Improved Systemic Immunochemotherapy Employing an Oxaliplatin-TLR7/8 Agonist Prodrug Strategy

Area of Science:

• Oncology
• Immunology
• Medicinal Chemistry

Background:

• Systemic Toll-like receptor 7/8 (TLR7/8) agonist administration for cancer is limited by uncontrolled immune activation.
• Developing targeted delivery systems is crucial for effective immunochemotherapy.

Purpose of the Study:

• To design and synthesize platinum(IV)-based prodrugs for simultaneous, tumor-selective delivery of an oxaliplatin chemotherapeutic and a TLR7/8 agonist.
• To evaluate the in vitro and in vivo efficacy of these prodrugs in a cancer model.

Main Methods:

• Synthesis of two platinum(IV)-based prodrugs: Ox-Gardi-PEG and Ox-Gardi-Mal, incorporating the TLR7/8 agonist gardiquimod.
• In vitro assessment of cytotoxicity and immune pathway activation under standard and reducing conditions.
• In vivo evaluation of anticancer efficacy, survival, and immune cell modulation in cancer-bearing mice.

Main Results:

• Prodrugs showed reduced activity in standard conditions and enhanced activity under reducing conditions, confirming activation-by-reduction.
• Ox-Gardi-Mal demonstrated superior, TLR7/8-dependent anticancer efficacy and prolonged survival in mice.
• Treatment mitigated oxaliplatin-induced hematotoxicity and modulated the tumor microenvironment by increasing CD8+ T cells and decreasing M2 macrophages.

Conclusions:

• Tumor-targeted platinum(IV)-based prodrugs carrying TLR7/8 agonists enable potent dual-release immunochemotherapy.
• This strategy improves therapeutic outcomes while minimizing systemic immune-related adverse events.