Dual-targeted NIS polyplexes-a theranostic strategy toward tumors with heterogeneous receptor expression

Area of Science:

• Oncology
• Gene Therapy
• Nanomedicine

Background:

• Tumor heterogeneity poses challenges for targeted cancer therapies, often leading to resistance.
• Nonviral vectors, particularly polymer-formulated ones, offer a promising platform for cancer gene delivery.
• Single-targeting strategies can be limited by variable receptor expression in heterogeneous tumors.

Purpose of the Study:

• To develop a dual-targeting nonviral vector for enhanced gene delivery in hepatocellular cancer.
• To evaluate the efficacy of dual-targeting vectors carrying the sodium iodide symporter (NIS) gene.
• To improve the clinical applicability of gene therapy for diverse cancer types and patient populations.

Main Methods:

• Synthetic LPEI-PEG2kDa polymer backbones were conjugated with two tumor-specific peptide ligands: GE11 (EGFR-targeting) and cMBP (cMET-targeting).
• Dual-targeted polyplexes were designed to deliver the theranostic NIS gene to hepatocellular cancer cells.
• In vitro and in vivo studies, including 124I-PET imaging, were conducted to assess transduction efficiency and therapeutic effects.

Main Results:

• Dual-targeted polyplexes demonstrated enhanced tumor-specific transduction efficiency compared to single-targeted vectors in vitro and in vivo.
• 124I-PET imaging confirmed successful gene delivery and functional NIS expression in tumors.
• Significantly reduced tumor growth and perfusion, along with prolonged animal survival, were observed, indicating therapeutic efficacy.

Conclusions:

• Dual-targeting strategies represent a bifunctional approach beneficial for clinical translation of gene therapy.
• This approach enables efficient targeting of heterogeneic tumors with variable receptor expression levels.
• Bioimaging-based NIS-mediated radiotherapy holds promise for treating diverse cancers.