Introduction:: Introduction: Hepatocellular carcinoma (HCC) is a form of primary liver cancer with limited curative treatment options due to underlying liver damage preventing surgical resection and lack of donor availability for liver transplantation. Thus, there is a critical need for minimally invasive therapies to resolve early-stage HCC. Percutaneous ethanol injection (PEI) is a cost-effective ablative therapy for small tumor nodules, but its efficacy is limited by ethanol leakage and poor distribution within the tumor. Photodynamic therapy (PDT) is another safe, minimally invasive treatment that uses a light-triggered photosensitizer to induce cell death, but its clinical translation for HCC is hindered by the non-specific accumulation of photosensitizers in normal liver tissues and poor red light penetration depth. To address these challenges, our Light Activatable, Sustained-exposure Ethanol Injection Technology (LASEIT) combines the two therapies together into a novel formulation that achieves enhanced biodistribution, light propagation of PDT, and efficacy.


Materials and Methods::

Materials and Methods: To study the biodistribution of the LASEIT formulation in tissues, a cellulose derivative polymer (ethyl cellulose, EC), pure ethanol, and photosensitizer (benzoporphyrin derivative, BPD) were mixed and injected into tissue mimicking phantoms and excised swine livers to form a uniform depot. Under fluorescence microscopy, the photosensitizer can be excited to reveal the distribution volume of the depot within the phantoms and tissues. To detect the generation of singlet oxygen after red-light activation, Singlet Oxygen Sensor Green was combined with LASEIT during phantom injection. To evaluate light propagation properties, EC, pure water, and Intralipid, a commonly used light scattering agent, were added to a test tube. Lastly, to investigate the efficacy of LASEIT in vivo, LASEIT and BPD-PBS control group were injected intratumorally into a tumor-burden animal model, with the depot imaged under IVIS imaging. The tumor burden was monitored over a period of 14 days.

Results, Conclusions, and Discussions:: Results and Discussion: LASEIT formed depots of ~1.5 cm in diameter in tissue mimicking phantoms and swine livers (Fig. 1A and 1B). EC enhanced the light propagative ability in test tubes by 4 cm (Fig. 1C). IVIS imaging showed that LASEIT achieved a larger depot in tumors compared to monotherapy and control groups (Fig. 1D). LASEIT yielded a decreased tumor burden (Fig. 1E) and decreased tumor growth slope (Fig. 1F) compared to monotherapy and control groups over 14 days.

Conclusions: Real-time monitoring of LASEIT distribution in tissue mimicking phantoms, swine liver tissues, and animal tumors is achieved via photosensitizer fluorescence imaging. We showed that LASEIT increased drug distribution, increased light propagation, and reduced tumor burden, demonstrating its potential as a viable treatment for unresectable tumors, such as HCCs.


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