Transporter targeted-carnitine modified pectin-chitosan nanoparticles for inositol hexaphosphate delivery to the colon: An in silico and in vitro approach.

Orally targeted delivery systems have attracted ample interest in colorectal cancer management. In this investigation, we developed Inositol hexaphosphate (IHP) loaded Tripolyphosphate (Tr) crosslinked Pectin (Pe) Chitosan (Ch) nanoparticles (IHP@Tr*Pe-Ch-NPs) and modified them with l-Carnitine (CE) (CE-IHP@Tr*Pe-Ch-NPs) to improve uptake in colon cells. The formulated CE-IHP@Tr*Pe-Ch-NPs displayed a monodisperse distribution with 219.3 ± 5.5 nm diameter and 30.17 mV surface charge. Cell-line studies revealed that CE-IHP@Tr*Pe-Ch-NPs exhibited excellent biocompatibility in J774.2 and decreased cell viability in DLD-1, HT-29, and MCF7 cell lines. More cell internalization was seen in HT-29 and MCF7 due to overexpression of the OCTN2 and ATB0,+ transporter (CE transporters) compared to DLD-1. The cell cycle profile, reactive oxygen species, apoptosis, and mitochondrial membrane potential assays were performed to explore the chemo-preventive mechanism of CE-IHP@Tr*Pe-Ch-NPs. Moreover, the in-silico docking studies revealed enhanced interactive behavior of CE-IHP@Tr*Pe-Ch-NPs, thereby proving their targeting ability. All the findings suggested that CE-IHP@Tr*Pe-Ch-NPs could be a promising drug delivery approach for colon cancer targeting.

Synthesis of flaxseed gum/melanin-based scaffold: A novel approach for nano-encapsulation of doxorubicin with enhanced anticancer activity.

Doxorubicin is a powerful chemotherapy medicine that is frequently used to treat cancer, but because of its extremely destructive side effects on other healthy cells, its applications have been severely constrained. With the aim of using lower therapeutic doses of doxorubicin while maintaining the same anti-cancerous activity as those of higher doses, the present study designs nano-encapsulation of doxorubicin by acrylamide grafted melanin as core and acrylic acid grafted flax seed gum as shell (DOX@AAM-g-ML/AA-g-FSG-NPs) for studies in-vivo and in-vitro anticancer activity. For biological studies, the cytotoxicity of DOX@AAM-g-ML/AA-g-FSG-NPs was examined on a cancerous human cell line (HCT-15) and it was observed that DOX@AAM-g-ML/AA-g-FSG-NPs exhibited very high toxicity towards HCT-15. In-vivo investigation in colon cancer-inflicted rat model also showed that DOX@AAM-g-ML/AA-g-FSG-NPs showed better anticancer activity against cancerous cells as compared to free doxorubicin. The drug release behavior of DOX@GML-GFS-NPs was studied at several pH and maximum drug release (95 %) was recorded at pH -7.2, and kinetic data of drug release was follows the Higuchi (R2 = 0.9706) kinetic model. Our study is focussed on reducing the side effects of doxorubicin by its nano-encapsulation in acrylamide grafted melanin as core and acrylic acid grafted flax seed gum that will also enhance its efficiency.

Polymeric Gel Scaffolds and Biomimetic Environments for Wound Healing.

Infected wounds that do not heal are a worldwide problem that is worsening, with more people dying and more money being spent on care. For any disease to be managed effectively, its root cause must be addressed. Effective wound care becomes a bigger problem when various traditional wound healing methods and products may not only fail to promote good healing. Still, it may also hinder the healing process, causing wounds to stay open longer. Progress in tissue regeneration has led to developing three-dimensional scaffolds (3D) or constructs that can be leveraged to facilitate cell growth and regeneration while preventing infection and accelerating wound healing. Tissue regeneration uses natural and fabricated biomaterials that encourage the growth of tissues or organs. Even though the clinical need is urgent, the demand for polymer-based therapeutic techniques for skin tissue abnormalities has grown quickly. Hydrogel scaffolds have become one of the most imperative 3D cross-linked scaffolds for tissue regeneration because they can hold water perfectly and are porous, biocompatible, biodegradable, and biomimetic. For damaged organs or tissues to heal well, the porosity topography of the natural extracellular matrix (ECM) should be imitated. This review details the scaffolds that heal wounds and helps skin tissue to develop. After a brief overview of the bioactive and drug-loaded polymeric hydrogels, the discussion moves on to how the scaffolds are made and what they are made of. It highlights the present uses of in vitro and in-vivo employed biomimetic scaffolds. The prospects of how well bioactiveloaded hydrogels heal wounds and how nanotechnology assists in healing and regeneration have been discussed.

Assessment of anti-arthritic activity of lipid matrix encased berberine in rheumatic animal model.

The purpose of this study was to evaluate the drug delivery and therapeutic potential of berberine (Br) loaded nanoformulation in rheumatoid arthritis (RA)-induced animal model. The Br-loaded NLCs (nanostructured lipid carriers) were prepared employing melt-emulsification process, and optimised through Box-Behnken design. The prepared NLCs were assessed for in-vitro and in-vivo evaluations. The optimised NLCs exhibited a mean diameter of 180.2 ± 0.31 nm with 88.32 ± 2.43% entrapment efficiency. An enhanced anti-arthritic activity with reduced arthritic scores to 0.66 ± 0.51, reduction in ankle diameter to 5.80 ± 0.27 mm, decline in paw withdrawal timing, and improvements in walking behaviour were observed in the Br-NLCs treated group. The radiographic images revealed a reduction in bone and cartilage deformation. The Br-NLCs showed promising results in the management of RA disease, can be developed as an efficient delivery system at commercial levels, and may be explored for clinical application after suitable experiments in the future.

Downregulation of pro-inflammatory markers IL-6 and TNF-α in rheumatoid arthritis using nano-lipidic carriers of a quinone-based phenolic: an in vitro and in vivo study.

Rheumatoid arthritis (RA) is a joint ailment with multi-factorial immune-mediated degenerative pathogenesis, including genetic and environmental defects. Resistance to disease-modifying anti-rheumatic drugs (DMARDs) happens due to excessive drug efflux over time, rendering the concentration insufficient to elicit a response. Thymoquinone (TQ) is a quinone-based phenolic compound with antioxidant and anti-inflammatory activities that downregulate numerous pro-inflammatory cytokines. However, its pharmaceutical importance and therapeutic utility are underexplored due to intrinsic physicochemical characteristics such as inadequate biological stability, short half-life, low hydrophilicity, and less systemic availability. Tamanu oil-stabilised nanostructured lipid carriers (TQ-NLCs) were prepared and optimised using Box-Behnken design (BBD) with the size of 153.9 ± 0.52 nm and surface charge of -30.71 mV. The % entrapment efficiency and drug content were found to be 84.6 ± 0.50% and 14.75 ± 0.52%, respectively. Furthermore, the TQ-loaded NLCs (TQ-NLCs) assayed for skin permeation for transdermal delivery which significantly (p < 0.05) increased skin enhancement ratio 14.6 times compared to the aqueous solution of TQ. Tamanu oil displayed the synergistic anti-inflammatory potential with TQ in comparison to pure TQ, as evidenced against carrageenan (CRG)-induced paw oedema model and Freund's adjuvant-induced arthritic model. The arthritic and X-ray scores significantly (p < 0.05) reduced in TQ-NLCs and standard formulation-treated groups. Moreover, serum pro-inflammatory marker TNF-α and IL-6 levels were also significantly (p < 0.05) reduced in TQ-NLCs gel-treated group compared to the arthritic control group.

QbD-assisted development of lipidic nanocapsules for antiestrogenic activity of exemestane in breast cancer.

Some breast cancers are caused by hormonal imbalances, such as estrogen and progesterone. These hormones play a function in directing the growth of cancer cells. The hormone receptors in hormone receptor-positive breast cancer lead breast cells to proliferate out of control. Cancer therapy such as hormonal, targeted, radiation is still unsatisfactory because of these challenges namely multiple drug resistance (MDR), off-targeting, severe adverse effects. A novel aromatase inhibitor exemestane (Exe) exhibits promising therapy in breast cancer. This study aims to develop and optimize Exe-loaded lipid nanocapsules (LNCs) by using DSPC, PF68 and olive oil as lipid, surfactant and oil phase, respectively and to characterize the same. The prepared nanocapsules were investigated via in vitro cell culture and in vivo animal models. The LNCs exhibited cytotoxicity in MCF-7 cell lines and enhanced anti-cancer activity and reduced cardiotoxicity in DMBA-induced animal model when compared to the drug. Additionally, in vivo pharmacokinetics revealed a 4.2-fold increased oral bioavailability when compared with Exe suspension. This study demonstrated that oral administration of Exe-loaded LNCs holds promise for the antiestrogenic activity of exemestane in breast cancer.

Effective uptake of folate-functionalized ethionamide-loaded hybrid system: targeting alveolar macrophages.

Aim: To assess the targeting ability of hybrid nanosystems functionalized with folate. It also aimed to reduce stomach intolerance by substituting the oral route for parenteral delivery. Method: The nanosystems, prepared by nanoprecipitation technique, utilized a one-step method to prepare nanoparticles followed by surface functionalization through adsorption. The prepared nanosystems underwent physical characterization, in vitro and in vivo evaluations. Result: The nanosystems were effective in targeting the alveolar macrophages. Ethionamide was released from the formulation over 5 days. Fourier-transform infrared results proved the structural characteristics, and the positive charge further improved the targeting efficacy on the functionalized system. Conclusion: The hybrid formulation improved the release characteristics. Reduction in dosing frequency due to prolonged release improves compliance with the dosage regimen.

Functionalized bosutinib liposomes for target specific delivery in management of estrogen-positive cancer.

This study was designed to create surface-functionalized bosutinib liposomes that could be used for the management of estrogen-positive cancers. The novelty of this work was the anti-cancer activity of bosutinib-loaded liposomes (Bos-LPs) in estrogen-positive cancer via estrogen response elements, responsible for the malignancy of cancer cells. Biotin effectively delivers active moiety to tumor tissues because it interacts with the biotin receptor and operates through the Sodium-dependent multivitamin transporters (SMVT) transporter. The prepared liposomes had a 257.73 ± 4.50 nm particle size, - 28.07 ± 5.81 mV zeta potential, 87.78 ± 1.16 % encapsulation efficiency and 85.56 ± 0.95 % drug release for 48 h. The surface architecture of biotin-modified bosutinib-loaded liposomes (b-Bos-LPs) was confirmed using scanning electron and transmission electron microscopies. In-vitro experiments revealed that b-Bos-LPs outperformed Bos and Bos-LPs in terms of significantly reduced cell viability in MCF-7 cells. According to biodistribution and pharmacokinetic studies, b-Bos-LPs have a higher Bos concentration in tumor tissues as compared to the other organs and also possess better pharmacokinetic activity, indicating that they can be used to treat carcinogen-induced estrogen-positive cancers. This is the first study to show that b-Bos-LPs can display activity against estrogen-positive cancer via biotin targeting. As evidenced by various parameters, b-Bos-LPs showed improved anticancer targeting, therapeutic safety and efficacy in carcinogen-induced estrogen-positive cancer. The receptor protein estrogen, which is primarily responsible for this cancer was downregulated by b-Bos-LPs in an immunoblotting assay. The results showed that biotinylated distearoylphosphatidylcholine (DSPC) augmented LPs loaded with Bosutinib can cause apoptosis in estrogen-positive breast cancer and be an effective way to treat estrogen-positive cancer.

Appraisal of fluoroquinolone-loaded carubinose-linked hybrid nanoparticles for glycotargeting to alveolar macrophages.

There is a curious case in Alveolar macrophages (AM), the frontline defence recruits that contain the spread of all intruding bacteria. In response to Mycobacterium tuberculosis (M.tb), AM either contain the spread or are modulated by M.tb to create a region for their replication. The M.tb containing granulomas so formed are organised structures with confined boundaries. The limited availability of drugs inside AM aid drug tolerance and poor therapeutic outcomes in diseases like tuberculosis. The present work proves the glycotargeting efficiency of levofloxacin (LVF) to AM. The optimised formulation developed displayed good safety with 2% hemolysis and a viability of 61.14% on J774A.1 cells. The physicochemical characterisations such as Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) proved that carubinose linkage was accomplished and LVF is entrapped inside carubinose-linked hybrid formulation (CHF) and hybrid formulation (HF) in amorphous form. The transmission electron microscopy (TEM) images revealed a core-shell structure of HF. The particle size of 471.5 nm estimated through dynamic light scattering (DLS) is enough to achieve active and passive targeting to AM. The nanoparticle tracking analysis (NTA) data revealed that the diluted samples were free from aggregates. Fluorescence-activated cell sorting (FACS) data exhibited excellent uptake via CHF (15 times) and HF(3 times) with reference to plain fluorescein isothiocyanate (FITC). The pharmacokinetic studies revealed that CHF and HF release the entrapped moiety LVF in a controlled manner over 72 h. The stability studies indicated that the modified formulation remains stable over 6 months at 5 ± 3℃. Hence, hybrid systems can be efficiently modified via carubinose to target AM via the parenteral route.

Recent Findings on Thymoquinone and Its Applications as a Nanocarrier for the Treatment of Cancer and Rheumatoid Arthritis.

Cancer causes a considerable amount of mortality in the world, while arthritis is an immunological dysregulation with multifactorial pathogenesis including genetic and environmental defects. Both conditions have inflammation as a part of their pathogenesis. Resistance to anticancer and disease-modifying antirheumatic drugs (DMARDs) happens frequently through the generation of energy-dependent transporters, which lead to the expulsion of cellular drug contents. Thymoquinone (TQ) is a bioactive molecule with anticancer as well as anti-inflammatory activities via the downregulation of several chemokines and cytokines. Nevertheless, the pharmacological importance and therapeutic feasibility of thymoquinone are underutilized due to intrinsic pharmacokinetics, including short half-life, inadequate biological stability, poor aqueous solubility, and low bioavailability. Owing to these pharmacokinetic limitations of TQ, nanoformulations have gained remarkable attention in recent years. Therefore, this compilation intends to critically analyze recent advancements in rheumatoid arthritis and cancer delivery of TQ. This literature search revealed that nanocarriers exhibit potential results in achieving targetability, maximizing drug internalization, as well as enhancing the anti-inflammatory and anticancer efficacy of TQ. Additionally, TQ-NPs (thymoquinone nanoparticles) as a therapeutic payload modulated autophagy as well as enhanced the potential of other drugs when given in combination. Moreover, nanoformulations improved pharmacokinetics, drug deposition, using EPR (enhanced permeability and retention) and receptor-mediated delivery, and enhanced anti-inflammatory and anticancer properties. TQ's potential to reduce metal toxicity, its clinical trials and patents have also been discussed.

Synthesis of pH-sensitive crosslinked guar gum-g-poly(acrylic acid-co-acrylonitrile) for the delivery of thymoquinone against inflammation.

The present work aims to synthesize the pH-sensitive crosslinked guar gum-g-poly(acrylic acid-co-acrylonitrile) [guar-g-(AA-co-ACN)] via microwave-assisted technique for the sustained release of thymoquinone. The synthesized material [guar-g-(AA-co-ACN)] was optimized by varying synthetic parameters viz. monomer concentration, reaction time, and microwave power to obtain the maximum yield of the crosslinked guar gum grafted product as well as maximum encapsulation of thymoquinone. The synthesized material [guar-g-poly(AA-co-ACN)] was characterized by FT-IR, SEM, XRD, NMR, zeta potential, and thermal techniques. This synthesized material was used to encapsulate thymoquinone (TQ) for effective nanotherapeutic delivery. In-vitro thymoquinone release behavior of guar-g-poly(AA-co-ACN) based nanoparticles (NpTGG) was investigated. The maximum thymoquinone release (78%) was achieved at pH 7.4 and time (6 h). The NpTGG also exhibited better antioxidant activity and hemocompatibility as compared to thymoquinone. Cytotoxicity of uar-g-(AA-co-ACN) and NpTGG was also evaluated against the human kidney VERO cell line and found to be nontoxic. Current research provides a cost-effective and green approach for the synthesis of guar-g-(AA-co-ACN) and NpTGG for sustained release of thymoquinone.

Credible Protein Targets and Curative Strategies for COVID-19: a Review.

The pandemic of coronavirus infection 2019 (COVID-19) due to the serious respiratory condition created by the coronavirus 2 (SARS-CoV-2) presents a challenge to recognize effective strategies for management and treatment. In general, COVID-19 is an acute disease that can also be fatal, with an ongoing 10.2% case morbidity rate. Extreme illness may bring about death because of enormous alveolar damage and hemorrhage along with progressive respiratory failure. The rapidly expanding information with respect to SARS-CoV-2 research suggests a substantial number of potential drug targets. The most encouraging treatment to date is suggested to be with the help of remdesivir, hydroxychloroquine, and many such repurposed drugs. Remdesivir has a strong in vitro activity for SARS-CoV-2, yet it is not the drug of choice as affirmed by the US Food and Drug Administration and presently is being tried in progressing randomized preliminaries. The COVID-19 pandemic has been the worst worldwide general health emergency of this age and, possibly, since the pandemic influenza outbreak of 1918. The speed and volume of clinical preliminaries propelled to examine potential treatments for COVID-19 feature both the need and capacity to create abundant evidence even in the center of a pandemic. No treatments have been demonstrated as accurate and dependable to date. This review presents a concise precise of the targets and broad treatment strategies for the benefit of researchers.

Tamanu oil potentiated novel sericin emulgel of levocetirizine: repurposing for topical delivery against DNCB-induced atopic dermatitis, QbD based development and in vivo evaluation.

The present study was aimed at preparing and evaluating levocetirizine (LCZD) loaded emulgel containing tamanu oil and sericin for atopic dermatitis (AD) therapy. The emulgel envisaged topical delivery of LCZD utilising natural antioxidants for superior therapeutic outcomes when compared with other conventional therapy. Tamanu oil based microemulsion (ME) was optimised utilising Box-Behnken design (BBD). The OPT-ME displayed globule size 379.5 ± 2.33 nm, polydispersity index 0.284, drug loading 0.41 ± 0.01% w/w, entrapment efficiency 94.34 ± 2.11% w/w and drug release 86.24 ± 4.90% respectively over a period of 24 h. The optimised formulation (OPT-ME) was further incorporated into sericin gel to form emulgel (LSE). In vivo pharmacodynamic studies revealed enhanced therapeutic potential of emulgel in terms of reduced scratching frequency and erythema score when compared with conventional gel. The superior therapeutic potential was further witnessed through histopathological and biochemical studies. The emulgel can be an alternative appropriate dosage form for the treatment of AD.