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Factors affecting the morphology of some organic and inorganic nanostructures for drug delivery: characterization, modifications, and toxicological perspectives

Raychaudhuri R, Pandey A, Hegde A, Abdul Fayaz SM, Chellappan DK, Dua K, et al.

Expert Opin Drug Deliv, 2020 12;17(12):1737-1765.
PMID: 32878492 DOI: 10.1080/17425247.2020.1819237

Introduction: In this review, we aim to highlight the impact of various processes and formulation variables influencing the characteristics of certain surfactant-based nanoconstructs for drug delivery. Areas covered: The review includes the discussion on processing parameters for the preparation of nanoconstructs, especially those made up of surfactants. Articles published in last 15 years (437) were reviewed, 381 articles were selected for data review and most appropriate articles (215) were included in article. Effect of variables such as surfactant concentration and type, membrane additives, temperature, and pH-dependent transitions on morphology has been highlighted along with effect of shape on nanoparticle uptake by cells. Various characterization techniques explored for these nanostructures with respect to size, morphology, lamellarity, distribution, etc., and a separate section on polymeric vesicles and the influence of block copolymers, type of block copolymer, control of block length, interaction of multiple block copolymers on the structure of polymersomes and chimeric nanostructures have been discussed. Finally, applications, modification, degradation, and toxicological aspects of these drug delivery systems have been highlighted. Expert opinion: Parameters influencing the morphology of micelles and vesicles can directly or indirectly affect the efficacy of small molecule cellular internalization as well as uptake in the case of biologicals.[Figure: see text].
Fulltext Emerging prospects of vitamin D3 in metabolic syndrome: A proof of concept (POC) approach targeting inflammation

Singh Y, Gupta G, Gilhotra RM, Singh SK, Prasher P, Krishnan A, et al.

EXCLI J, 2020;19:1512-1516.
PMID: 33312109 DOI: 10.17179/excli2020-2964
Rutin loaded liquid crystalline nanoparticles inhibit lipopolysaccharide induced oxidative stress and apoptosis in bronchial epithelial cells in vitro

Paudel KR, Wadhwa R, Mehta M, Chellappan DK, Hansbro PM, Dua K

Toxicol In Vitro, 2020 Oct;68:104961.
PMID: 32771431 DOI: 10.1016/j.tiv.2020.104961

Airway inflammation and infections are the primary causes of damage in the airway epithelium, that lead to hypersecretion of mucus and airway hyper-responsiveness. The role of reactive oxygen species (ROS) and their components in the pathophysiological mechanisms of airway inflammation have been well-studied and emphasized for the past several decades. Rutin, a potent bioflavonoid, is well-known for its antioxidant, anti-inflammatory, especially in bronchial inflammation. However, poor solubility and rapid metabolism have led to its low bioavailability in biological systems, and hence limit its application. The present study aims to investigate the beneficial effects of rutin-loaded liquid crystalline nanoparticles (LCNs) against lipopolysaccharide (LPS) induced oxidative damage in human bronchial epithelial cell line (BEAS-2-B) cells in vitro. LPS was used to stimulate BEAS-2-B cells, causing the generation of nitric oxide (NO) and other reactive oxygen species (ROS) that had led to cellular apoptosis. The levels of NO and ROS were detected by, Griess reagent kit and dichlorodihydrofluorescein diacetate (DCFH-DA) respectively, whereas, cell apoptosis was studied by Annexin V-FITC and PI staining. The findings revealed that rutin-loaded LCNs significantly reduced NO, ROS levels and prevented apoptosis in BEAS-2B cells. The observations and findings provide a mechanistic understanding of the effectiveness of rutin-loaded LCNs in protecting the bronchial cells against airway inflammation, thus possessing a promising therapeutic option for the management of airway diseases.
Patented therapeutic drug delivery strategies for targeting pulmonary diseases

Thakur AK, Chellappan DK, Dua K, Mehta M, Satija S, Singh I

Expert Opin Ther Pat, 2020 May;30(5):375-387.
PMID: 32178542 DOI: 10.1080/13543776.2020.1741547

Introduction: Pulmonary route is one of the preferred routes for the administration of therapeutically active agents for systemic as well as localized delivery. Chronic obstructive pulmonary disease (COPD), bronchial asthma, pneumonia, pulmonary hypertension, bronchiolitis, lung cancer, and tuberculosis are the major chronic diseases associated with the pulmonary system. Knowledge about the affecting factors, namely, the etiology, pathophysiology, and the various barriers (mechanical, chemical, immunological, and behavioral) in pulmonary drug delivery is essential to develop an effective drug delivery system. Formulation strategies and mechanisms of particle deposition in the lungs also play an important role in designing a suitable delivery system.Areas covered: In the present paper, various drug delivery strategies, viz. nanoparticles, microparticles, liposomes, powders, and microemulsions have been discussed systematically, from a patent perspective.Expert opinion: Patent publications on formulation strategies have been instrumental in the evolution of new techniques and technologies for safe and effective treatment of pulmonary diseases. New delivery systems are required to be simple/reproducible/scalable/cost-effective scale for manufacturing ability and should be safe/effective/stable/controllable for meeting quality and regulatory compliance.
Fulltext miRNA nanotherapeutics: potential and challenges in respiratory disorders

Mehta M, Chellappan DK, Wich PR, Hansbro NG, Hansbro PM, Dua K

Future Med Chem, 2020 06;12(11):987-990.
PMID: 32270706 DOI: 10.4155/fmc-2020-0066
Fulltext Incipient need of targeting airway remodeling using advanced drug delivery in chronic respiratory diseases

Mehta M, Satija S, Paudel KR, Liu G, Chellappan DK, Hansbro PM, et al.

Future Med Chem, 2020 05;12(10):873-875.
PMID: 32352313 DOI: 10.4155/fmc-2020-0091
Applications and practice of advanced drug delivery systems for targeting Toll-like receptors in pulmonary diseases

Chan Y, Prasher P, Löbenberg R, Gupta G, Singh SK, Oliver BG, et al.

Nanomedicine (Lond), 2021 04;16(10):783-786.
PMID: 33733817 DOI: 10.2217/nnm-2021-0056
Emerging role of nanocarriers based topical delivery of anti-fungal agents in combating growing fungal infections

Waghule T, Sankar S, Rapalli VK, Gorantla S, Dubey SK, Chellappan DK, et al.

Dermatol Ther, 2020 11;33(6):e13905.
PMID: 32588940 DOI: 10.1111/dth.13905

The incidences of fungal infections have greatly increased over the past few years, particularly in humid and industrialized areas. The severity of such infections ranges from being asymptomatic-mild to potentially life-threatening systemic infections. There are limited classes of drugs that are approved for the treatment of such infections like polyenes, azoles, and echinocandins. Some fungi have developed resistance to these drugs. Therefore, to counter drug resistance, intensive large scale studies on novel targeting strategies and formulations are being conducted, which have gained impetus lately. Conventional formulations have limitations such as higher doses, frequent dosing, and several side effects. Such limiting factors have paved the path for the emergence of nanotechnology and its applications. This further gave formulation scientists the possibility of encapsulating the existing potential drug moieties into nanocarriers, which when loaded into gels or creams provided prolonged release and improved permeation, thus giving on-target effect. This review thus discusses the newer targeting strategies and the role of nanocarriers that could be administered topically for the treatment of various fungal infections. Furthermore, this approach opens newer avenues for continued and sustained research in pharmaceuticals with much more effective outcomes.
Recent update on barbiturate in relation to brain disorder

Pathak S, Gupta G, Thangavelu L, Singh SK, Dua K, Chellappan DK, et al.

EXCLI J, 2021;20:1028-1032.
PMID: 34267614 DOI: 10.17179/excli2021-3687
Role of the Tristetraprolin (Zinc Finger Protein 36 Homolog) Gene in Cancer

Gupta G, Bebawy M, Pinto TJA, Chellappan DK, Mishra A, Dua K

Crit Rev Eukaryot Gene Expr, 2018;28(3):217-221.
PMID: 30311568 DOI: 10.1615/CritRevEukaryotGeneExpr.2018021188

Cancer is a complicated transformational progression that fiercely changes the appearance of cell physiology as well as cells' relations with adjacent tissues. Developing an oncogenic characteristic requires a wide range of modifications in a gene expression at a cellular level. This can be achieved by activation or suppression of the gene regulation pathway in a cell. Tristetraprolin (TTP or ZFP36) associated with the initiation and development of tumors are regulated at the level of mRNA decay, frequently through the activity of AU-rich mRNA-destabilizing elements (AREs) located in their 3'-untranslated regions. TTP is an attractive target for therapeutic use and diagnostic tools due to its characteristic appearance in cancer tissue alone. Thus, the illumination of TTP in diverse types of cancer might deliver additional effective remedies in the coming era for cancer patients. The objective of this review is to familiarize the reader with the TTP proteins, focus on efficient properties that endow them with their effective oncogenic potential, describe their physiological role in cancer cells, and review the unique properties of TT, and of TTP-driven cancer.
Sugar-based nanoparticles for respiratory diseases: a new paradigm in the nanoworld

Chan Y, Ng SW, Mehta M, Gupta G, Chellappan DK, Dua K

Future Med Chem, 2020 11;12(21):1887-1890.
PMID: 33054387 DOI: 10.4155/fmc-2020-0206
3D-printing: an emerging and a revolutionary technology in pharmaceuticals

Singhvi G, Patil S, Girdhar V, Chellappan DK, Gupta G, Dua K

Panminerva Med, 2018 Dec;60(4):170-173.
PMID: 29856179 DOI: 10.23736/S0031-0808.18.03467-5

One of the novel and progressive technology employed in pharmaceutical manufacturing, design of medical device and tissue engineering is three-dimensional (3D) printing. 3D printing technologies provide great advantages in 3D scaffolds fabrication over traditional methods in the control of pore size, porosity, and interconnectivity. Various techniques of 3D-printing include powder bed fusion, fused deposition modeling, binder deposition, inkjet printing, photopolymerization and many others which are still evolving. 3D-printing technique been employed in developing immediate release products, various systems to deliver multiple release modalities etc. 3D printing has opened the door for new generation of customized drug delivery with built-in flexibility for safer and effective therapy. Our mini-review provides a quick snapshot on an overview of 3D printing, various techniques employed, applications and its advancements in pharmaceutical sciences.
Emerging landscape in psoriasis management: From topical application to targeting biomolecules

Rapalli VK, Singhvi G, Dubey SK, Gupta G, Chellappan DK, Dua K

Biomed Pharmacother, 2018 Oct;106:707-713.
PMID: 29990862 DOI: 10.1016/j.biopha.2018.06.136

Psoriasis is a chronic autoimmune skin disorder affecting 2-3% of the world population. It has characteristic features such as increased keratinocyte proliferation and production of inflammatory mediators. The treatment involves various strategies including topical, systemic, phototherapy and biologics. Topical therapies are preferred for mild to moderate psoriasis conditions over the systemic therapies which are ideal in severe disease conditions. The systemic therapies include immunosuppressants, biological agents and recently approved phosphodiesterase-4 (PDE4) inhibitors. There are various limitations associated with the existing therapies where the new findings in the pathogenesis of psoriasis are paving a path for newer therapeutics to target at the molecular level. Various small molecules, PDE-4 inhibitors, biologics, and immunomodulator proved efficacious including the new molecules targeting Janus kinases (JAK) inhibitors that are under investigation. Furthermore, the role of genetic and miRNAs in psoriasis is still not completely explored and may further help in improving the treatment efficacy. This review provides an insight into various emerging therapies along with currently approved treatments for psoriasis.
An Overview of Circular RNAs

Awasthi R, Singh AK, Mishra G, Maurya A, Chellappan DK, Gupta G, et al.

Adv Exp Med Biol, 2018 9 28;1087:3-14.
PMID: 30259353 DOI: 10.1007/978-981-13-1426-1_1

Circular RNAs (cirRNAs) are long, noncoding endogenous RNA molecules and covalently closed continuous loop without 5'-3' polarity and polyadenylated tail which are largely concentrated in the nucleus. CirRNA regulates gene expression by modulating microRNAs and functions as potential biomarker. CirRNAs can translate in vivo to link between their expression and disease. They are resistant to RNA exonuclease and can convert to the linear RNA by microRNA which can then act as competitor to endogenous RNA. This chapter summarizes the evolutionary conservation and expression of cirRNAs, their identification, highlighting various computational approaches on cirRNA, and translation with a focus on the breakthroughs and the challenges in this new field.
Phyllanthus emblica fruit extract attenuates lipid metabolism in 3T3-L1 adipocytes via activating apoptosis mediated cell death

Balusamy SR, Veerappan K, Ranjan A, Kim YJ, Chellappan DK, Dua K, et al.

Phytomedicine, 2019 Oct 31;66:153129.
PMID: 31794911 DOI: 10.1016/j.phymed.2019.153129

BACKGROUND: Phyllanthus emblica L. (Indian gooseberry) is widely used in the Ayurveda for thousands of years to treat health complications including disorders of the immune system, diabetes, and obesity.
PURPOSE: For the first time, our study aims to demonstrate the molecular mechanisms of the fruit extract of Phyllanthus emblica (PEFE) involved in the promotion of fat cell apoptosis and alleviation of adipogenesis.
METHODS: The active constituents from PEFE were identified using high performance liquid chromatography-mass spectrometry (HPLC-MS). We carried out the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay to evaluate the cytotoxic effects of PEFE using 3T3-L1 pre-adipocytes. The colonogenic assay was carried out to determine the inhibitory effect of 3T3-L1 adipocytes after PEFE treatment. In addition, inhibition of pancreatic lipase activity was performed and the lipolytic activity of PEFE and digallic acid was compared with the well-known standard drug orlistat. Besides, the molecular interaction and ligand optimization between digallic and adipogenesis/apoptosis markers were also carried out. Furthermore, to confirm fat cell apoptosis we have used several detection methods that includes Hoechst staining, PI staining, Oil staining and qPCR respectively.
RESULTS: Digallic acid was identified as a major component in the PEFE. The IC50 values of digallic acid and PEFE were found to be 3.82 µg/ml and 21.85 µg/ml respectively. PEFE and digallic acid showed significant anti-lipolytic activity compared to the standard drug orlistat. In the mature adipocytes, PEFE significantly decreased triglyceride accumulation by downregulating adiponectin, PPARγ, cEBPα, and FABP4 respectively. We further analyzed the expression of apoptosis related genes upon PEFE treatment. Apoptotic process initiated through upregulation of BAX and downregulation of BCL2 resulting in an increased caspase-3 activity. In addition, we have also confirmed the apoptosis and DNA fragmentation in 3T3-L1 cells using Hoechst, PI and TUNEL assays.
CONCLUSION: PEFE negatively regulates adipogenesis by initiating fat cell apoptosis and therefore it can be considered as a potential herbal medicinal product for treating obesity.
Recent update on anti-dengue drug discovery

Dighe SN, Ekwudu O, Dua K, Chellappan DK, Katavic PL, Collet TA

Eur J Med Chem, 2019 Aug 15;176:431-455.
PMID: 31128447 DOI: 10.1016/j.ejmech.2019.05.010

Dengue is the most important arthropod-borne viral disease of humans, with more than half of the global population living in at-risk areas. Despite the negative impact on public health, there are no antiviral therapies available, and the only licensed vaccine, Dengvaxia®, has been contraindicated in children below nine years of age. In an effort to combat dengue, several small molecules have entered into human clinical trials. Here, we review anti-DENV molecules and their drug targets that have been published within the past five years (2014-2018). Further, we discuss their probable mechanisms of action and describe a role for classes of clinically approved drugs and also an unclassified class of anti-DENV agents. This review aims to enhance our understanding of novel agents and their cognate targets in furthering innovations in the use of small molecules for dengue drug therapies.
Rosmarinic acid attenuates inflammation in experimentally induced arthritis in Wistar rats, using Freund's complete adjuvant

Gautam RK, Gupta G, Sharma S, Hatware K, Patil K, Sharma K, et al.

Int J Rheum Dis, 2019 Jul;22(7):1247-1254.
PMID: 31155849 DOI: 10.1111/1756-185X.13602

AIM: The purpose of our investigation is to evaluate the anti-arthritic potential of isolated rosmarinic acid from the rind of Punica granatum.
METHOD: Rosmarinic acid was isolated by bioactivity-guided isolation from butanolic fraction of Punica granatum and acute toxicity of rosmarinic acid was carried out. The experiment was conducted at doses of 25 and 50 mg/kg, in Freund's complete adjuvant (FCA)-induced arthritic rats. Various parameters, that is arthritic score, paw volume, thickness of paw, hematological, antioxidant and inflammatory parameters such as glutathione (GSH), superoxide dismutase (SOD), malonaldehyde (MDA) and tumor necrosis factor-α (TNF-α) were also estimated.
RESULTS: Rosmarinic acid significantly decreased the arthritic score, paw volume, joint diameter, white blood cell count and erythrocyte sedimentation rate. It also significantly increased body weight, hemoglobin and red blood cells. The significantly decreased levels of TNF-α were observed in treated groups as compared to arthritic control rats (P
Fulltext COVID-19 transmission through host cell directed network of GPCR

Singh Y, Gupta G, Satija S, Pabreja K, Chellappan DK, Dua K

Drug Dev Res, 2020 09;81(6):647-649.
PMID: 32329083 DOI: 10.1002/ddr.21674
Fulltext RAAS blockers in hypertension posing a higher risk toward the COVID-19

Singh Y, Gupta G, Satija S, Negi P, Chellappan DK, Dua K

Dermatol Ther, 2020 Jul;33(4):e13501.
PMID: 32359088 DOI: 10.1111/dth.13501
Fulltext Overcoming drug delivery barriers and challenges in topical therapy of atopic dermatitis: A nanotechnological perspective

Hemrajani C, Negi P, Parashar A, Gupta G, Jha NK, Singh SK, et al.

Biomed Pharmacother, 2022 Mar;147:112633.
PMID: 35030434 DOI: 10.1016/j.biopha.2022.112633

Atopic dermatitis (AD) is an inflammatory disorder centered around loss of epidermal barrier function, and T helper 2 (Th2) immune responses. The current understanding of disease heterogeneity and complexity, limits the rational use of existing topical, systemic therapeutic agents, but paves way for development of advanced therapeutic agents. Additionally, advanced nanocarriers that deliver therapeutics to target cells, seem to offer a promising strategy, to overcome intrinsic limitations and challenges of conventional, and traditional drug delivery systems. Ever-evolving understanding of molecular target sites and complex pathophysiology, adverse effects of current therapeutic options, inefficient disease recapitulation by existing animal models are some of the challenges that we face. Also, despite limited success in market translatibility, nanocarriers have demonstrated excellent preclinical results and have been extensively studied for AD. Detailed research on behavior of nanocarriers in different patients and tailored therapy to account for phenotypic variability of the disease are the new research avenues that we look forward to.

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