Date of Award

2026

Document Type

Thesis

Degree Name

MS in Pharmaceutical Science

Department

Pharmaceutical Sciences

First Advisor

Nitesh Kunda

Second Advisor

Ketankumar Patel

Third Advisor

Carlos Chavez

Abstract

Lung cancer remains the leading cause of cancer related mortality globally, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of those cases. Conventional therapies are limited to systemic toxicity, inconsistent efficacy, and poor patient compliance. The emergence of targeted therapy has highlighted oncogenic BRAF mutations particularly the V600E variant of BRAF, which causes continuous activation of MAPK/ERK signaling pathway, leading to uncontrollable tumor cell proliferation. Therefore, selective inhibition of this aberrantly activated pathway provides a promising strategy for effective tumor control. Trametinib, a MEK1/2 inhibitor, was approved by the FDA in June 2017 in combination with dabrafenib for the treatment of BRAF V600E mutated metastatic non-small cell lung cancer (NSCLC) and has shown significant clinical benefits. Despite this, systemic administration of trametinib is hindered by poor solubility, limited bioavailability, and off target toxicity, emphasizing the need for improved delivery strategies. In this study, trametinib-loaded nanostructured lipid carrier (NLC) formulation was successfully developed and optimized for pulmonary delivery via nebulization to maximize local drug concentration in the lungs while reducing systemic exposure. The optimized trametinib-loaded nanostructured lipid carriers (TRB-NPs) exhibited a mean particle size of 90.86 ± 8.86 nm with a PDI of 0.32 ± 0.09, and a zeta potential of -28.95 ± 1.59 mV. The formulation achieved an entrapment efficiency of 75.87 ± 9.59 % and drug loading of 25.15 ± 2.75 µg/mg, with XRD and DSC confirming drug incorporation within the lipid matrix. TRB-NPs demonstrated sustained release of around 90% in a span of 5 days. Furthermore, short-term stability studies confirmed the formulation's physical integrity, maintaining consistent particle size, zeta potential, and drug loading. The TRB-NPs showed superior anti-tumor activity against NSCLC cell line (HCC364), effectively halting cell migration and shrinking tumor spheroids. These results validate the potential of NLC-based inhalation therapy and provide a clear pathway for future preclinical studies.

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