Cancer Stem-Like Cells-Oriented Surface Self-Assembly to Conquer Radioresistance

Area of Science:

• Biomedical Engineering
• Oncology
• Nanotechnology

Background:

• Cancer stem-like cells (CSCs) drive tumor radiotherapy (RT) resistance.
• CSCs' deep tumor location and hypoxic, acidic niche exacerbate radioresistance.
• Hypoxic CSCs overexpress carbonic anhydrase IX (CAIX) on their surface.

Purpose of the Study:

• To develop a CAIX-targeted drug delivery system for overcoming CSC-mediated radioresistance.
• To investigate the efficacy of the system in deep-seated tumors and hypoxic microenvironments.
• To enhance RT by promoting CSC differentiation and increasing DNA damage.

Main Methods:

• Constructed a peptide-based drug delivery system (CA-Pt) that self-assembles on CSC surfaces.
• Utilized a sequential process: monomer release, target accumulation, and surface self-assembly.
• Evaluated CA-Pt's deep penetration, CAIX inhibition, cellular uptake, and microenvironment modulation.

Main Results:

• CA-Pt demonstrated deep tumor penetration and enhanced CAIX inhibition.
• The system effectively relieved the hypoxic and acidic microenvironment, promoting CSC differentiation.
• CA-Pt combined with RT significantly boosted DNA damage, suppressed tumor growth, and reduced invasion/metastasis in mouse and zebrafish models.

Conclusions:

• Surface-induced self-assembly targeting CAIX offers a novel strategy to overcome radioresistance.
• This approach effectively differentiates hypoxic CSCs, enhancing radiotherapy outcomes.
• The developed system presents a potential universal treatment strategy for radioresistant tumors.