Multimodal Therapeutic Platforms Based on Self‐Assembled Metallacycles/Metallacages for Cancer Radiochemotherapy

Abstract

Discrete organometallic complexes with defined structures are proceeding rapidly in combating malignant tumors due to their multipronged treatment modalities. Many innovative superiorities, such as high antitumor activity, extremely low systemic toxicity, active targeting ability, and enhanced cellular uptake, make them more competent for clinical applications than individual precursors. In particular, coordination‐induced regulation of luminescence and photophysical properties of organic light‐emitting ligands has demonstrated significant potential in the timely evaluation of therapeutic efficacy by bioimaging and enabled synergistic photodynamic therapy (PDT) or photothermal therapy (PTT). This review highlights instructive examples of multimodal radiochemotherapy platforms for cancer ablation based on self‐assembled metallacycles/metallacages, which would be classified by functions in a progressive manner. Finally, the essential demands and some plausible prospects in this field for cancer therapy are also presented.

Supramolecular Coordination Complexes for Synergistic Cancer Therapy

“…49 However, these compounds have drawbacks, such as low water solubility, high toxicity, and poor pharmacological behavior. 52 Additionally, they can induce toxic side effects (such as neurotoxicity, nausea, vomiting, diarrhea, alopecia, stomatitis, peripheral neuropathy, and extravasation) in healthy tissues, causing fatigue in patients. 61 Furthermore, the emergence of drug resistance in tumor tissues can significantly compromise the therapeutic efficacy of these platinum-based antitumor agents.…”

“…8,63,64 Compared with monochemotherapy, combination chemotherapy holds promise for overcoming limitations associated with tumor heterogeneity and drug resistance, thereby significantly improving therapeutic efficacy. 48,52 Additionally, combination therapy enables the administration of smaller doses of each drug, potentially reducing adverse effects. A critical challenge in optimizing combination chemotherapy is achieving precise control over drug loading, which directly influences optimal therapeutic efficacy.…”

“…Platinum-based antitumor agents, such as cisplatin, carboplatin, and oxaliplatin, are highly effective in clinical oncology and demonstrate potent activity against various malignant tumors . However, these compounds have drawbacks, such as low water solubility, high toxicity, and poor pharmacological behavior . Additionally, they can induce toxic side effects (such as neurotoxicity, nausea, vomiting, diarrhea, alopecia, stomatitis, peripheral neuropathy, and extravasation) in healthy tissues, causing fatigue in patients .…”

“…SCCs have garnered significant attention owing to their antiproliferative effects against various cancer cell lines, which is attributed to the inherent antitumor activity of the incorporated metal ions (Pt, Pd, Rh, Ru, and Ir). − ,− ,− Notably, platinum-based SCCs have been used in antitumor therapy owing to their high anticancer effects. − For example, our research group successfully designed a highly emissive tetraphenylethene (TPE)-based metallacage in 2016, which was a crucial component of theranostic supramolecular nanoparticles (NPs) for cancer chemotherapy . Because cancer-treatment technologies have shifted from single-modality chemotherapy to synergistic multimodal therapy, , researchers are actively developing SCCs with well-defined structures to combat malignant tumors through multipronged treatment modalities. − By leveraging the combined advantages of different components, SCC-based (such as the formation of metallacycles and metallacages) therapeutic strategies can enhance antitumor efficacy. , SCCs possess several advantages, such as high antitumor activity, low systemic toxicity, active tumor-targeting ability, and enhanced cellular uptake, rendering them superior to individual precursors for clinical applications. , Additionally, peripheral modifications with the targeting groups and encapsulation of metallacycles or metallacages within amphiphilic polymers significantly enhance the targeted delivery of therapeutic agents to tumor sites. , Therefore, integrating different diagnostic (e.g., imaging) and treatment methods (e.g., chemotherapy, photothermal therapy (PTT), and photodynamic therapy (PDT)) within a single platform holds immense potential to mitigate cancer while minimizing the risk of cancer recurrence and metastasis. − …”

Augmenting Cancer Therapy with a Supramolecular Immunogenic Cell Death Inducer: A Lysosome-Targeted NIR-Light-Activated Ruthenium(II) Metallacycle

“…Their allure lies in their remarkable structures, promising photophysical properties, and versatile functionalities. − Notably, Pt(II)- and Ru(II)-based metallacycles have demonstrated overwhelming advantages over their small-molecule counterparts in the fields of bioimaging, chemotherapy, and photodynamic therapy. This superiority is attributed to their high cellular uptake, good selectivity between normal and cancer cells, and prolonged tumor retention time. − Importantly, the incorporation of long-wavelength (>1000 nm) fluorescent ligands into these metallacycles has promoted their applicability for deep-tissue fluorescence imaging and ROS production. − Moreover, the rigid large macrocyclic structure, combined with the heavy-atom effect, confers robust resistance to fluorescence/ROS quenching while boosting ROS generation through the promotion of intersystem crossing (ISC). − Considering these advantages, metallacycles show great promise as scaffolds for developing ICD inducers that activate deep tumor immune responses without causing noticeable side effects. It is worth mentioning, however, that the exploration of metallacycles as potential ICD inducers is an area that remains relatively unexplored.…”