Self-Assembled Nano-PROTAC Enables Near-Infrared Photodynamic Proteolysis for Cancer Therapy

Abstract

Confining the protein degradation activity of proteolysis-targeting chimera (PROTAC) to cancer lesions ensures precision treatment. However, it still remains challenging to precisely control PROTAC function in tumor regions in vivo. We herein describe a near-infrared (NIR) photoactivatable nano-PROTAC (NAP) for remote-controllable proteolysis in tumorbearing mice. NAP is formed by molecular self-assembly from an amphiphilic conjugate of PROTAC linked with an NIR photosensitizer through a singlet oxygen ( 1 O 2 )-cleavable linker. The activity of PROTAC is initially silenced but can be remotely switched on upon NIR photoirradiation to generate 1 O 2 by the photosensitizer. We demonstrated that NAP enabled tumorspecific degradation of bromodomain-containing protein 4 (BRD4) in an NIR light-instructed manner. This in combination with photodynamic therapy (PDT) elicited an effective suppression of tumor growth. This work thus presents a novel approach for spatiotemporal control over targeted protein degradation by PROTAC.

Nano-PROTACs: state of the art and perspectives

“…In addition, in the presence of PCB, a photo-metabolic cancer immunotherapy effect was achieved, consequently improving tumor immunogenicity together with PROTACs. A similar building-block strategy has been reported recently in a number of PROTAC prodrug nanoparticles, with several PROTACs (such as COX-1/2, 14 bromodomain-containing 4 (BRD4), 29 indoleamine 2,3-dioxygenase (IDO), 30 and Src homology 2 domain-containing phosphatase 2 (SHP2) 31 ), stimuli-cleavable segments (such as CatB-cleavable, 14,30 1 O 2 -cleavable, 29 and caspase 3-cleavable 31 ), and photosensitizers (such as PCB, 14,30 PA, 29 and PplX 31 ). These systems thus present a novel approach for spatiotemporal control over targeted protein degradation by PROTACs.…”

“…Based on this strategy, light-controllable PROTAC prodrug nanoparticles to address the on-target off-tissue toxicity of PROTACs have recently been reported to spatiotemporally activate and release PROTACs. 14,29–33 Briefly, PROTAC molecules are modified with responsive fragments with photo-caged groups to release PROTACs upon certain irradiation, accompanied by the de-caging and subsequent self-immolated cleavage of versatile responsive linkers (Fig. 2A).…”

Polydopamine-Coated Self-Assembled Lipid Nanoparticles for Highly Effective Chemo–Photothermal Combination Therapy

“…17 Traditional cancer treatment methods, such as chemotherapy, chemodynamic therapy, 18,19 surgery, and combination therapy, 20 still face tumor multidrug resistance, 21 low efficacy, systemic side effects, and so on. 22 Therefore, a variety of combination therapy strategies have been designed to overcome the shortcomings of single therapy, 23 such as chemotherapy, phototherapy, photodynamic therapy, 24,25 immunotherapy 26,27 and so on. 28 Among them, the common combination of phototherapy and chemotherapy, 29 such as photothermal therapy or photodynamic therapy combined with chemotherapy, 30 has been widely studied because it is less invasive and less harmful to normal tissues.…”

“…Traditional cancer treatment methods, such as chemotherapy, chemodynamic therapy, , surgery, and combination therapy, still face tumor multidrug resistance, low efficacy, systemic side effects, and so on . Therefore, a variety of combination therapy strategies have been designed to overcome the shortcomings of single therapy, such as chemotherapy, phototherapy, photodynamic therapy, , immunotherapy , and so on . Among them, the common combination of phototherapy and chemotherapy, such as photothermal therapy or photodynamic therapy combined with chemotherapy, has been widely studied because it is less invasive and less harmful to normal tissues. , Compared with photodynamic therapy, which can cause a high level of reactive oxygen species and produce toxic side effects for a long time, − photothermal therapy has been widely studied for its small toxic side effects and high specificity. , More importantly, photothermal reagent has excellent photothermal properties, which can be used to kill tumor cells directly, stimulate immunogenic cell death, and promote cell uptake by photothermal effect .…”

Enhancing Fractionated Cancer Therapy: A Triple-Anthracene Photosensitizer Unleashes Long-Persistent Photodynamic and Luminous Efficacy

“…Cancer continues to be a significant global health burden and presents challenges for current treatment modalities. − Traditional approaches, such as chemotherapy, radiotherapy, and hyperthermia, are widely used but have limitations, including poor tumor selectivity and severe side effects. − In contrast, photodynamic therapy (PDT) has emerged as a promising alternative due to its precision, noninvasiveness, repeatability, minimal drug resistance, and less side effects. ,− PDT has demonstrated efficacy in preclinical and clinical settings for various cancer types, including skin cancer, early obstructive lung cancer, superficial bladder cancer, bile duct cancer, esophagus cancer, and head and neck cancers. ,− However, there are several challenges hindering the widespread application of PDT. The photosensitizers used in PDT mainly rely on type II photosensitization, involving the exchange of electron spin between the photosensitizer (T 1 ) and oxygen to generate singlet oxygen ( 1 O 2 ). ,− Insufficient production of reactive oxygen species (ROS) may occur if the triplet energy of the photosensitizer is too low or if the tumor environment has limited oxygen. − Additionally, the limited lifetime (approximately 1 ns) and diffusion distance (less than 100 nm) of ROS generated during PDT restrict their reach to targeted areas and impede sustained therapy. − Prolonging the irradiation duration to generate more ROS may result in irreversible vascular damage and rapid depletion of oxygen in the tumor microenvironment …”