Chitosan-based nanotheranostics integrated dual-modal imaging and combinatorial tumor therapy for EGFR-TKI resistance...

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Oncology

Background:

• Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are standard treatments for EGFR-mutated non-small cell lung cancer (NSCLC).
• Acquired resistance to EGFR-TKIs significantly limits their long-term efficacy in NSCLC patients.
• Developing strategies to overcome acquired resistance is crucial for improving NSCLC treatment outcomes.

Purpose of the Study:

• To develop a multifunctional nanoplatform for overcoming EGFR-TKI resistance in NSCLC.
• To integrate chemo-phototherapy, diagnostic imaging, and tumor microenvironment (TME) modulation into a single theranostic system.
• To evaluate the efficacy of the developed nanoplatform in overcoming EGFR-TKI resistance in NSCLC.

Main Methods:

• A multifunctional nanoplatform (CsO/IGA) was synthesized by encapsulating osimertinib and an indocyanine green-gadolinium (ICG-Gd) probe within oleanolic acid (OA)-modified chitosan.
• The nanoplatform was characterized for size, stability, and its ability to generate singlet oxygen and hyperthermia upon laser irradiation.
• The anti-cancer effects, TME modulation, and in vivo performance, including imaging capabilities and therapeutic efficacy, were evaluated in NSCLC cells and animal models.

Main Results:

• The CsO/IGA nanoplatform (∼100 nm) exhibited excellent stability and generated singlet oxygen and hyperthermia under 808 nm irradiation.
• The nanoplatform demonstrated potent anti-cancer effects by inducing reactive oxygen species, reducing mitochondrial membrane potential, and downregulating EGFR/phosphorylated EGFR in sensitive and resistant NSCLC cells.
• In vivo studies showed tumor-specific accumulation, deep tumor penetration, FLI/MRI capability, and superior antitumor efficacy due to synergistic chemo-phototherapy and TME remodeling by the OA component.

Conclusions:

• The OA-integrated CsO/IGA nanoplatform offers a promising theranostic strategy for overcoming EGFR-TKI resistance in NSCLC.
• This approach combines targeted therapy, phototherapy, TME modulation, and diagnostic imaging for enhanced therapeutic outcomes.
• The developed nanoplatform holds potential for improving the treatment of resistant NSCLC by addressing multiple therapeutic challenges simultaneously.