and reasonably contribute to the initiation of malignancy, cell proliferation, metastasis, and drug resistance. Knowing the role and interplay of each protein in initiation to progression of CC, their therapeutic significance has been elucidated. The present study observations demonstrate that E6 and E7 are the major cause of HPV-mediated CC progression. E1, E2, and E5 also act as a backbone for E6 and E7 and most of the current approaches have targeted E6 and E7 mediated action only. CONCLUSION: The present review illustrates the structural organization as well as function and regulation of all early proteins of HPV and their association with several cellular signaling pathways. The observations provide clue on the regulatory aspect of these proteins in initiation to progression and reasonably represent that targeting these proteins could be a novel therapeutic strategy for CC. In particular, its seemingly appears that inhibition of the activity of E6 and E7 oncoproteins may be a better selective target to delay the progression of CC. The review reaffirms the role of E proteins and encourages future studies on developing diagnostics, and most importantly therapeutics strategies targeting E6 and E7 oncoproteins to tackle CC related morbidity and mortality.

Molecular Insights into Therapeutic Potentials of Hybrid Compounds Targeting Alzheimer's Disease.

Alzheimer's disease (AD) is one of the most complex progressive neurological disorders involving degeneration of neuronal connections in brain cells leading to cell death. AD is predominantly detected among elder people (> 65 years), mostly diagnosed with the symptoms of memory loss and cognitive dysfunctions. The multifarious pathogenesis of AD comprises the accumulation of pathogenic proteins, decreased neurotransmission, oxidative stress, and neuroinflammation. The conventional therapeutic approaches are limited to symptomatic benefits and are ineffective against disease progression. In recent years, researchers have shown immense interest in the designing and fabrication of various novel therapeutics comprised of naturally isolated hybrid molecules. Hybrid therapeutic compounds are developed from the combination of pharmacophores isolated from bioactive moieties which specifically target and block various AD-associated pathogenic pathways. The method of designing hybrid molecules has numerous advantages over conventional multitarget drug development methods. In comparison to in silico high throughput screening, hybrid molecules generate quicker results and are also less expensive than fragment-based drug development. Designing hybrid-multitargeted therapeutic compounds is thus a prospective approach in developing an effective treatment for AD. Nevertheless, several issues must be addressed, and additional researches should be conducted to develop hybrid therapeutic compounds for clinical usage while keeping other off-target adverse effects in mind. In this review, we have summarized the recent progress on synthesis of hybrid compounds, their molecular mechanism, and therapeutic potential in AD. Using synoptic tables, figures, and schemes, the review presents therapeutic promise and potential for the development of many disease-modifying hybrids into next-generation medicines for AD.

Re-establishing the comprehension of phytomedicine and nanomedicine in inflammation-mediated cancer signaling.

Recent mounting evidence has revealed extensive genetic heterogeneity within tumors that drive phenotypic variation affecting key cancer pathways, making cancer treatment extremely challenging. Diverse cancer types display resistance to treatment and show patterns of relapse following therapy. Therefore, efforts are required to address tumor heterogeneity by developing a broad-spectrum therapeutic approach that combines targeted therapies. Inflammation has been progressively documented as a vital factor in tumor advancement and has consequences in epigenetic variations that support tumor instigation, encouraging all the tumorigenesis phases. Increased DNA damage, disrupted DNA repair mechanisms, cellular proliferation, apoptosis, angiogenesis, and its incursion are a few pro-cancerous outcomes of chronic inflammation. A clear understanding of the cellular and molecular signaling mechanisms of tumor-endorsing inflammation is necessary for further expansion of anti-cancer therapeutics targeting the crosstalk between tumor development and inflammatory processes. Multiple inflammatory signaling pathways, such as the NF-κB signaling pathway, JAK-STAT signaling pathway, MAPK signaling, PI3K/AKT/mTOR signaling, Wnt signaling cascade, and TGF-ß/Smad signaling, have been found to regulate inflammation, which can be modulated using various factors such as small molecule inhibitors, phytochemicals, recombinant cytokines, and nanoparticles (NPs) in conjugation to phytochemicals to treat cancer. Researchers have identified multiple targets to specifically alter inflammation in cancer therapy to restrict malignant progression and improve the efficacy of cancer therapy. siRNA-and shRNA-loaded NPs have been observed to downregulate STAT3 signaling pathways and have been employed in studies to target tumor malignancies. This review highlights the pathways involved in the interaction between tumor advancement and inflammatory progression, along with the novel approaches of nanotechnology-based drug delivery systems currently used to target inflammatory signaling pathways to combat cancer.