PhD student, Centre for Research in Medical Devices (CURAM), National University of Ireland-Galway, Ireland
Nano drug carriers selectively target to positive inflammatory mucosa for effective colitis therapy
I am doing my PhD in biomedical engineering in the Centre for Research in Medical Devices (CURAM), National University of Ireland, Galway. By training, I am a pharmaceutical chemist interested in developing advanced disease responsive nano-pharmaceuticals by combining biomaterial/polymer chemistry with nano-engineering to produce targeted, disease responsive delivery systems. I am greatly fascinated to understand the inflammatory, cancer disease biology in order to design targeted therapeutic platforms.
As a part of my PhD work, I have proposed this research topic because my research interests lie in the area of fabricating viable biomaterials and developing advanced delivery systems using different drugs/protein/gene/peptide loaded multi-modal reservoir systems. I have always been fascinated by inflammatory diseases and the challenge of finding a clinically targeted specific treatment for treating gastro-intestinal associated diseases such as inflammatory bowel disease-IBD (crohn’s disease, ulcerative colitis) and colon cancer. It is estimated that approximately 10 million people suffer from IBD and colorectal cancer is the third most common cancer worldwide. Moreover, treatments impose a financial burden to meet the cost of hospitalization, therapy, surgery, as well as health related issues. Therefore, there is a need for improved and safe therapies. It is a challenge that truly enthuses me.
I believe that I am suited for this research field because of my extensive background in the Pharmaceutical and Biomedical Sciences fields. After my Masters’ degree in Pharmaceutical Sciences, I secured a Research Fellow position in Institute for Stem Cell Biology and Regenerative Medicine (inStem), Bangalore, India. I have gained significant experience in harnessing the potential of self-assembled biomaterials as 'next generation therapeutics' for the treatment of inflammatory diseases in the field of translational research.
To present time, I have published more than 10 papers in peer-reviewed journals avilable at https://www.researchgate.net/profile/Niranjan_Kotla4
I would like to gain broader exposure in the field of biomaterials-based translational research. In the long term, considering the depth of my research interests, I realize that an immense amount of knowledge is yet to be gained and my passion towards research will motivate me to extend the boundaries further, so that at each bend, I step beyond my comfort zone and do good science.
Abstract: The main objective of the present paper has been the development and study of two new biodegradable polyurethanes, PU(dithiodiethanol-DTDI) and PU[((i)Pr)Man-DTDI], to be used as sustained matrix forming excipients. Furthermore, their capacity to act as excipient for colon drug delivery systems has been evaluated. Thus, SeDeM diagrams have been obtained to investigate their suitability to be processed through a direct compression process. Matrices containing 10-30% w/w of the polymers and theophylline anhydrous as model drug have been manufactured. Release studies have been carried out using a modified dissolution assay simulating pH and redox conditions for the gastro intestinal tract, including colon. Drug dissolution data have been analyzed according to the main kinetic models and their Excipient Efficiencies for prolonged release have been calculated. The principal parameters of the SeDeM Expert system, such as the parametric profile (mean radius) and the good compression index obtained for the polymers are above the values considered as adequate for direct compression even without addition of flow agents. The obtained values for Excipient Efficiency show good ability of the polymer to control the drug release. Finally, in the case of PU(dithiodiethanol-DTDI), a clear increase in the release rate has been observed when the formulation is subjected to colon simulating conditions.
Pub.: 22 Jan '17, Pinned: 29 Sep '17
Abstract: Drugs such as mesalamine (5-ASA) are currently recommended for the treatment of inflammatory bowel disease (IBD). To reduce the frequency of their administration and improve their therapeutic effect, this study investigated the adhesion efficacy, wound healing promotion, and decrease in inflammation in ulcers in the colonic tissue of rats with colitis after combined treatment with hyaluronic acid (HA) and 5-ASA (IBD98-M). HA-fluoresceinamine (FL) conjugates successfully adhered to the mucosal layer and were conjugated in the vascular tissue. In addition, macroscopic and microscopic observations indicated that colonic injuries reduced significantly after treatment with IBD98-M. Compared with PBS and 5-ASA treatment alone, treatment with IBD98-M more effectively reduced bowel inflammation and promoted colonic mucosal healing in TNBS-induced colitis. IBD98-M treatment also reduced myeloperoxidase activity and the expression levels of cyclooxygenase 2 and tumor necrosis factor-αin the colitis tissue. In conclusion, IBD98-M treatment strongly promoted wound healing in colonic injuries and significantly inhibited MPO activity in the inflamed colon tissue of rats. Combined treatment with HA and 5-ASA can accelerate wound healing and reduce inflammatory reaction in rat colitis.
Pub.: 31 May '17, Pinned: 29 Sep '17
Abstract: To evaluate the anti-inflammatory and anti-apoptotic effects of rosuvastatin by regulation of oxidative stress in a dextran sulfate sodium (DSS)-induced colitis model.An acute colitis mouse model was induced by oral administration of 5% DSS in the drinking water for 7 d. In the treated group, rosuvastatin (0.3 mg/kg per day) was administered orally before and after DSS administration for 21 d. On day 21, mice were sacrificed and the colons were removed for macroscopic examination, histology, and Western blot analysis. In the in vitro study, IEC-6 cells were stimulated with 50 ng/mL tumor necrosis factor (TNF)-α and then treated with or without rosuvastatin (2 μmol/L). The levels of reactive oxygen species (ROS), inflammatory mediators, and apoptotic markers were measured.In DSS-induced colitis mice, rosuvastatin treatment significantly reduced the disease activity index and histological damage score compared to untreated mice (P < 0.05). Rosuvastatin also attenuated the DSS-induced increase of 8-hydroxy-2'-deoxyguanosine and NADPH oxidase-1 expression in colon tissue. Multiplex ELISA analysis revealed that rosuvastatin treatment reduced the DSS-induced increase of serum IL-2, IL-4, IL-5, IL-6, IL-12 and IL-17, and G-CSF levels. The increased levels of cleaved caspase-3, caspase-7, and poly (ADP-ribose) polymerase in the DSS group were attenuated by rosuvastatin treatment. In vitro, rosuvastatin significantly reduced the production of ROS, inflammatory mediators and apoptotic markers in TNF-α-treated IEC-6 cells (P < 0.05).Rosuvastatin had the antioxidant, anti-inflammatory and anti-apoptotic effects in DSS-induced colitis model. Therefore, it might be a candidate anti-inflammatory drug in patients with inflammatory bowel disease.
Pub.: 26 Jul '17, Pinned: 29 Sep '17
Abstract: There is a clinical need for new, more effective treatments for chronic and debilitating inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis. Targeting drugs selectively to the inflamed intestine may improve therapeutic outcomes and minimize systemic toxicity. We report the development of an inflammation-targeting hydrogel (IT-hydrogel) that acts as a drug delivery system to the inflamed colon. Hydrogel microfibers were generated from ascorbyl palmitate, an amphiphile that is generally recognized as safe (GRAS) by the U.S. Food and Drug Administration. IT-hydrogel microfibers loaded with the anti-inflammatory corticosteroid dexamethasone (Dex) were stable, released drug only upon enzymatic digestion, and demonstrated preferential adhesion to inflamed epithelial surfaces in vitro and in two mouse colitis models in vivo. Dex-loaded IT-hydrogel enemas, but not free Dex enemas, administered every other day to mice with colitis resulted in a significant reduction in inflammation and were associated with lower Dex peak serum concentrations and, thus, less systemic drug exposure. Ex vivo analysis of colon tissue samples from patients with ulcerative colitis demonstrated that IT-hydrogel microfibers adhered preferentially to mucosa from inflamed lesions compared with histologically normal sites. The IT-hydrogel drug delivery platform represents a promising approach for targeted enema-based therapies in patients with colonic IBD.
Pub.: 14 Aug '15, Pinned: 29 Sep '17
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