Tumor microenvironment responsive polypeptide-based supramolecular nanoprodrugs for combination therapy

Area of Science:

• Biomedical Engineering
• Nanomedicine
• Cancer Therapy

Background:

• Tumor microenvironment-responsive nanomedicine offers potential for combination therapy but faces challenges in minimizing side effects and maximizing anti-tumor efficacy.
• Developing sophisticated drug delivery systems that target the tumor microenvironment is crucial for advancing cancer treatment.
• Current combination therapies often struggle with off-target toxicity and limited therapeutic outcomes.

Purpose of the Study:

• To develop a pH/ROS dual-responsive supramolecular polypeptide nanoprodrug for synergistic combination therapy.
• To investigate the combined effects of glucose degradation, chemodynamic therapy (CDT), and chemotherapy (CT) using this novel nanomedicine.
• To evaluate the anti-tumor efficiency and safety profile of the developed nanoprodrug in a tumor model.

Main Methods:

• Fabrication of a pH/ROS dual-responsive nanoprodrug (PFW-DOX/GOD) using a pillar[5]arene-based host-guest strategy.
• Incorporation of glucose oxidase (GOD) and a doxorubicin (DOX) prodrug within the polypeptide nanostructure.
• Assessment of pH-triggered disassembly, GOD-mediated glucose degradation, ferrocene-catalyzed Fenton reaction for ROS generation, and DOX release upon ROS induction.
• Evaluation of in vitro and in vivo anti-tumor efficacy, including tumor inhibitory rate (TIR) and assessment of side effects.

Main Results:

• The PFW-DOX/GOD nanoprodrug demonstrated pH-triggered disassembly in acidic intracellular environments.
• Released GOD catalyzed glucose to produce hydrogen peroxide (H2O2), which was converted to hydroxyl radicals (•OH) via the Fenton reaction mediated by ferrocene.
• ROS triggered the release and activation of the DOX prodrug, leading to combined therapeutic effects.
• The combination therapy achieved a significant tumor inhibitory rate (TIR) of 96% with minimal observed side effects.

Conclusions:

• The developed supramolecular polypeptide nanoprodrug effectively integrates glucose degradation, CDT, and CT for synergistic anti-tumor activity.
• The dual-responsive nature and cascade reactions within the tumor microenvironment contribute to enhanced therapeutic efficacy and reduced systemic toxicity.
• This nanomedicine platform represents a promising strategy for advanced combination cancer therapy.