DEVELOPMENT OF NANOPARTICLE MEDIATED DRUG DELIVERY SYSTEM FOR ANTICANCER BIOACTIVE COMPOUNDS

Abstract

Colorectal cancer remains a significant global health challenge, particularly affecting individuals aged 50 and older. Primary prevention strategies, including healthy lifestyle choices, risk avoidance, and early detection through regular screening, are crucial in reducing its incidence and impact. Early detection methods such as stool based tests and colonoscopies, along with treatments tailored to the cancer stage, play a pivotal role in managing the disease. While current treatments like surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy are effective, they often come with substantial side effects. The effectiveness of FDA-approved anticancer drugs in treating colorectal cancer is limited, and they often come with significant side effects. Our research delves into the alterations in gene expression induced by chemotherapeutic agents and explores the potential of various natural compounds to counteract these disruptions. We aim to mitigate the dysregulation in gene expression provoked by chemotherapy administration by strategically using natural compounds. By elucidating these mechanisms, we seek to enhance the efficacy of cancer treatment while minimizing adverse effects on gene expression. The current research performs expression profiling of gene alterations in colorectal cancer and the effects of chemotherapy with an irinotecan based on datasets GSE62322 and GSE72484. Parsing differentially expressed genes in colorectal cancer versus normal tissue and in samples after chemotherapy versus not-treated ones helped explain irinotecan's effect on gene expression and its relation to serious side effects. Our findings demonstrate that many genes altered by chemotherapy are involved in crucial cancer progression pathways and are thus associated with adverse effects, such as anemia, bone marrow depression, nausea, fatigue, diarrhea, neutropenia, and cholinergic syndrome. We intended to identify specific molecular targets that could be associated with the side effects of FDA-approved drugs. In this respect, such unintended adverse reactions could be expected when these drugs interact with their targets. While considering substitutes for traditional chemotherapy, we focused on the potential use of natural Ph.D. thesis III | P a g e compounds, especially EGCG, as potent agents against cancer with minimized side effects. Our study in molecular dynamics revealed a promising interaction of EGCG against human TOPO I, showing its potential to act as an inhibitor of the tumor as irinotecan does and evade AChE that causes cholinergic syndrome. While EGCG is a naturally occurring substance, it can potentially produce dose-dependent toxicity in normal human cells. To address this issue, we have developed drug delivery through nanoparticle-mediated mechanisms. Because calcium carbonate nanoparticles (CCN) have been shown in the literature to have the following properties: abundant, less harmful to cells, safe, biocompatible, pH-responsive, and gradually biodegradable, we synthesized CCN using the chemical precipitation method. Calcium carbonate nanoparticles (CaCO3) would be ideal for targeted drug delivery to cancer cells during therapy because they are stable in neutral and basic pH conditions but dissolve in an acidic environment. Because cancerous cells have a low pH, they cause CaCO3 to dissolve and release encapsulated medications, such as EGCG. The drug releases very little at a neutral pH, similar to healthy tissues' pH, but a lot more when the pH is acidic (pH 4-6). By maintaining therapeutic levels, this controlled release minimizes potential risks associated with EGCG overdose, including nephrotoxicity and myelosuppression. Furthermore, it was observed that the drug-loaded CaCO3 nanoparticles showed decreased cell viability based on the results of the MTT assay. Flow cytometry analysis revealed significantly higher incidents of both the early and late apoptosis stages than the drug administered alone. The results thus indicate that the CaCO₃ nanoparticle delivery system has improved the therapeutic efficacy of the drug while potentially reducing its cytotoxic side effects. In conclusion, our discovery opens up prospective pathways for customized medicine and improved patient care in the field of cancer treatment by offering insights into the molecular reactions responsible for the side effects of FDA-approved drugs. The findings of the study might act as a basis for further investigation and treatment advancements in the field of oncology. In conclusion, different cancers have high death rates and varied biology and molecular characteristics. We can learn more about the pathogenic mechanisms behind colorectal cancer by employing bioinformatics techniques and undertaking thorough investigations of gene expression, biological Ph.D. thesis IV | P a g e processes, and pathways. This information offers insightful information for further investigation of treatment plans, including combinatorial therapies. Continued research can lead to innovative cancer treatments inspired by nature, transforming the therapeutic landscape for better outcomes. In summary, our findings provide significant insight into the molecular mechanisms underlying irinotecan-mediated side effects and thereby offer a new dimension in cancer therapy through the rational use of natural compounds and nanoparticle mediated drug delivery. This nanoparticle-mediated delivery system showed promise for safe and efficient targeted cancer therapy. Future research should elucidate the mechanisms of selective toxicity and conduct in vivo testing to evaluate the pharmacokinetics, biodistribution, and therapeutic efficacy of EGCG-loaded CCNPs using animal models. Additionally, exploring this nanocarrier system for other therapeutic agents could broaden its application within nanomedicine. Expanding studies to include various natural compounds could identify new candidates with superior efficacy and minimal side effects. Our study underscores the potential of integrating bioinformatics, molecular biology, and nanotechnology to develop novel, targeted cancer treatments, enhancing patient care and overcoming limitations of conventional therapies. We shall strive to unravel these mechanisms with the idea of developing better cancer treatment strategies with reduced adverse effects, thus leading to the ultimate goal of personalized medicine and improved patient care in oncology. Further research in this line could lead to nature-inspiring and innovative cancer therapies that will transform treatment landscapes and be more effective for patients with colorectal cancer and beyond.