Targeting‐Triggered Porphysome Nanostructure Disruption for Activatable Photodynamic Therapy

Abstract

Photodynamic therapy (PDT) and photothermal therapy (PTT) possess advantages over the conventional therapies with additional treatment selectivity achieved with local laser irradiation. Comparing to PTT that ablates target tissue via thermal necrosis, PDT induces target cell death via singlet oxygen without damaging the underling connective tissue, thus preserving its biological function. Activatable photosensitizers provide an additional level of treatment selectivity via the disease-associated activation mechanism. In this study, folate-conjugated porphysomes are introduced as targeting-triggered activatable nano-sized beacons for PDT. Porphysomes are reported previously as the most stable and efficient delivery system of porphyrin, but their nanostructure converts the singlet oxygen generation mechanism to thermal ablation mechanism. By folate-receptor-mediated endocytosis, folate-porphysomes are internalized into cells rapidly and resulted in efficient disruption of nanostructures, thus switching back on the photodynamic activity of the densely packed porphyrins for effective PDT. In both in vitro and in vivo studies, folate-porphysomes can achieve folate receptor-selective PDT efficacy, which proves the robustness of targeting-triggered PDT activation of porphysome nanostructure for highly selective tumor ablation. The formulation of porphysomes can be modified with other targeting ligands as activatable photosensitizers for personalized treatment in future.

Activatable Photosensitizers: Agents for Selective Photodynamic Therapy

“…[66] An example of a non-enzymatic protein acting as an effector for aPS is seen in studies by Jin et al The targeting and triggered activatable system is composed of a folate-porphysome assembled from porphyrin-phospholipid conjugates. [68] The folate receptor-targeting porphysome containing a FA-PEG moiety in the porphysome base displays nano structureinduced super-quenching of photoactivities of the porphyrin (>90%) as compared with the corresponding disassembled form of Adv. Funct.…”

“…In both cell and animal studies, FAporphysome were observed to have folate receptor-targeted PDT activity, which demonstrates the applicability of targeting-responsive PDT reactivation of porphysome for cancer-specific therapy. [68] Several non-enzymatic proteins are overexpressed in both tumor and non-tumor cells in cancer tissues. For example, the biotin receptor is overexpressed to a greater extent than the folate receptor in a large number of cancer cell lines.…”

Rethinking translational nanomedicine: insights from the ‘bottom-up’ design of the Porphysome for guiding the clinical development of imageable nanomaterials

“…Disruption of the Porphysome nanostructure -which in vivo may be the combined consequence of the enhanced permeability and retention effect [27] and from targeting the Porphysome to a receptor-mediated endocytic pathway [28] -restores the near infrared (NIR) fluorescence and ROS generation of porphyrin in an activatable structurally dependent manner (see Figure 1). In vivo investigations of the antitumoural efficacy of Porphysome photodynamic [28,29] and photothermal [10 ,20 ,28,29,30] therapies, as well as on the photoacoustic [10 ,30,31] and fluorescence [10 ,30,31,32 ,33,34] image-guided tumour delineation have been reported extensively elsewhere.…”

“…In vivo investigations of the antitumoural efficacy of Porphysome photodynamic [28,29] and photothermal [10 ,20 ,28,29,30] therapies, as well as on the photoacoustic [10 ,30,31] and fluorescence [10 ,30,31,32 ,33,34] image-guided tumour delineation have been reported extensively elsewhere.…”

Multimodal Image-Guided Surgical and Photodynamic Interventions in Head and Neck Cancer: From Primary Tumor to Metastatic Drainage

“…Therefore, a significant clinical interest is to explore alternative treatment modalities that have fewer and smaller risks but retain a high level of efficacy to improve treatment outcomes and overall quality of life. Photodynamic therapy (PDT), which generates cytotoxic singlet oxygen through interactions between optical light and a photosensitizer in the presence of oxygen, has emerged as a viable tool for localized treatment of malignant tissues (15)(16)(17). Because of the extremely short life time and subsequent short diffusion distance (10-300 nm) of singlet oxygen, PDT damage is restricted to photosensitizer accumulation, enabling local tumor ablation without damaging underlining connective tissues unlike other ablation techniques (18,19).…”