Tumor microenvironment-activatable Fe-doxorubicin preloaded amorphous CaCO₃ nanoformulation triggers ferroptosis in...

Area of Science:

• Biomedical Engineering
• Oncology
• Nanotechnology

Background:

• Tumor treatment resistance is a major challenge in clinical oncology.
• Ferroptosis, a regulated cell death pathway, shows therapeutic promise but requires synergistic mechanisms for enhanced efficacy.
• Existing ferroptosis inducers are limited by endogenous factors, necessitating novel strategies.

Purpose of the Study:

• To develop an amorphous calcium carbonate (ACC)-based nanoassembly for targeted ferroptosis therapy.
• To investigate the synergistic therapeutic interaction between doxorubicin (DOX) and Fe2+ mediated by the ACC nanoplatform.
• To enhance tumor-specific drug delivery and therapeutic outcomes in cancer treatment.

Main Methods:

• Fabrication of an ACC-based nanoassembly functionalized with dendrimers for controlled drug release.
• Modification of the nanoplatform with metalloproteinase-2 (MMP-2)-sheddable PEG or targeting ligands for improved pharmacokinetics and tumor targeting.
• In vitro and in vivo evaluation of the nanoformulation's efficacy in inducing ferroptosis and inhibiting tumor growth.

Main Results:

• The ACC nanoassembly demonstrated efficient intracellular release of therapeutic cargo triggered by acidic tumor microenvironments.
• Doxorubicin (DOX) amplified ferroptosis by generating hydrogen peroxide (H2O2) in the presence of Fe2+.
• The nanoformulation exhibited potent ferroptosis efficacy and tumor-specific uptake, balancing circulation longevity and targeting.

Conclusions:

• The developed ACC-based nanoassembly offers a promising strategy for tumor-targeted ferroptosis therapy.
• This synergistic approach combining DOX and Fe2+ overcomes limitations of single-agent ferroptosis induction.
• The nanoformulation holds potential for clinical translation in overcoming cancer treatment resistance.