List of Pre-Clinical Research Projects

Malnutrition is a significant problem in paediatric oncology, and carries poor prognosis due to higher toxicity and poor response to treatment in malnourished patients. In this study, we used animal model of early-life moderate malnutrition to assess changes in pharmacokinetics and toxicity of anticancer drugs, and the associated molecular mechanisms. We have found significant metabolomic and proteomic changes in malnourished animals. These changes were found to be correlated with changes in pharmacokinetics and increased toxicity of chemotherapy drugs. 

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and contributes 85% of all lung cancers. Mitochondria play a vital role in cell survival and are also the primary source of ROS generation that regulates the cellular redox homeostasis. However, excess production of ROS can trigger apoptotic cell death. Hence, targeting mitochondria can be a good strategy for killing cancer cells. The dedicated thioredoxin and glutathione redox systems are the central antioxidant defense mechanisms by which mitochondria neutralize the excess ROS. In cancer these anti-oxidant systems get upregulated to cope with oxidative stress insult caused due to dysfunctional mitochondria. This upregulated antioxidant system leads to drug resistance in lung cancer. Thus targeting these upregulated antioxidant system may provide novel therapy against NSCLC. Mitocurcumin (MiC) is the derivative of curcumin that contains triphenylphosphonium moiety, which can be selectively targeted to the mitochondria.

Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumour. Challenges associated with therapeutic modalities involve the diffusion constraints of the blood-brain barrier (BBB). Limitations associated with conventional treatment necessitate the development of alternative approaches for radiotherapy adjuvant drugs. Selenium functionalised gold nanocomposites were synthesised and optmised. To decorate Au nanoparticles with diselenide (-Se-Se-), firstly, diselenide functionalized gelatin (G-Se-Se-G) was prepared by covalently conjugating gelatin with diselenodipropionic acid through EDC/NHS coupling chemistry and subsequently used to replace citrate from AuNP surface, thus obtaining Au@G-Se-Se-G NPs. Au@G-Se-Se-G NPs were of spherical morphology with an average size of about 15 nm and were characterized by TEM, EDS, Raman spectra, DLS, FTIR, CV and CD. Later, Au@G-Se-Se-G's radiosensitizing effect on LN229 cells was investigated. The cells were subjected to γ-radiation (4 Gy) in combination with either Au@G-Se-Se-G (2 nM) or Au@G (2 nM). The findings showed that radiation exposure alone caused a 50% reduction in LN229 cell survival and the combination of drug and radiation together lead to significant reduction in survival fraction by 75%. The study to determine the Au@G-Se-Se-G dose modification factor for radiosensitizing activity in glioblastoma cells and the in-vivo pharmacokinetics, biodistribution and toxicity is under underway. Together, the above results establish an in-house shape and size selective selenium functionalised gold nanoparticles and that selenium functionalization of gold nanoparticles is an effective strategy to achieve radio-sensitization in the cellular models of GBM. Validation of the above results shall be confirmed using mouse models of GBM.

NSCLC is any type of epithelial lung cancer other than Small Cell Lung Cancer (SCLC), it constitutes 85% of all lung cancers. Except for the well-localized tumours, the standard care treatment outcomes are poor for NSCLC largely due to rapid metastases and the prevailing chemo-resistance. Only 0.01% of cells leaving the primary tumor successfully metastasize, yet it contributes to 90% of cancer related deaths. Mitocurcumin (mitoC) is a biologically active targeted herbal mitocan with greater lipid solubility and selectivity to mitochondrial cell membrane.In preclinical studies, mitoC revealed significant cytotoxic and anti-proliferative activities against MCF-7, MDAMB-231, SKNSH, DU-145 and HeLa cancer cells with considerably lower IC50 values than curcumin. Recent studies have highlighted the role of mitochondrial dynamics in cancer metastasis, and interestingly in our observation mitocurcumin treatment caused significant changes in mitochondrial dynamics. In addition to this, in-vitro results from our lab showed a decrease in the migration and invasion of cells (A549,H1299 and LLC-1) upon mitocurcumin treatment. These results were observed at a dose as low as 1uM of mitocurcumin, hence it might also be effective in mitigating metastasis. With an array of activities mediated through novel mechanisms, mitoC can be a candidate molecule for NSCLC metastasis. Hence this study is planned to evaluate the anti-metastatic activity of mitoC in syngeneic and CDX derived lung metastasis model.

Hematopoietic Stem Cell Transplantation (HSCT) is a procedure of infusing healthy blood forming stem cells into the patient’s body for treatment of several malignant (AML, ALL, CML, lymphoma, Multiple Myelomas) and non-malignant (SCID, Sickle cell disease, Thalassemia) complications. While HSCT is a life saving treatment, it is compromised by several endothelial complications such as Transplant associated- thrombotic microangiopathy (TA-TMA), Idiopathic pulmonary syndrome (IPS), Hepatic Veno-occlusive disease (HVOD), Engraftment syndrome. These are potentially life-threatening complications that root from the occurrence of endothelial injury and subsequent dysfunction post-HSCT. My work in the lab focuses on development of drugs against TA-TMA and HVOD. With high incidence and mortality rates, these complications undermine and weaken the efficacy of HSCT procedure. Although there are a few drugs available, these drugs are exorbitantly priced debilitating financially the suffering patient. My project revolves around screening of drugs from natural product libraries and then evaluating and testing their potential in the preclinical stage through various invitro and in-vivo models.

Radiation therapy and chemotherapy are potent tools against cancer, yet they often result in unintended harm to surrounding healthy tissues. This is particularly evident in the gastrointestinal (GI) tract due to its sensitivity to radiation and chemotherapy drugs like Melphalan. Therefore, there is a crucial need to examine the intricate interplay between radiation exposure and chemotherapy treatment on gut health. This study aims to explore the effects of radiation exposure and chemotherapy treatment on physiological parameters in mice, specifically focusing on gut integrity and microbial diversity. Additionally, it seeks to evaluate the potential of phytochemicals like Chlorophyllin, Withaferin etc., commercially available prebiotics such as FOS, and probiotics for example Bacillus clausii as preventive measures for gut toxicity and mitigating microbial dysregulation. Yet in another approach, we aim to study effect of chlorophyllin and natural herbs based sprinkler formulation to enhance the gut health and maintain microbial diversity.

Ayurvedic medicinal plants have been traditionally used for their therapeutic properties, and modern scientific approaches are increasingly being employed to understand their pharmacological potential. This study aimed to comprehensively profile the phytochemical composition of whole extracts from Ayurvedic medicinal plants using liquid chromatography-mass spectrometry (LC-MS). Additionally, an in silico evaluation is planned to be conducted to assess the components of these extracts followed by the physico-chemico-biological evaluations. Furthermore, we aim to perform in vitro and in vivo absorption, distribution, metabolism, and excretion (ADME) characterization and herb-drug interaction (HDI) studies for the whole extracts of Ayurvedic medicinal plants, along with standard-of-care chemotherapeutic drugs used in a known cancer type.  This study will provide a platform for evaluation of drugs including in vitro and invitro models. The study will provide valuable insights into the potential therapeutic effects and safety profiles of ayurvedic formulations in presence of chemotherapeutic drugs.

Approximately 40% children with cancer are malnourished at diagnosis. Malnutrition in young children with cancer can be a result of poor dietary intake or due to cachexia induced by cancer itself. In cancer, malnutrition is often associated with adverse outcomes in terms of safety, tolerability an efficacy of drugs. The effect could be mediated either through an inherent vulnerability of a child with malnutrition to the toxicity of chemotherapy, thereby affecting dose intensity and loos of efficacy. Alternatively, malnourishment may alter the pharmacokinetics of chemotherapeutic drugs leading to higher exposures and subsequent toxicity. Hence, with the aid of a sprinkler formulation containing all the micronutrients and macronutrients we aim to replenish the nutrients, which in turn, may improve the pharmacokinetics of the chemotherapeutic drugs leading to less or no adverse effects.