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  1. Targeting microRNAs using nanotechnology in pulmonary diseases
    Dua K, Chellappan DK, Singhvi G, de Jesus Andreoli Pinto T, Gupta G, Hansbro PM
    Panminerva Med, 2018 Dec;60(4):230-231.
    PMID: 30563304 DOI: 10.23736/S0031-0808.18.03459-6
  2. Search for new therapeutics against HIV-1 via dual inhibition of RNase H and integrase: current status and future challenges
    Kharkwal H, Kumar BK, Murugesan S, Singhvi G, Avasthi P, Goyal A, et al.
    Future Med Chem, 2021 02;13(3):269-286.
    PMID: 33399497 DOI: 10.4155/fmc-2020-0257
    Reverse transcriptase and integrase are key enzymes that play a pivotal role in HIV-1 viral maturation and replication. Reverse transcriptase consists of two active sites: RNA-dependent DNA polymerase and RNase H. The catalytic domains of integrase and RNase H share striking similarity, comprising two aspartates and one glutamate residue, also known as the catalytic DDE triad, and a Mg2+ pair. The simultaneous inhibition of reverse transcriptase and integrase can be a rational drug discovery approach for combating the emerging drug resistance problem. In the present review, the dual inhibition of RNase H and integrase is systematically discussed, including rationality of design, journey of development, advancement and future perspective.
  3. 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.
  4. Emerging innovations in nano-enabled therapy against age-related macular degeneration: A paradigm shift
    Kumar Dubey S, Pradhan R, Hejmady S, Singhvi G, Choudhury H, Gorain B, et al.
    Int J Pharm, 2021 May 01;600:120499.
    PMID: 33753164 DOI: 10.1016/j.ijpharm.2021.120499
    Age-related macular degeneration (AMD), a degenerative eye disease, is the major cause of irreversible loss of vision among individuals aged 50 and older. Both genetic and environmental factors are responsible for the progressive damage to central vision. It is a multifactorial retinal disease with features such as drusen, hypopigmentation and/or hyperpigmentation of the retinal pigment epithelium, and even choroidal neovascularization in certain patients. AMD is of two major forms: exudative (wet) and atrophic (dry) with changes affecting the macula leading to impaired vision. Although the retina remains an accessible portion for delivering drugs, there are no current options to cure or treat AMD. The existing expensive therapeutics are unable to treat the underlying pathology but display several side effects. However, recent innovations in nanotherapeutics provide an optimal alternative of drug delivery to treat the neovascular condition. These new-age technologies in the nanometer scale would enhance bioactivity and improve the bioavailability of drugs at the site of action to treat AMD. The nanomedicine also provides sustained release of the drug with prolonged retention after penetrating across the ocular tissues. In this review, the insights into the cellular and molecular mechanisms associated with the pathophysiology of AMD are provided. It also serves to review the current progress in nanoparticle-based drug delivery systems that offer feasible treatments in AMD.
  5. Oral peptide delivery: challenges and the way ahead
    Dubey SK, Parab S, Dabholkar N, Agrawal M, Singhvi G, Alexander A, et al.
    Drug Discov Today, 2021 04;26(4):931-950.
    PMID: 33444788 DOI: 10.1016/j.drudis.2021.01.001
    Peptides and proteins have emerged as potential therapeutic agents and, in the search for the best treatment regimen, the oral route has been extensively evaluated because of its non-invasive and safe nature. The physicochemical properties of peptides and proteins along with the hurdles in the gastrointestinal tract (GIT), such as degrading enzymes and permeation barriers, are challenges to their delivery. To address these challenges, several conventional and novel approaches, such as nanocarriers, site-specific and stimuli specific delivery, are being used. In this review, we discuss the challenges to the oral delivery of peptides and the approaches used to tackle these challenges.
  6. Recent advances in targeted nanomedicine as promising antitumor therapeutics
    Hejmady S, Pradhan R, Alexander A, Agrawal M, Singhvi G, Gorain B, et al.
    Drug Discov Today, 2020 12;25(12):2227-2244.
    PMID: 33011342 DOI: 10.1016/j.drudis.2020.09.031
    A tumor serves as a major avenue in drug development owing to its complexity. Conventional therapies against tumors possess limitations such as suboptimal therapeutic efficacy and extreme side effects. These display poor pharmacokinetics and lack specific targeting, with non-specific distribution resulting in systemic toxicity. Therefore, nanocarriers targeted against cancers are increasingly being explored. Nanomedicine aids in maintaining a balance between efficacy and toxicity by specifically accumulating in tumors. Nanotherapeutics possess advantages such as increased solubility of chemotherapeutics, encapsulation of multiple drugs and improved biodistribution, and can ensure tumor-directed drug delivery and release via the approaches of passive targeting and active targeting. This review aims to offer a general overview of the current advances in tumor-targeting nanocarriers for clinical and diagnostic use.
  7. 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.
  8. 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.
  9. Bacterial biofilms associated skin disorders: Pathogenesis, advanced pharmacotherapy and nanotechnology-based drug delivery systems as a treatment approach
    Vyas T, Rapalli VK, Chellappan DK, Dua K, Dubey SK, Singhvi G
    Life Sci, 2021 Dec 15;287:120148.
    PMID: 34785190 DOI: 10.1016/j.lfs.2021.120148
    BACKGROUND: Biofilms are microcolonies of microbes that form communities with a variety of microbes, exhibit the same gene composition but differ in gene expression. Biofilm-associated infections have been in existence for a long, however, biofilm-associated skin disorders have not been investigated much.

    OBJECTIVES: Biofilms, which are made mostly of the matrix can be thought of as communities of microbes that are more virulent and more difficult to eradicate as compared to their planktonic counterparts. Currently, several formulations are available in the market which have the potential to treat biofilm-assisted skin disorders. However, the existing pharmacotherapies are not competent enough to cure them effectively and entirely, in several cases.

    KEY FINDINGS: Especially with the rising resistance towards antibiotics, it has become particularly challenging to ameliorate these disorders completely. The new approaches are being used to combat biofilm-associated skin disorders, some of them being photodynamic therapy, nanotherapies, and the use of novel drug delivery systems. The focus of attention, however, is nanotherapy. Micelles, solid lipid nanoparticles, quatsomes, and many others are being considered to find a better solution for the biofilm-associated skin disorders.

    SIGNIFICANCE: This review is an attempt to give a perspective on these new approaches for treating bacterial biofilms associated with skin disorders.

  10. Fulltext Peroxisome proliferator-activated receptor gamma: promising target in glioblastoma
    Gupta G, Singhvi G, Chellappan DK, Sharma S, Mishra A, Dahiya R, et al.
    Panminerva Med, 2018 Sep;60(3):109-116.
    PMID: 30176701 DOI: 10.23736/S0031-0808.18.03462-6
    Glioblastoma, also known as glioblastoma multiforme, is the most common and worldwide-spread cancer that begins within the brain. Glioblastomas represent 15% of brain tumors. The most common length of survival following diagnosis is 12 to 14 months with less than 3% to 5% of people surviving longer than five years. Without treatment, survival is typically 3 months. Among all receptors, special attention has been focused on the role of peroxisome proliferator-activated receptors (PPARs) in glioblastoma. PPARs are ligand-activated intracellular transcription factors. The PPAR subfamily consists of three subtypes encoded by distinct genes named PPARα, PPARβ/δ, and PPARγ. PPARγ is the most extensively studied subtype of PPAR. There has been interesting preliminary evidence suggesting that diabetic patients receiving PPARγ agonists, a group of anti-diabetics, thiazolidinedione drugs, have an increased median survival for glioblastoma. In this paper, the recent progresses in understanding the potential mechanism of PPARγ in glioblastoma are summarized.
  11. Multi-drug resistant Mycobacterium tuberculosis & oxidative stress complexity: Emerging need for novel drug delivery approaches
    Dua K, Rapalli VK, Shukla SD, Singhvi G, Shastri MD, Chellappan DK, et al.
    Biomed Pharmacother, 2018 Nov;107:1218-1229.
    PMID: 30257336 DOI: 10.1016/j.biopha.2018.08.101
    Tuberculosis (caused by Mycobacterium tuberculosis, Mtb) treatment involves multiple drug regimens for a prolonged period. However, the therapeutic benefit is often limited by poor patient compliance, subsequently leading to treatment failure and development of antibiotic resistance. Notably, oxidative stress is a crucial underlying factor that adversely influences the various treatment regimens in tuberculosis. Little information is available with advanced drug delivery systems that could be effectively utilized, in particular, for targeting the oxidative stress in tuberculosis. Thus, this presents an opportunity to review the utility of various available, controlled-release drug delivery systems (e.g., microspheres, liposomes, niosomes, solid lipid nanoparticles, dendrimers) that could be beneficial in tuberculosis treatments. This will help the biological and formulation scientists to pave a new path in formulating a treatment regimen for multi-drug resistant Mtb.
  12. Increasing complexity and interactions of oxidative stress in chronic respiratory diseases: An emerging need for novel drug delivery systems
    Dua K, Malyla V, Singhvi G, Wadhwa R, Krishna RV, Shukla SD, et al.
    Chem Biol Interact, 2019 Feb 01;299:168-178.
    PMID: 30553721 DOI: 10.1016/j.cbi.2018.12.009
    Oxidative stress is intensely involved in enhancing the severity of various chronic respiratory diseases (CRDs) including asthma, chronic obstructive pulmonary disease (COPD), infections and lung cancer. Even though there are various existing anti-inflammatory therapies, which are not enough to control the inflammation caused due to various contributing factors such as anti-inflammatory genes and antioxidant enzymes. This leads to an urgent need of novel drug delivery systems to combat the oxidative stress. This review gives a brief insight into the biological factors involved in causing oxidative stress, one of the emerging hallmark feature in CRDs and particularly, highlighting recent trends in various novel drug delivery carriers including microparticles, microemulsions, microspheres, nanoparticles, liposomes, dendrimers, solid lipid nanocarriers etc which can help in combating the oxidative stress in CRDs and ultimately reducing the disease burden and improving the quality of life with CRDs patients. These carriers improve the pharmacokinetics and bioavailability to the target site. However, there is an urgent need for translational studies to validate the drug delivery carriers for clinical administration in the pulmonary clinic.
  13. Fulltext Gene therapy and type 1 diabetes mellitus
    Chellappan DK, Sivam NS, Teoh KX, Leong WP, Fui TZ, Chooi K, et al.
    Biomed Pharmacother, 2018 Dec;108:1188-1200.
    PMID: 30372820 DOI: 10.1016/j.biopha.2018.09.138
    BACKGROUND: Type 1 diabetes mellitus (T1DM) is an autoimmune disorder characterized by T cell-mediated self-destruction of insulin-secreting islet β cells. Management of T1DM is challenging and complicated especially with conventional medications. Gene therapy has emerged as one of the potential therapeutic alternatives to treat T1DM. This review primarily focuses on the current status and the future perspectives of gene therapy in the management of T1DM. A vast number of the studies which are reported on gene therapy for the management of T1DM are done in animal models and in preclinical studies. In addition, the safety of such therapies is yet to be established in humans. Currently, there are several gene level interventions that are being investigated, notably, overexpression of genes and proteins needed against T1DM, transplantation of cells that express the genes against T1DM, stem-cells mediated gene therapy, genetic vaccination, immunological precursor cell-mediated gene therapy and vectors.

    METHODS: We searched the current literature through searchable online databases, journals and other library sources using relevant keywords and search parameters. Only relevant publications in English, between the years 2000 and 2018, with evidences and proper citations, were considered. The publications were then analyzed and segregated into several subtopics based on common words and content. A total of 126 studies were found suitable for this review.

    FINDINGS: Generally, the pros and cons of each of the gene-based therapies have been discussed based on the results collected from the literature. However, there are certain interventions that require further detailed studies to ensure their effectiveness. We have also highlighted the future direction and perspectives in gene therapy, which, researchers could benefit from.

  14. The potential of siRNA based drug delivery in respiratory disorders: Recent advances and progress
    Dua K, Wadhwa R, Singhvi G, Rapalli V, Shukla SD, Shastri MD, et al.
    Drug Dev Res, 2019 09;80(6):714-730.
    PMID: 31691339 DOI: 10.1002/ddr.21571
    Lung diseases are the leading cause of mortality worldwide. The currently available therapies are not sufficient, leading to the urgent need for new therapies with sustained anti-inflammatory effects. Small/short or silencing interfering RNA (siRNA) has potential therapeutic implications through post-transcriptional downregulation of the target gene expression. siRNA is essential in gene regulation, so is more favorable over other gene therapies due to its small size, high specificity, potency, and no or low immune response. In chronic respiratory diseases, local and targeted delivery of siRNA is achieved via inhalation. The effectual delivery can be attained by the generation of aerosols via inhalers and nebulizers, which overcomes anatomical barriers, alveolar macrophage clearance and mucociliary clearance. In this review, we discuss the different siRNA nanocarrier systems for chronic respiratory diseases, for safe and effective delivery. siRNA mediated pro-inflammatory gene or miRNA targeting approach can be a useful approach in combating chronic respiratory inflammatory conditions and thus providing sustained drug delivery, reduced therapeutic dose, and improved patient compliance. This review will be of high relevance to the formulation, biological and translational scientists working in the area of respiratory diseases.
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