Abstract

Medicines in the form of nanoparticles called nanomedicines, stand at the forefront of revolutionary advancements in healthcare, offering precise drug delivery and diagnostic capabilities. A recent example of nanomedicine in the clinic is the COVID-19 vaccine, which helped prevent death during the pandemic. While the potential benefits are immense, a myriad of challenges complicate their seamless integration into clinical practice. The design and fabrication of nanoparticles demand meticulous attention to biocompatibility and toxicity. Interactions with biological systems are complex, requiring a delicate balance between therapeutic efficacy and safety. The reticuloendothelial system's rapid clearance of nanoparticles, their instability in physiological environments, and the limited understanding of long-term effects pose significant hurdles. Regulatory obstacles pose significant barriers to advancing nanomedicines from laboratory settings to clinical applications. Establishing approval and standardization protocols for these groundbreaking therapies is imperative, requiring comprehensive guidelines to guarantee their safety and effectiveness. Comprehending how nanoparticles move within the body is vital for maximizing their effectiveness in therapy. The intricate relationship between nanoparticles and biological systems emphasizes the necessity for in-depth investigations into potential immune responses, prompting a comprehensive exploration.

The goal of this Thesis is to contribute valuable insights into the multifaceted challenges faced by nanoparticles and nanomedicines. By addressing issues related to biocompatibility, toxicity, regulatory approval, and scalability, the research aims to pave the way for the successful integration of these innovative technologies into mainstream healthcare, ultimately advancing personalized and targeted therapeutic approaches.

Towards this endeavor, we have explored nano formulation strategies to maximize cellular delivery of CMPI(3-(2-chlorophenyl)-5-(5-methyl-1-(piperidin-4-yl)-1H-pyrrazol-4yl) isoxazole) , a potent positive allosteric modulator of α4β2 nAChRs. A biodegradable and biocompatible, the US-FDA-approved, poly(l-lactic-co-glycolic) acid (PLGA) was used to engineer nanoparticles (NPs) to solubilize CMPI in its hydrophobic core in an aqueous environment using the nanoprecipitation with the drug loading content by weight of NPs. Thus, synthesized polymeric NPs were characterized for their colloidal properties and biological activities. The hydrodynamic size of these NPs was found stable for a prolonged period in biological media. An in-vitro drug release study was conducted to envision a sustained release of CMPI under physiological conditions, which shows distinct kinetics of CMPI under experimental conditions in which released drugs from NPs were collected using dialysis techniques. These NPs were found to be highly biocompatible when challenged against the human embryonic kidney-293 (HEK293) cell line that stably expressed α4β2 (HEKα4β2) nAChRs in a wide range of concentrations. (Chapter 2)

Similarly, our next interest is a first-line anticancer drug, Docetaxel, a member of the taxane family, has emerged as a potent chemotherapeutic agent for the treatment of various cancers, including breast cancer discussed in Chapter 3.

In vitro preclinical studies utilizing Docetaxel have demonstrated with MTT cytotoxicity assay, which showed its efficacy in inhibiting microtubule depolymerization, thereby disrupting mitotic spindle function and inducing apoptosis in cancer cells, well-known mechanism by which Docetaxel arrests cancer cells. One particularly aggressive subtype of breast cancer, triple-negative breast cancer (TNBC), often exhibits resistance to conventional therapies. To investigate potential therapeutic strategies for TNBC, researchers frequently employ the MDA-MB231 cell line, derived from a metastatic site of a human breast adenocarcinoma. The MDA-MB231 cell line is widely utilized as an in vitro model due to its triple-negative phenotype and invasive characteristics, making it a valuable tool for studying the efficacy and mechanisms of action of novel chemotherapeutic agents.

Date of publication

Spring 4-15-2024

Document Type

Thesis

Language

english

Persistent identifier

http://hdl.handle.net/10950/4691

Committee members

Santosh Aryal, Ayman Hamouda, Dustin Patterson

Degree

Masters of Science in Chemistry

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