Biomedicine & Translational Research
The cellular molecules are the basis of life and the mechanistic tools for scientists to study and understand how the living system works. We utilize various cellular and molecular biology techniques and integrate multidisciplinary principles involving biochemistry, cell biology, immunology, pathology, and pharmacology to explore and understand the normal physiology and development of human diseases like cancer.
In collaboration with National Cancer Hospital and Research Center (NCHRC) and exploiting patients’ clinical and molecular data, we aim to identify and establish different diagnostic, prognostic and treatment biomarkers for different types of cancer. We also aim to explore the potential of local natural products in treating various cancers.
Synthesis and characterization of non-viral vectors for efficient gene delivery.
The World Academy of Sciences (TWAS), Italy
Link: http://twas.ictp.it/
Viral vectors are usually used for gene therapy to deliver genes into cells. However, the delivery of genes by virus raises safety concerns. As an alternative, synthetic polymer-based (non-viral) vectors have emerged as a promising gene vehicle because cationic polymers have the ability to make complexation with genes to form polymeric nanoparticles for gene transfection. Importantly, a successful gene delivery requires to overcome several limitations, such as cytotoxicity, cellular uptake and endosomal escape. Although each barrier represents a critical step in determining the final efficiency of gene delivery, the release of DNA from endosomes, that is, endosomal escape prior to their degradation in lysosomes, appears to be a major bottleneck. It is now well-documented that polyethylenimine (PEI) induces endosomal escape due to its buffering capacity. Although the high density of positive charges of PEI is rewarding to polymer for buffering capacity, it contributes to high cytotoxicity. Hence, much attention has been given to design polymeric vectors aiming for efficient transfection with low cytotoxicity. Although the scope of non-viral gene delivery is promising, no report has been published from any institute or University till date from Nepal. This study aims to synthesize various gene delivery vectors, and test them for possible use in gene transfection.
Utilizing cationic peptides for the development of novel antibacterial hydrogels for addressing bacterial infections in an environment of increasing bacterial resistance to existing antibiotics.
The World Academy of Sciences (TWAS), Italy
Link: http://twas.ictp.it/
Hydrogels are becoming popular in the field of biomedical research due its applicability in many functional applications. While conventional hydrogels use synthetic polymers, hydrogels formed by molecules that self-assemble via noncovalent forces are gaining popularity due to enhanced biocompatibility. Therefore Low Molecular Weight (LMW) based hydrogelators are an attractive alternative to the synthetic polymer gelators due to its reduced cost and synthetic customizability. My previous work has shown that cationic peptides such as (FKFK)2 and Fmoc-Phe derivatives have the ability to spontaneously self-assemble to form rigid hydrogels that satisfies most of the criteria needed for cell culture applications. It has also been reported that cationic polymers and peptides have the ability to display efficient antibacterial activities. Hence, we can hypothesize that the polymeric fibrils of these cationic molecules can be also utilized to form hydrogels that can support mammalian cells while displaying antibacterial properties. Such gels are highly desirable because these gels can be potentially applied against bacterial infectivity in countries such as Nepal where bacterial infections impose a great threat in the general public health. For our research, we plan to utilize these gels to probe its ability to sustain mammalian cells while inhibiting bacterial cells by using spectrophotometer, fluorescence/confocal microscope to quantify live/dead assay of the cells within the gel.
Monitoring circulating Cell free DNA and KRAS mutation presence in Circulation as a candidate biomarker in colorectal cancer patients of Nepal
The World Academy of Sciences (TWAS), Italy
Link: http://twas.ictp.it/
Colorectal cancer (CRC) originates in cells of the colon or rectum. CRC is the third most common cancer worldwide. Surgery, radiation and chemotherapy remained the mainstream care of treatment. CRC is one of the major disease problems in Nepal. Patients not only die of loco-regional disease but also due the recurrent disease. There is an urgent need for biomarkers that allow early detection of relapse in colorectal cancer. We here propose that one such biomarker may be Circulating Cell-free DNA (CCFDNA) measurement. Recently, circulating cell-free DNA has attracted considerable interest in the cancer biomarker field. Increased levels of CCFDNA has been observed in cancer patients as compared to healthy donors. In a developing country like Nepal, finding a cancer biomarker using high throughput technology is challenging due to financial and human resources reasons. In addition to that, biomarkers should be easily isolated and should have a clinical utility. CCFDNA can easily be isolated from the plasma of cancer patients indicating a promising candidate as a non-invasive biomarker of cancer. Measurement of CCFDNA over time may allow oncologists to detect and treat recurrence early enough to improve disease outcomes. However, it has not been evaluated whether monitoring CCFDNA has any diagnostic, predictive /prognostic utility in context of colorectal cancer patients from Nepal. In addition, KRAS mutation is one of the most frequent molecular abnormalities in colorectal cancer. KRAS mutation presence in CCFDNA associates with shorter survival of CRC patients. This study will also evaluate KRAS mutation in CRC using CCFDNA.
Exploration of Alternative Vectors of Leishmania Parasites at Higher Altitudes of Nepal.
Nepal Health Research Council (NHRC)
Link: http://nhrc.gov.np/
The main aim of this research is explore and understand the distribution of the sand fly (Phlebotomus argentipes) as well as the potential alternative vector capable of carrying Leishmania parasites in the high altitude regions of Nepal with particular focus in the Dolpa district since several cases have been reported from the area either by our team or others.
Utilization of potent tripeptide for the development of novel anti-inflammatory systems towards inflammatory bowel disease treatment
The World Academy of Sciences (TWAS), Italy
Link: http://twas.ictp.it/
Inflammatory bowel disease (IBD) is a chronic and debilitating disease of the gastrointestinal tract with a high and growing prevalence worldwide. Current treatments primarily offer symptomatic relief and are often associated with severe side effects. Lysine-proline-valine (KPV), a novel and potent naturally occurring anti-inflammatory tripeptide, has emerged as a promising drug candidate for IBD treatment. This project investigated the formulation and characterization of KPV-loaded microparticles comprising KPV, octaarginine (R8), polyglutamic acid (PGA), and chitosan (CS) using a complexation technique. Physicochemical characterization encompassed particle size, zeta potential, polydispersity index, encapsulation efficiency, and drug loading capacity, followed by evaluation of their stability in simulated gastrointestinal fluids. In vitro cytotoxicity assessments were performed using an intestinal cell line. An in vitro Caco-2 cell monolayer model was established and validated using model drugs with varying permeability characteristics. Subsequently, the intestinal permeability of the developed KPV-loaded microparticles was evaluated within this model. The developed KPV-PGA-R8 nanocomplex exhibited a size of 102 ± 0.5 nm with high KPV encapsulation efficiency and demonstrated stability in simulated gastrointestinal fluids. After chitosan coating, the particle size significantly increased to 5668 ± 1.9 nm, while maintaining a high encapsulation efficiency of 99.1%. The chitosan-coated nanocomplex exhibited stability during storage and in simulated colonic fluid. In vitro cellular viability studies demonstrated no significant toxicity in intestinal cells. An in vitro Caco-2 cell monolayer model was established and validated using model drugs with varying permeability characteristics. The model accurately reflected the permeability characteristics of these drugs. Utilizing this model, the intestinal permeability of the developed KPV-loaded microparticles was evaluated, yielding an apparent permeability coefficient of 1.67 × 105 cm/s. These findings suggest the potential of the developed microparticle formulation for the oral delivery of KPV, offering improved stability, enhanced cellular uptake, and promising intestinal permeability. Further in vivo studies are warranted to assess the efficacy and safety of these particles in vivo.
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