Recent Advances in the Enzyme-Activatable Organic Fluorescent Probes for Tumor Imaging and Therapy.

The exploration of advanced probes for cancer diagnosis and treatment is of high importance in fundamental research and clinical practice. In comparison with the traditional "always-on" probes, the emerging activatable probes enjoy advantages in promoted accuracy for tumor theranostics by specifically releasing or activating fluorophores at the targeting sites. The main designing principle for these probes is to incorporate responsive groups that can specifically react with the biomarkers (e. g., enzymes) involved in tumorigenesis and progression, realizing the controlled activation in tumors. In this review, we summarize the latest advances in the molecular design and biomedical application of enzyme-responsive organic fluorescent probes. Particularly, the fluorophores can be endowed with ability of generating reactive oxygen species (ROS) to afford the photosensitizers, highlighting the potential of these probes in simultaneous tumor imaging and therapy with rational design. We hope that this review could inspire more research interests in the development of tumor-targeting theranostic probes for advanced biological studies.

Promoted NIR-II Fluorescence by Heteroatom-Inserted Rigid-Planar Cores for Monitoring Cell Therapy of Acute Lung Injury.

Fluorophores with emission in the second near-infrared (NIR-II) window have displayed salient advantages for biomedical applications. However, exploration of new luminogens with high NIR-II fluorescent brightness is still challenging. Herein, based on the "ring-fusion" strategy, a series of heteroatom-inserted rigid-planar cores is proposed to achieve the bathochromic NIR-II fluorophores with aggregation-induced emission (AIE) performance. Interestingly, one of the representative fluorophores, 4,4'-(5,5'-([1,2,5]thiadiazolo[3,4-i]dithieno[2,3-a:3',2'-c]phenazine-8,12-diyl)bis(4-octylthiophene-5,2-diyl))bis(N,N-diphenylaniline) (TTQiT), enjoys a maximum emission beyond 1100 nm because of the efficiently narrowed energy bandgap by electron-rich sulfur-atom-inserted core, which is verified by theoretical calculation. Taking advantage of the bright NIR-II emission of TTQiT nanoparticles, the desirable in vivo NIR-II imaging with high signal-to-background ratios is successfully performed and a long-term stem cell tracking in the detection of acute lung injury is further realized. Therefore, it is anticipated that this work will provide a promising molecular engineering strategy to enrich the scope of NIR-II fluorophores for catering to diverse demands in biomedical applications.

Type I macrophage activator photosensitizer against hypoxic tumors.

Photodynamic immunotherapy has emerged as a promising strategy to treat cancer. However, the hypoxic nature of most solid tumors and notoriously immunosuppressive tumor microenvironment could greatly compromise the efficacy of photodynamic immunotherapy. To address this challenge, we rationally synthesized a type I photosensitizer of TPA-DCR nanoparticles (NPs) with aggregation-enhanced reactive oxygen species generation via an oxygen-independent pathway. We demonstrated that the free radicals produced by TPA-DCR NPs could reprogram M0 and M2 macrophages into an anti-tumor state, which is not restricted by the hypoxic conditions. The activated M1 macrophages could further induce the immunogenic cell death of cancer cells by secreting pro-inflammatory cytokines and phagocytosis. In addition, in vivo anti-tumor experiments revealed that the TPA-DCR NPs could further trigger tumor immune response by re-educating tumor-associated macrophages toward M1 phenotype and promoting T cell infiltration. Overall, this work demonstrates the design of type I organic photosensitizers and mechanistic investigation of their superior anti-tumor efficacy. The results will benefit the exploration of advanced strategies to regulate the tumor microenvironment for effective photodynamic immunotherapy against hypoxic tumors.

Photoacoustic Force-Guided Precise and Fast Delivery of Nanomedicine with Boosted Therapeutic Efficacy.

Precise and efficient delivery of nanomedicine to the target site has remained as a major roadblock in advanced cancer treatment. Here, a novel photoacoustic force (PAF)-guided nanotherapeutic system is reported based on a near-infrared (NIR)-absorbing semiconducting polymer (SP), showing significantly improved tumor accumulation and deep tissue penetration for enhanced phototherapeutic efficacy. The accumulation of nanoparticles in 4T1 tumor-bearing mice induced by the PAF strategy displays a fivefold enhancement in comparison with that of the traditional passive targeting pathway, in a significantly shortened time (45 min vs 24 h) with an enhanced penetration depth in tumors. Additionally, a tumor-bearing mouse model is rationally designed to unveil the mechanism, indicating that the nanoparticles enter solid tumors through enhanced transportation across blood vessel barriers via both inter-endothelial gaps and active trans-endothelial pathways. This process is specifically driven by PAF generated from the nanoparticles under NIR laser irradiation. The study thus demonstrates a new nanotherapeutic strategy with low dose, enhanced delivery efficiency in tumor, and boosted therapeutic efficacy, opening new doors for designing novel nanocarriers.

Targeted NIR-II emissive nanoprobes for tumor detection in mice and rabbits.

The functional NIR-II emissive nanoprobe loaded with AIEgen (cRGD-TTB NPs) achieved a high quantum yield (10.32%) and a high signal-to-background (S/B) ratio of 7.7 when employed for the visualization of large tumors (∼600 mm3) in rabbit models for the first time. This work will aid in the investigation of tumor targeting effect of therapeutic agents in large animal models.

A 2,3-dialkoxynaphthalene-based naphthocage.

A 2,3-dialkoxynaphthalene-based naphthocage has been synthesized. This naphthocage prefers to bind small organic cations with its low-symmetry conformation, which is in contrast to 2,6-dialkoxynaphthalene-based naphthocages. Self-sorting of these two naphthocages with two structurally similar guests tetramethylammonium and tetraethylammonium was achieved as well.

A conformationally adaptive macrocycle: conformational complexity and host-guest chemistry of zorb[4]arene.

Large amplitude conformational change is one of the features of biomolecular recognition and is also the basis for allosteric effects and signal transduction in functional biological systems. However, synthetic receptors with controllable conformational changes are rare. In this article, we present a thorough study on the host-guest chemistry of a conformationally adaptive macrocycle, namely per-O-ethoxyzorb[4]arene (ZB4). Similar to per-O-ethoxyoxatub[4]arene, ZB4 is capable of accommodating a wide range of organic cations. However, ZB4 does not show large amplitude conformational responses to the electronic substituents on the guests. Instead of a linear free-energy relationship, ZB4 follows a parabolic free-energy relationship. This is explained by invoking the influence of secondary C-H···O hydrogen bonds on the primary cation···π interactions based on the information obtained from four representative crystal structures. In addition, heat capacity changes (ΔCp) and enthalpy-entropy compensation phenomena both indicate that solvent reorganization is also involved during the binding. This research further deepens our understanding on the binding behavior of ZB4 and lays the basis for the construction of stimuli-responsive materials with ZB4 as a major component.

Light-Controlled Switching of a Non-photoresponsive Molecular Shuttle.

In this research, we report that the acid/base-switchable molecular shuttle without any photoresponsive group can be controlled photochemically by coupling to the indazole-based photoacid via an intermolecular proton-transfer process. The photocontrolled shuttling of the wheel can be conveniently monitored by following the fluorescent evolution during the photoirradiation.

H2S-Responsive Lower Critical Solution Temperature of the Host-Guest Complex Based on Oxatub[4]arene with Tri(ethylene oxide) Moieties.

A water-soluble oxatub[4]arene with tri(ethylene oxide) moieties was synthesized. The lower critical solution temperature (LCST) behavior of this macrocyclic receptor was tunable by changing its concentration or by adding an appropriate guest. Most interestingly, the LCST behavior of the host-guest complex showed a response to the presence of the physiological gasotransmitter H2S through nitro group reduction.