Large animal models for investigating the applications of photodynamic therapy

Abstract

Photodynamic therapy (PDT) is an emerging minimally invasive therapeutic modality that relies on the activation of a photosensitizing agent by light of a specific wavelength in the presence of molecular oxygen, leading to the generation of reactive oxygen species (ROS). This mechanism facilitates selective cytotoxic effects within pathological tissues and has demonstrated therapeutic potential across diverse disease contexts. However, the broader clinical applications remain limited by photosensitizer selectivity, shallow light penetration, and the risk of off-target cytotoxicity. Recent advancements in PDT have focused on the development of next-generation photosensitizers, the integration of nanotechnology for enhanced delivery and targeting, and the strategic combination of PDT with complementary therapeutic approaches. Experimental animal models play a crucial role in validating the efficacy and safety of PDT, optimizing its therapeutic parameters, and determining its mechanisms of action. This review provides a comprehensive overview of PDT applications in various disease models, including oncological, infectious, and nonconventional indications. Special emphasis is placed on the importance of large animal models in PDT research, such as rabbits, pigs, dogs, and non-human primates, which provide experimental platforms that more closely resemble human physiological and pathological states. The use of these models for understanding the mechanisms of PDT, optimizing therapeutic regimens, and evaluating clinical outcomes is also discussed. This review aims to inform future directions in PDT research and emphasizes the importance of selecting appropriate preclinical animal models to facilitate successful clinical translation.

Keywords: Animal models; Cancer; Infection; Photodynamic therapy.

Figure 1

Schematic of photodynamic therapy (PDT) mechanism in cancer cells In cancer treatment, the PDT mechanism involves administration of a photosensitizer (PS), which accumulates in tumor cells. Upon exposure to specific-wavelength light, the PS generates reactive oxygen species (ROS) and singlet oxygen (¹O₂) to induce tumor cell death and damage tumor vasculature, leading to ischemic cell death. PDT also triggers inflammation and immune responses against tumor progression. Figure created with Bioender.com.

Figure 2

PDT applications in rabbits for different pathological conditions, including cancer, bacterial infections, and neoplastic conditions, highlighting specific disease models CSC: Central serous chorioretinopathy; CNV: Choroidal neovascularization; PCO: Posterior capsular opacification; WHHL: Watanabe hereditary hyperlipidemia; BK: Bacterial keratitis. Figure created with BioRender.com.

Figure 3

Utilization of large animal models (dogs, pigs, sheep, and NHPs) in PDT research, demonstrating translational potential for various diseases Figure created with BioRender.com.

Figure 4

Overview of alternative models used in PDT research, including zebrafish, cell culture, and ex vivo models Zebrafish at various developmental stages are utilized to evaluate the anticancer effects of PDT, screen the toxicity of novel PS, and image PS uptake and biodistribution, with no ethical restrictions up to 5 days. Cell culture and 3D models are widely applied in dermatology, cardiovascular, oncology, and infectious disease research. Ex vivo tissues and organ-on-a-chip models also contribute to relevant PDT research in similar fields. HPF: Hours post-fecundation; DPF: Days post-fertilization. Figure created with BioRender.com.

Figure 5

Advantages, disadvantages, and disease applications of in vivo and in vitro models in PDT research This figure summarizes key features of various experimental models used in PDT research, including rabbit, dog, pig, NHP, sheep, zebrafish models, as well as cell culture systems, 3D constructs, ex vivo tissues, and organ-on-a-chip models. Each model has its own strengths and limitations and is suited to specific disease contexts such as oncology, ophthalmology, and infectious and inflammatory conditions. Figure created with BioRender.com.