A novel pH-activated AIEgen probe for dynamic lysosome tracking and high-efficiency photodynamic therapy.

A novel AIEgen molecular probe (N-3QL) with typical AIE effects, good biocompatibility, lysosome targeting, pH activation, excellent photostability, and high brightness was synthesized using two simple synthetic steps. Spectroscopic and cytotoxicity experiments indicate that N-3QL can not only be used for the dynamic monitoring of cancer cell lysosomes, but also for photodynamic therapy (PDT) ablation of cancer cells.

Endogenous Enzyme-Activatable Spherical Nucleic Acids for Spatiotemporally Controlled Signal Amplification Molecular Imaging and Combinational Tumor Therapy.

Due to the adjustable hybridization activity, antinuclease digestion stability, and superior endocytosis, spherical nucleic acids (SNAs) have been actively developed as probes for molecular imaging and the development of noninvasive diagnosis and image-guided surgery. However, since highly expressed biomarkers in tumors are not negligible in normal tissues, an inevitable background signal and the inability to precisely release probes at the chosen region remain a challenge for SNAs. Herein, we proposed a rationally designed, endogenous enzyme-activatable functional SNA (Ep-SNA) for spatiotemporally controlled signal amplification molecular imaging and combinational tumor therapy. The self-assembled amphiphilic polymer micelles (SM-ASO), which were obtained by a simple and rapid copper-free strain-promoted azide-alkyne cycloaddition click reaction between dibenzocyclooctyne-modified antisense oligonucleotide and azide-containing aliphatic polymer polylactic acid, were introduced as the core elements of Ep-SNA. This Ep-SNA was then constructed by connecting two apurinic/apyrimidinic (AP) site-containing trailing DNA hairpins, which could occur via a hybridization chain reaction in the presence of low-abundance survivin mRNA to SM-ASO through complementary base pairing. Notably, the AP site-containing trailing DNA hairpins also empowered the SNA with the feasibility of drug delivery. Once this constructed intelligent Ep-SNA nanoprobe was specifically cleaved by the highly expressed cytoplasmic human apurinic/apyrimidinic endonuclease 1 in tumor cells, three key elements (trailing DNA hairpins, antisense oligonucleotide, and doxorubicin) could be released to enable subsequent high-sensitivity survivin mRNA imaging and combinational cancer therapy (gene silencing and chemotherapy). This strategy shows great application prospects of SNAs as a precise platform for the integration of disease diagnosis and treatment and can contribute to basic biomedical research.

A novel AIEgen photosensitizer with an elevated intersystem crossing rate for tumor precise imaging and therapy.

Herein, we have designed and synthesized a quinolinyl-AIE photosensitizer (TPE-4QL+) with an alternative elevated intersystem crossing (ISC) rate, which exhibits not only highly efficient photosensitivity but also high tumor cell specificity and an excellent mitochondrial targeting ability. In vitro experiments indicate that using TPE-4QL+ as a photosensitizer can induce a series of tumor cells to die with a low dose of radiation, but with no obvious toxicity to normal cells. The in vivo studies on a mouse model bearing a subcutaneous 4T1 xenograft also show that TPE-4QL+ can be used with high efficiency as a photosensitizer in PDT.

Tannic Acid-Assisted Biomineralization Strategy for Encapsulation and Intracellular Delivery of Protein Drugs.

Protein therapy has been considered to be one of the most direct and safe ways to regulate cell function and treat tumors. However, safe and effective intracellular delivery of protein drugs is still a key challenge. Herein, we developed a tannic acid-assisted biomineralization strategy for the encapsulation and intracellular delivery of protein drugs. RNase A and glucose oxidase (GOD) were choose as the protein drug model. RNase A, GOD, TA, and Mn2+ are mixed in one pot to attain RG@MT, and CaCO3 coating is subsequently carried out to construct RG@MT@C through biomineralization. Once RG@MT@C is endocytosed, the acidic environment of the lysosome will dissolve the protective layer of CaCO3 and produce plenty of CO2 to cause lysosome bursting, ensuring the lysosome escape of the RG@MT@C and thus releasing the generated TA-Mn2+, RNase A, and GOD into the cytoplasm. The released substances would activate starvation therapy, chemodynamic therapy, and protein therapy pathways to ensure a high performance of cancer therapy. Due to simple preparation, low toxicity, and controlled release in the tumor microenvironment, we expect it can realize efficient and nondestructive delivery of protein drugs and meet the needs for precise, high performance of synergistically antitumor therapy in biomedical applications.

Microemulsion-Confined Assembly of Magnetic Nanoclusters for pH/H2O2 Dual-Responsive T2-T1 Switchable MRI.

In this work, a T2-T1 switchable superparamagnetic iron oxide nanoprobe with a pH/H2O2 dual response was obtained using a microemulsion method. This novel method for the controllable assembly of small iron clusters followed by their independent modification was reported, which could not be prepared by common synthetic methods. The size of the assembled nanoprobe was uniform and controllable, with a stable T2 magnetic resonance imaging (MRI) signal under a single condition. When the nanoprobe was exposed to the tumor environment, the higher H+ and H2O2 concentrations at the tumor site could dissociate the nanoprobe and redisperse into small iron clusters. When this occurred, the T2 MRI signal was converted into a T1 MRI signal, achieving specific detection of tumors by a pH/H2O2 dual-response T2-T1 MRI.

Microemulsion-Confined Biomineralization of PEGylated Ultrasmall Fe3O4 Nanocrystals for T2-T1 Switchable MRI of Tumors.

Ultrasmall superparamagnetic iron oxide nanoparticles (USPIONs) are a novel T1 contrast agent with good biocompatibility and switchable imaging signal that have not been widely applied for magnetic resonance imaging (MRI) because it is difficult to induce their relatively close ideal agglomeration. Here, by combining the microemulsion method with the biomineralization principle, a pH-responsive T2-T1 switchable MRI nanoprobe was constructed via the microemulsion-confined biomineralization of PEGylated USPIONs (PEG-USPIONs). The size of the formed CaCO3-coated PEG-USPION conjugates (PEG-USPIONs@CaCO3 nanoprobe) was uniform and controllable, and the preparation method was simple. The PEG-USPIONs inside the nanoconjugates agglomerate more tightly, and the T1-MRI signal of the nanoprobe is converted to the T2-MRI signal. When exposed to the acidic environment of the tumor tissue or internal organelles, the CaCO3-coating of the nanoprobes is dissolved, and free PEG-USPIONs are released, thus realizing the T1-weighted imaging of the tumors. The suitability of the PEG-USPIONs@CaCO3 nanoprobe for tumor MRI detection was successfully demonstrated using a mouse model bearing a subcutaneous 4T1 xenograft.

Photoactivatable Red Chemiluminescent AIEgen Probe for In Vitro/Vivo Imaging Assay of Hydrazine.

Here, we have developed a novel photoactivatable red chemiluminescent AIEgen probe (ACL), based on the combination of the red-emission AIEgen fluorophore (TPEDC) that shows excellent singlet oxygen (1O2)-generation ability and the precursor of Schaap's dioxetane (the linker connected to adamantane is the C═C bond) that can be modified to target various analytes, for in vitro and in vivo measurement of hydrazine. Prior to applying for sensing detection, the C═C bond connected to adamantane in ACL was first converted into dioxetane by irradiation to form the activated chemiluminescent AIEgen probe (ACLD). Then, the self-immolative reaction was triggered upon the deprotection of the acylated phenolic hydroxyl group in ACLD in the presence of hydrazine, resulting in the release of the high energy held in the 1,2-dioxetanes, and then, the chemiexcitation was triggered, thereby producing red chemiluminescence through the intramolecular chemiluminescence resonance energy transfer from Schaap's dioxetane to TPEDC. This chemiluminescent AIEgen probe was evaluated in a clean buffer environment as well as using living cells and mouse models.

PEGylated AIEgen molecular probe for hypoxia-mediated tumor imaging and photodynamic therapy.

We report a novel PEGylated aggregation-induced emission luminogen (AIEgen) molecular probe for hypoxia-mediated tumor imaging and photodynamic therapy by linking a PEG chain to the AIE-active photosensitizer via a hypoxia-sensitive azo group.