Photoactivatable nanoagonists chemically programmed for pharmacokinetic tuning and in situ cancer vaccination

Abstract

Immunotherapy holds great promise for the treatment of aggressive and metastatic cancers; however, currently available immunotherapeutics, such as immune checkpoint blockade, benefit only a small subset of patients. A photoactivatable toll-like receptor 7/8 (TLR7/8) nanoagonist (PNA) system that imparts near-infrared (NIR) light-induced immunogenic cell death (ICD) in dying tumor cells in synchrony with the spontaneous release of a potent immunoadjuvant is developed here. The PNA consists of polymer-derived proimmunoadjuvants ligated via a reactive oxygen species (ROS)-cleavable linker and polymer-derived photosensitizers, which are further encapsulated in amphiphilic matrices for systemic injection. In particular, conjugation of the TLR7/8 agonist resiquimod to biodegradable macromolecular moieties with different molecular weights enabled pharmacokinetic tuning of small-molecule agonists and optimized delivery efficiency in mice. Upon NIR photoirradiation, PNA effectively generated ROS not only to ablate tumors and induce the ICD cascade but also to trigger the on-demand release of TLR agonists. In several preclinical cancer models, intravenous PNA administration followed by NIR tumor irradiation resulted in remarkable tumor regression and suppressed postsurgical tumor recurrence and metastasis. Furthermore, this treatment profoundly shifted the tumor immune landscape to a tumoricidal one, eliciting robust tumor-specific T cell priming in vivo. This work highlights a simple and cost-effective approach to generate in situ cancer vaccines for synergistic photodynamic immunotherapy of metastatic cancers.

Proton-Gradient-Driven Porphyrin-Based Liposome Remote-Loaded with Imiquimod as In Situ Nanoadjuvants for Synergistically Augmented Tumor Photoimmunotherapy

“…therapeutic agents, such as PDT, oxaliplatin, and doxorubicin, could induce ICD to enhance antitumor immunotherapy. 35,45 CRT as a marker of the endoplasmic reticulum translocated to the cell surface and subsequent release of HMGB-1 from the tumor cell nuclei were the typical characteristics of ICD, releasing "eat me" and "danger" signals to activate BMDCs and antigen presentation. 46−48 We first investigated whether PBL upon irradiation could induce the ICD effect.…”

“…Compared to these mentioned TLR agonists, the TLR7 agonist R837 has the following unique features: (1) high specificity; (2) a well-tolerated safety profile approved by the FDA; and (3) specifically activate cellular and humoral immunity. , Nevertheless, TLR agonists (e.g., imiquimod, R837) are highly hydrophobic, and the target of TLR agonists is on the inner membrane of endosomes or lysosomes; then, systemic administration of small-molecule drugs tends to induce hyperimmunity or off-target effects, such as headache, and even cytokine storms. − Fortunately, nanodrug delivery systems can not only improve the solubility of poorly soluble drugs but, more importantly, also endow them with controlled release and targeted distribution in vivo . At present, the main strategies for delivering TLR agonists are still suffering from low levels of delivery (physical encapsulation) , and the comprised drug activity (chemical conjugation). − Therefore, delivering R837 with high stability in the physical environment and retention of drug activity still faces huge challenges.…”

(Nano)platforms in breast cancer therapy: Drug/gene delivery, advanced nanocarriers and immunotherapy

“…Various types of external stimuli systems have been reported for cancer therapy, including light, magnetic field, ultrasound, and so forth 215–217 . One of the most common external stimuli for purpose of cancer therapy is the development of nanostructures that can be sensitive to NIR light, and this results in immunogenic cell death that is of importance for purpose of immunotherapy and future insights towards development of cancer vaccines 218 . In this section, some of those techniques that have been applied more in breast cancer therapy are summarized.…”

Nanomedicines Based on Responsive Nanocarriers for Cancer Therapy

“…The NIR irradiation effectively promoted PNA‐generated ROS, which not only ablated tumors and induced the ICD cascade but also triggered the on‐demand release of agonists for cancer vaccination. [ 72 ] In summary, the above light‐responsive strategies provide a new idea for photodynamic precise anti‐tumor therapy.…”