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Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids
Published on: November 22, 2021
Inhalable Anti-EGFR Antibody-Conjugated Osimertinib Liposomes for Non-Small Cell Lung Cancer
Apoorva Daram1, Shruti S Sawant1, Dhwani A Mehta1
1Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, New York City, NY 11439, USA.
Abstract:
Background: Non-small cell lung cancer (NSCLC) is a leading cause of cancer deaths globally. The most extensive treatment is Tyrosine Kinase Inhibitors (TKIs) that target epidermal growth factor receptor (EGFR) overexpression. Osimertinib, a third-generation TKI is approved to target EGFR exon 19 deletions or exon 21 L858R mutations. However, resistance is inevitable due to emergence of triple mutations (sensitizing mutations, T790M and C797S). To overcome this challenge, a combinatorial approach was used wherein Osimertinib liposomes were conjugated with cetuximab (CTX), an anti-EGFR monoclonal antibody, to improve drug efficacy and delivery. Additionally, pulmonary administration was employed to minimize systemic toxicity and achieve high lung concentrations. Methods: Osimertinib liposomes (OB-LPs) were prepared using thin film hydration method and immunoliposomes (CTX-OB-LPs) were prepared by conjugating the OB-LPs surface with CTX. Liposomes were characterized for particle size, zeta-potential, drug loading, antibody conjugation efficiency, in vitro drug release, and aerosolization performance. Further, the in vitro efficacy of immunoliposomes was evaluated in H1975 cell line. Results: Immunoliposomes exhibited a particle size of 150 nm, high antibody conjugation efficiency (87%), efficient drug release, and excellent aerosolization properties with an aerodynamic diameter of 3 μm and fine particle fraction of 88%. Furthermore, in vitro studies in H1975 cells showed enhanced cytotoxicity with CTX-OB-LPs displaying 1.7-fold reduction and 1.2-fold reduction in IC50 compared to Osimertinib and OB-LPs, respectively. The CTX-OB-LPs also significantly reduced tumor cell migration and colonization compared to Osimertinib and OB-LPs. Conclusions: These successful results for EGFR-targeting inhalable immunoliposomes exhibited potential for contributing to greater anti-tumor efficacy for the treatment of non-small cell lung cancer.
Insights
New inhalable immunoliposomes combine Osimertinib with cetuximab to overcome non-small cell lung cancer (NSCLC) resistance. This targeted approach enhances drug delivery to the lungs, improving efficacy against EGFR-mutated NSCLC.
Area of Science:
- Nanotechnology in drug delivery
- Cancer therapeutics
- Pulmonary drug administration
Background:
- Non-small cell lung cancer (NSCLC) is a major global health concern, with EGFR-TKIs like Osimertinib as a primary treatment.
- Acquired resistance to Osimertinib, often due to triple mutations (T790M and C797S), necessitates novel therapeutic strategies.
- Current treatments face challenges in efficacy and systemic toxicity, highlighting the need for improved drug delivery methods.
Purpose of the Study:
- To develop and characterize inhalable immunoliposomes combining Osimertinib with cetuximab (CTX) for enhanced NSCLC treatment.
- To evaluate the in vitro efficacy and aerosolization performance of the novel immunoliposome formulation.
- To investigate the potential of pulmonary administration for targeted delivery and reduced systemic toxicity in NSCLC therapy.
Main Methods:
- Osimertinib liposomes (OB-LPs) were prepared via thin-film hydration and conjugated with cetuximab (CTX) to form immunoliposomes (CTX-OB-LPs).
- Characterization included particle size, zeta-potential, drug loading, antibody conjugation efficiency, in vitro drug release, and aerosolization performance.
- In vitro cytotoxicity, tumor cell migration, and colonization assays were performed using the H1975 NSCLC cell line.
Main Results:
- CTX-OB-LPs demonstrated optimal particle size (~150 nm), high conjugation efficiency (87%), and excellent aerosolization properties (3 μm aerodynamic diameter, 88% fine particle fraction).
- In vitro studies showed significantly enhanced cytotoxicity of CTX-OB-LPs, with 1.7-fold and 1.2-fold reductions in IC50 compared to Osimertinib and OB-LPs, respectively.
- The immunoliposomes effectively reduced NSCLC cell migration and colonization compared to unconjugated formulations.
Conclusions:
- Inhalable EGFR-targeting immunoliposomes show significant promise for improving anti-tumor efficacy in NSCLC treatment.
- This combinatorial approach offers a potential strategy to overcome resistance mechanisms and enhance therapeutic outcomes.
- Pulmonary delivery of immunoliposomes represents a viable method for targeted NSCLC therapy with reduced systemic side effects.
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