Bioorthogonal strategy-triggered In situ co-activation of aggregation-induced emission photosensitizers and chemotherapeutic prodrugs for boosting synergistic chemo-photodynamic-immunotherapy

Abstract

In situ activation of prodrugs or photosensitizers is a promising strategy for specifically killing tumor cells while avoiding toxic side effects. Herein, we originally develop a bioorthogonally activatable prodrug and pro-photosensitizer system to synchronously yield an aggregation-induced emission (AIE) photosensitizer and a chemotherapeutic drug for synergistic chemo-photodynamic-immunotherapy of tumors. By employing molecular engineering strategy, we rationally design a family of tetrazine-functionalized tetraphenylene-based photosensitizers, one of which (named TzPS5) exhibits a high turn-on ratio, a NIR emission, a typical AIE character, and an excellent ROS generation efficiency upon bioorthogonal-activation. With the aid of integrin- or mitochondria-pretargeting, TzPS5 is successfully applied for highly effective PDT ablation of cancer cells both in vitro and in vivo. On this basis, tumor-targeting TzPS5 (TzPS5-cRGD) is constructed and used jointly with a bioorthogonal prodrug, DOX-TCO, and the two are mutually activated to induce cooperative and tumor-specific PDT and chemotherapy, resulting in amplified therapeutic outcomes and improved biosafeties. Moreover, this combination modality elicits robust immunogenic cell death, stimulates systemic antitumor immunity, thereby suppressing both primary and distant tumors, and blocking the pulmonary tumor metastasis. This work is expected to provide a useful guidance for the rational design of activatable phototheranostic agents, and offer a new strategy for co-activation of prodrugs/pro-photosensitizers to boost synergistic antitumor chemo-photodynamic-immunotherapy.

Keywords: Activatable photosensitizers; Aggregation-induced emission; Bioorthogonal reaction; Prodrugs; Synergistic therapy.