C77-46 Design of Experiment (DOE)-Enabled Development and Optimization of Inhaled Lorlatinib-Loaded Lipid Carriers for Lung Cancer Therapeutics

Introduction

Globally, lung cancer is one of the most common types of cancer. Despite advances in treatment, the clinical outcomes are poor due to tumor recurrence, acquired resistance, and off-target side effects. Therefore, there is a need for new treatment strategies. In this study, we improve the anticancer activity of FDA-approved third-generation ALK tyrosine inhibitor Lorlatinib (Lorla), by encapsulating it in inhalable lipid-based nanocarriers for localized delivery of Lorla to the lungs to enable dose reduction and bypassing systemic accumulation. We developed inhalable lipid-based nanocarriers for localized delivery of Lorla in the vicinity of the tumor environment, to enable dose reduction and bypassing systemic accumulation. We hypothesize that lipid-based nanocarriers will enhance physicochemical properties, including drug solubility, which will aid in the overall goal of dose reduction and localized drug accumulation.

Methods

The solubility of Lorla was screened in solid and liquid lipids. The target profiles for the DoE included Particle size <70 nm, PDI <0.5, %EE >80%, and Drug loading > 5%. A 32 factorial design was created to develop Lorlatinib-loaded nanostructured lipid carriers (NLCs). In-Vitro studies included release profile in simulated lung fluid (SLF), aerosolization performance using a next-generation impactor (NGI), cytotoxicity studies on NSCLC cell lines, followed by tumor cell migration, tumor mitigation, and 3D spheroid assays.

Results

Gelucire 44/14 and oleic acid were chosen along with 2% Tween 80. Based on the target profile, the optimized formulation had a vesicle size of 44.8±2.8nm, high drug loading of 5.1±0.2%w/w, and a zeta potential of -22.8±2.2mV. The release profile in SLF showed that NLCs had a sustained release of 54.3±9.0% for up to 48h and followed a Higuchi release kinetics. The lung simulation studies using NGI demonstrated a mass median aerodynamic diameter (MMAD) of 4.69±0.45µm, indicating good aerosolization and deep lung deposition properties of the NLCs. 2D cytotoxicity studies revealed 2-3-fold enhancement in cell death with Lorla-loaded NLCs, as demonstrated by significant reduction in IC50 values of NLC encapsulated Lorla (A549: 10.9±0.3µM vs 28.0±0.5µM for plain drug; and H1299: 6.6±2.3µM vs 16.0±6.2µM for plain drug). The migration and 3D spheroid assays revealed that the NLCs inhibited the cells’ migration and tumor growth to a greater extent than that of the plain drug.

Conclusion

From this study, it can be concluded that Lorla-NLC showed greater efficacy against NSCLC when compared to the plain drug. In-vitro release study (48h) represented improved Lorlatinib release across the dialysis membrane.

This abstract is funded by: St. John’s University