(Nanowerk Spotlight) Most cancer patients are diagnosed after tumors have already grown large or spread, posing major challenges for treatment. Traditional therapies, such as surgery, chemotherapy, and radiation, often struggle to completely eliminate larger tumors, and side effects can significantly impact patients.
As researchers search for safer, more effective methods, light-based therapies like photothermal therapy (PTT) and photodynamic therapy (PDT) have shown potential as precise, minimally invasive options. These therapies use light to activate specific agents that selectively target and kill cancer cells, sparing surrounding tissue. However, until recently, the complexity of activating PTT and PDT together has limited their effectiveness, particularly against larger tumors.
A new study, reported in Advanced Materials (“Eradication of Large Tumors by Nanoscale Drug Self-Assembly”) and led by researchers from Southern Medical University in China, explores a solution by combining PTT and PDT into a single treatment system. This approach aims to harness both methods’ strengths to target large tumors effectively.
By self-assembling two drugs into nanoparticles that respond to a single type of light, the researchers hope to simplify treatment and enhance its effectiveness. The new particle system, called CM NAs (Ce6-Mitoxantrone NanoAssemblies), combines the photosensitizer chlorin e6 (Ce6) with the chemotherapy drug mitoxantrone (MTO), both of which are commonly used in cancer treatments.
The unique design of CM NAs allows them to deliver heat and reactive oxygen species (ROS) simultaneously when exposed to a specific near-infrared (NIR) wavelength of light. Together, these effects kill tumor cells and stimulate the immune system, potentially preventing tumor recurrence.
Schematic illustration of Ce6-Mitoxantrone NanoAssemblies in combination with laser irradiation to achieve comprehensive therapy for large tumors. (Image: reprinted with permission by Wiley-VCH Verlag)
Creating an effective combined treatment requires precise drug delivery. In CM NAs, Ce6 and MTO self-assemble into a stable, nanoscale particle that can circulate in the bloodstream without breaking down, increasing its likelihood of reaching the tumor intact. Once at the tumor site, CM NAs respond to a single 660 nm NIR wavelength, heating up and releasing reactive molecules that kill cancer cells.
The self-assembly process depends on molecular forces like hydrogen bonding and stacking interactions, allowing CM NAs to form without additional chemical carriers. This molecular arrangement also helps the particles remain small, stable, and slightly negatively charged, improving circulation and uptake by tumor cells.
The combined effects of photothermal heating and photodynamic ROS release produce powerful anti-tumor activity. In trials, the researchers observed that CM NAs effectively destroyed tumor cells from multiple cancer types, including colorectal, breast, and melanoma cells, without harming surrounding tissues. When activated by NIR light, CM NAs raised tumor cell temperatures by about 17.5 –C, sufficient to cause cell death without affecting nearby healthy cells.
This system also induces a form of cell death known as pyroptosis, a process that triggers the immune system to recognize and attack cancer cells. Unlike normal cell death, which often goes unnoticed by the immune system, pyroptosis causes cells to swell and burst, releasing inflammatory signals. This creates a highly visible “distress signal” for immune cells, which then target the tumor cells.
In this study, pyroptosis was achieved through a pathway involving Caspase-3 and gasdermin E (GSDME), proteins that play a role in cell membrane rupture and inflammation. The inflammatory molecules released through pyroptosis, such as lactate dehydrogenase (LDH) and cytokines IL-1β and IL-18, further strengthen the immune response.
Researchers also examined how CM NAs stimulated markers of immune response, known as immunogenic cell death (ICD), which helps the immune system recognize and remember cancer cells in the future. The CM NAs significantly increased the release of molecules like calreticulin (CRT), which signals immune cells to engulf and process tumor antigens. The study found that CM NAs promoted the release of ATP and HMGB1, molecules that recruit and activate immune cells at the tumor site. As a result, immune cells could respond more effectively to remaining cancer cells, providing a potential for long-term immunity.
In animal models, CM NAs displayed impressive results, especially when tested on larger tumors. Mice with various cancer types, including colorectal and melanoma, were treated with CM NAs combined with NIR light. Results showed significant tumor reduction and prolonged survival, with tumor sizes shrinking by 95% or more. When researchers tested the treatment on mice with large tumors (about 500 mm3), they observed significant tumor regression.
Mice that survived the treatment were later injected with cancer cells to simulate a recurrence. Over two months, most of the treated animals remained cancer-free, indicating that the immune system had “learned” to recognize and fight the cancer cells.
Importantly, CM NAs showed minimal side effects in treated mice. Unlike traditional therapies, which can cause weight loss and other health complications, animals treated with CM NAs maintained stable body weight, suggesting good compatibility and low toxicity. The particles remained intact in the bloodstream long enough to accumulate in tumors and were then safely cleared from the body.
The results from this study present an innovative approach to cancer treatment. By combining photothermal and photodynamic effects into a single, efficient system, CM NAs offer a new way to target and eliminate large tumors while stimulating an immune response that can prevent recurrence. This study’s findings are particularly promising for cancers with high recurrence risks, like colorectal and melanoma. However, further research is needed to determine if these results can be replicated in human cancers. The next step will be to test CM NAs in animal models that better simulate the complexity of human tumors.
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