(Nanowerk Spotlight) Liver cancer remains one of the deadliest forms of cancer worldwide, with limited treatment options for patients in advanced stages. Traditional therapies like chemotherapy often struggle to effectively target tumor cells while sparing healthy tissue, leading to severe side effects. However, recent advances in nanotechnology and biomaterials science are opening up promising new avenues for more precise and potent cancer treatments.
Researchers have long sought ways to selectively deliver anti-cancer drugs to tumor sites while minimizing exposure to the rest of the body. Various nanoparticle-based drug delivery systems have been explored, but many faced issues with biocompatibility, drug release control, and tumor targeting specificity. Concurrently, scientists have investigated localized hyperthermia – using heat to kill cancer cells – as a potential complementary therapy. But delivering heat precisely to tumors deep within the body proved technically challenging.
The emergence of “smart” nanoparticles responsive to external stimuli like light or magnetic fields has reinvigorated research into combined chemo-thermal cancer therapies. Polydopamine, a synthetic polymer inspired by the adhesive proteins found in mussels, has attracted particular interest as a nanoparticle material. Its biodegradability, drug-loading capacity, and ability to generate heat when exposed to near-infrared light make it a promising multifunctional nanoplatform for cancer treatment.
Another key development has been the advent of “cell membrane coating” techniques, which allow nanoparticles to be cloaked in the outer membrane of cancer cells. This biomimetic approach aims to exploit the natural cell-cell recognition mechanisms cancers use to spread, potentially enabling nanoparticles to home in on and infiltrate tumors more effectively.
Against this backdrop, a team of researchers led by Gianni Ciofani at the Istituto Italiano di Tecnologia (IIT) has developed an innovative nanoparticle-based system that combines targeted chemotherapy and photothermal therapy for treating liver cancer. Their work, published in ACS Applied Materials & Interfaces (“Polydopamine Nanoparticle-Based Combined Chemotherapy and Photothermal Therapy for the Treatment of Liver Cancer”), represents a significant step forward in translating these emerging technologies into a clinically viable treatment approach.
The researchers created polydopamine nanoparticles loaded with sorafenib, a chemotherapy drug used to treat liver cancer. They then coated these nanoparticles with membranes extracted from liver cancer cells, aiming to give them tumor-targeting capabilities. The resulting nanoparticles – dubbed CM-SRF-PDA NPs – were extensively characterized to confirm their structure, stability, and drug release properties.
Graphical abstract of the work. (Image: Reproduced from DOI:10.1021/acsami.4c08491, CC-BY-NC-ND 4.0)
In a series of experiments, the team demonstrated that their nanoparticles could selectively accumulate in liver cancer cells at much higher rates than in normal cells. Specifically, they found that after 30 minutes of exposure, 23.4% of cancer cells had taken up the membrane-coated nanoparticles, compared to only 14.3% for uncoated nanoparticles. When exposed to near-infrared light, the nanoparticles efficiently converted this energy to heat, raising temperatures inside cancer cells by up to 14.8 °C – a level capable of triggering cell death.
The researchers then evaluated the therapeutic effects of their nanoparticle system in various models of increasing complexity. In standard two-dimensional cell cultures, the combination of nanoparticles and light exposure reduced cancer cell metabolic activity to 42.3% of control levels, compared to 75.8% for nanoparticles alone. Similar results were observed in three-dimensional tumor spheroids, which better mimic the structure of real tumors.
To further validate their approach, the team conducted experiments using an innovative ex ovo model – liver cancer spheroids grafted onto the chorioallantoic membrane of developing quail embryos. This allowed them to assess how the nanoparticles behaved in a more physiologically relevant environment with active blood flow. Histological analysis revealed that the nanoparticles could penetrate the tumor grafts and, upon light exposure, induce visible areas of cell death and nuclear discoloration indicative of apoptosis.
“A standout feature of our study was its comprehensive investigation into the molecular mechanisms underlying the observed anti-cancer effects,” Ciofani, Principal Investigator at the Smart Bio-Interfaces group at IIT, explains to Nanowerk. “Using advanced proteomic analysis, we identified numerous changes in protein expression triggered by their nanoparticle treatment. These included the upregulation of proteins involved in cellular stress responses and apoptosis (programmed cell death), as well as the downregulation of proteins associated with cancer cell survival and proliferation.”
This multi-pronged assault on cancer cells – combining the targeted delivery of chemotherapy drugs, localized heat generation, and the modulation of key cellular pathways – represents a potentially powerful new treatment strategy. By simultaneously attacking tumors through multiple mechanisms, such an approach could help overcome the drug resistance that often develops with traditional chemotherapy alone.
The use of polydopamine as the nanoparticle base material offers several advantages. Unlike some inorganic nanoparticles previously explored for cancer therapy, polydopamine is biodegradable, reducing concerns about long-term accumulation in the body. Its ability to efficiently generate heat when exposed to near-infrared light – which can penetrate relatively deeply into tissue – makes it well-suited for treating internal tumors.
While the results of this study are promising, significant challenges remain before such a treatment could be translated to the clinic. Further research is needed to optimize several aspects of the system. These include fine-tuning the nanoparticle formulation to maximize drug loading and release kinetics, evaluating different coating strategies to enhance tumor targeting, and developing more advanced light delivery techniques for reaching tumors deep within the body.
Long-term safety studies in animal models will be crucial to assess any potential toxicity or unexpected effects of the nanoparticles. Additionally, researchers will need to optimize treatment protocols, determining the ideal timing and dosing of nanoparticle administration and light exposure to maximize therapeutic efficacy while minimizing side effects.
Another important consideration is the potential variability in treatment response. The effectiveness of this approach may depend on factors such as tumor size, location, and individual patient characteristics. Developing methods to predict and monitor treatment response will be essential for clinical application.
The scalability and reproducibility of nanoparticle production and cell membrane coating processes also present challenges that need to be addressed for widespread clinical use. Ensuring consistent quality and performance of these complex nanostructures will be critical for regulatory approval and clinical reliability.
As Ciofani points out, even despite these hurdles, this work represents an important advance in the development of next-generation cancer therapies: “By creatively combining multiple emerging technologies – smart nanoparticles, targeted drug delivery, and light-activated therapies – we have demonstrated a promising new approach to attacking liver cancer. As this and related technologies continue to evolve, they offer hope for more effective and less toxic treatments for one of the world’s most challenging cancers.”
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