Supramolecular Combination Chemotherapy: Directly Inducing Immunogenic Cell Death To Inhibit Tumor Metastasis via...

Area of Science:

• Biochemistry
• Oncology
• Materials Science

Background:

• Tumor metastasis presents a significant clinical challenge due to tumor heterogeneity and the development of drug-resistant cells.
• Current combination chemotherapy for solid tumors often suffers from reduced efficacy and significant side effects.
• There is a critical need for advanced therapeutic strategies with improved efficiency and reduced toxicity for treating metastatic cancers.

Purpose of the Study:

• To develop a supramolecular combination chemotherapeutic system, CLO, utilizing cucurbit[8]uril (CB[8]) host-guest interactions.
• To investigate the potential of CLO to induce immunogenic cell death (ICD) in colorectal cancer cells.
• To evaluate the efficacy of CLO in inhibiting tumor cell migration both in vitro and in vivo.

Main Methods:

• Fabrication of a supramolecular complex (CB[8]-lobaplatin-oxaliplatin, CLO) based on host-guest chemistry.
• Assessment of CLO's cytotoxicity on human colorectal cancer cells (HCT116) and normal colorectal cells (NCM460).
• Analysis of ICD markers, including high mobility group box 1 (HMGB1) and adenosine triphosphate (ATP) release, and calreticulin (CRT) exposure.
• In vitro and in vivo studies on tumor cell migration, supported by bio-atomic force microscopy (bio-AFM).
• Quantitative proteomics to elucidate the underlying molecular mechanisms of CLO's antitumor effects.

Main Results:

• CLO demonstrated potent inhibition of HCT116 cell viability at low concentrations (10 μM) while exhibiting reduced cytotoxicity towards normal NCM460 cells.
• CLO successfully triggered ICD in colorectal tumor cells, evidenced by increased HMGB1 and ATP release and enhanced CRT exposure.
• CLO significantly inhibited tumor cell migration in both in vitro and in vivo models, confirmed by bio-AFM.
• Proteomic analysis suggested that the citrate cycle (TCA cycle), endoplasmic reticulum protein processing, cGMP-PKG, p53, chemical carcinogenesis, and necroptosis pathways are involved in CLO's antitumor activity.

Conclusions:

• The supramolecular chemotherapeutic system CLO, based on CB[8] complexation, effectively induces ICD in colorectal cancer cells.
• CLO demonstrates significant potential for inhibiting tumor metastasis with reduced toxicity, representing a promising strategy for cancer immunotherapy.
• This supramolecular approach offers a novel platform for developing advanced cancer therapeutics with enhanced efficacy and safety.