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BACKGROUND T1, T2, and T1ρ might be potential biomarkers for assessing liver fibrosis. However, few studies reported the value of them in different animal models. PURPOSE To investigate and compare the performances of T1, T2, and T1ρ for noninvasively staging liver fibrosis in bile duct ligation (BDL) or carbon tetrachloride (CCl4 ) model. STUDY TYPE Prospective animal model. SUBJECTS Liver fibrosis was induced by BDL or injection of CCl4 in 120 rats. FIELD STRENGTH/SEQUENCE 11.7 T, T1 mapping with 10 repetition times, T2 mapping with 32 echo times, and T1ρ with 10 spin-lock times. ASSESSMENT T1, T2, and T1ρ were measured and correlated with liver fibrosis stages, as well as the degree of inflammation, steatosis, iron deposition, and the expression of cytokeratin 19. The discriminative performance of T1, T2, and T1ρ for staging liver fibrosis was compared. STATISTICAL TESTS One-way analysis of variance (ANOVA), Spearman's correlation analysis, factorial design ANOVA, and receiver operating characteristic curves (P

Despite the success of immune checkpoint blockade (ICB) therapy in cancer management, ICB-based immunotherapy of triple-negative breast cancer (TNBC) still suffers from immunosuppressive tumor microenvironment (ITM). To break through the bottleneck of TNBC immunotherapy, a self-cascaded unimolecular prodrug consisting of an acidic pH-activatable doxorubicin and an aggregation-induced emission luminogen (AIEgen) photosensitizer coupled to a caspase-3-responsive peptide was engineered. The generated prodrug, could not only release doxorubicin initiatively in acidic tumor microenvironment, but also activate apoptosis-related caspase-3. The activated caspase-3 could in turn trigger release and in situ aggregation of photosensitizers. Importantly, the unimolecular prodrug exhibits a renal clearance pathway similar to small molecules in vivo, while the aggregated AIEgens prolong tumor retention for long-term fluorescence imaging and repeatable photodynamic therapy (PDT) by only one single-dose injection. Furthermore, the tumor-detained PDT boosts both immunogenic cell death of TNBC cells and maturation of dendritic cells. Finally, the combination of repeatable PDT with ICB therapy further promotes the proliferation and intratumoral infiltration of cytotoxic T lymphocytes, and effectively suppresses tumor growth and pulmonary metastasis. This prodrug is a proof-of-concept that confirms the first self-cascaded chemo-PDT strategy to reverse the ITM and boost the ICB-mediated TNBC immunotherapy.

The use of peptide amphiphiles (PAs) is becoming increasingly popular, not only because of their unique self-assembly properties but also due to the versatility of designs, allowing biological responsiveness, biocompatibility, and easy synthesis, which could potentially contribute to new drug design and disease treatment concepts. Oligonucleotides, another major functional bio-macromolecule class, have been introduced recently as new functional building blocks into PAs, further enriching the tools available for the fabrication of bio-functional PAs. Taking advantage of this, in the present work, two nucleic base-linked (adenine, A and thymine, T) RGD-rich peptide amphiphiles (NPAs) containing the fluorophores naphthalimide and rhodamine (Nph-A and Rh-T) were designed and synthesized. The two NPAs exhibit distinctive assembly behaviours with spherical (Rh-T) and fibrous (Nph-A) morphologies, and mixing Nph-A with Rh-T leads to a densely crosslinked colloidal network (Nph-A/Rh-T) via mutually promoted supramolecular polymerization via nucleation-growth assembly. Because of the RGD-rich sequences in the crosslinked network, further research on in situ targeted cancer cell (MDA-MB-231) encapsulation via RGD–integrin recognition was performed, and the modulation of cell behaviours (e.g., cell viability and migration) was demonstrated using both confocal laser scanning microscopy (CLSM) imaging and a scratch wound healing assay., A cross-linking of peptide–nucleic base amphiphiles leads to a dense colloidal network that can perform targeted cancer cell encapsulation in situ.

T1, T2, and T1ρ might be potential biomarkers for assessing liver fibrosis. However, few studies reported the value of them in different animal models.To investigate and compare the performances of T1, T2, and T1ρ for noninvasively staging liver fibrosis in bile duct ligation (BDL) or carbon tetrachloride (CClProspective animal model.Liver fibrosis was induced by BDL or injection of CCl11.7 T, T1 mapping with 10 repetition times, T2 mapping with 32 echo times, and T1ρ with 10 spin-lock times.T1, T2, and T1ρ were measured and correlated with liver fibrosis stages, as well as the degree of inflammation, steatosis, iron deposition, and the expression of cytokeratin 19. The discriminative performance of T1, T2, and T1ρ for staging liver fibrosis was compared.One-way analysis of variance (ANOVA), Spearman's correlation analysis, factorial design ANOVA, and receiver operating characteristic curves (P 0.05 was considered statistically significant).T1, T2, and T1ρ (BDL: rho = 0.73, 0.85, 0.68; CClThe most sensitive and accurate method for staging liver fibrosis appeared to be T1 in our animal models followed by T1ρ. T2 may not be suitable for evaluating liver fibrosis.1 TECHNICAL EFFICACY STAGE: 2.

Tumor-derived alkaline phosphatase (ALP) is over-expressed in metastatic prostate cancer. The development of selective probes for ALP detection is therefore critical for early diagnosis and therapy of metastatic prostate cancer. Herein, we develop a mitochondria-targeted near-infrared activatable fluorescent/photoacoustic (NIR FL/PA) probe for the selective detection of prostate cancer-derived ALP and aggregation-enhanced photothermal therapy. Upon dephosphorylation, the probes are activated and they provide a red-shifted strong absorption and emission in the NIR window and thus enable NIR FL and PA imaging of ALP activity in tumor tissues. Particularly, the activated probes self-assemble in situ into a supramolecular network structure which induces cell apoptosis and significantly enhances the photothermal therapy efficacy.

Protein-assisted biomimetic synthesis has been an emerging offshoot of nanofabrication in recent years owing to its features of green chemistry, facile process, and ease of multi-integration. As a result, many proteins have been used for biomimetic synthesis of varying kinds of nanostructures. Although the efforts on exploring new proteins and investigating their roles in biomimetic chemistry are increasing, the most essential intrinsic properties of proteins are largely neglected. Herein we report a frequently used enzyme (horseradish peroxidase, HRP) to demonstrate the possibility of enzymatic activity retaining after accomplishing the roles in biomimetic synthesis of ultrasmall gadolinium (Gd) nanodots and stowing its substrate 2,2′-Azinobis (3-ethylbenzothiazoline-6-sulfonic acid ammonium salt) (ABTS), denoted as Gd@HRPABTS. It was found that ca. 70% of the enzymatic activity of HRP was preserved. The associated changes of protein structure with chemical treatments were studied by spectroscopic analys...

Because of the lack of specific targets, the highly aggressive triple negative breast cancer (TNBC) is unable to benefit from endocrine therapy or conventional targeting therapy. Even worse, current diagnostic and therapeutic approaches have limited value for TNBC. Therefore, developing TNBC-specific theranostic probes for accurate diagnosis and further selective therapy will build a powerful toolbox for TNBC management. In this contribution, we developed a sequential strategy to enhance the specificity of TNBC theranostics. In this theranostic system, a versatile nanoprobe (Pep-SQ@USPIO) was integrated legitimately for the fibronectin-targeting MR imaging and CTSB-activatable fluorescence imaging, followed with enhanced photodynamic therapy (PDT) of TNBC. First, the fibronectin overexpressed in the extracellular matrix (ECM) of TNBC was used as a biomarker for targeting theranostics using the Cys-Arg-Glu-Lys-Ala (CREKA) peptide. For another, the fluorescence and PDT capacity of self-developed squaraine photosensitizer (SQ) were prequenched by ultrasmall superparamagnetic iron oxide (USPIO), an MR imaging contrast agent. Once the linker, Gly-Phe-Leu-Gly (GFLG) peptide, was selectively cleaved by TNBC-derived CTSB, the liberated SQ photosensitizer allowed light-up fluorescence imaging and enhanced PDT of TNBC. Remarkably, this research demonstrates that tumor-ECM-targeting and endogenous enzyme-activated nanoprobes open a new avenue for TNBC theranostics.

Various squaraine dyes have been developed for biological imaging. Nevertheless, squaraine dyes with emission in the second window (NIR-II, 1000-1700 nm) have few reports largely due to the short of a simple and universal design strategy. In this contribution, molecular engineering strategy is explored to develop squaraine dyes with NIR-II emission. First, NIR-I squaraine dye SQ2 is constructed by the ethyl-grafted 1,8-naphtholactam as donor units and square acid as acceptor unit in a donor-acceptor-donor (D-A-D) structure. To red-shift the fluorescence emission into NIR-II window, malonitrile, as a forceful electron-withdrawing group, is introduced to strengthen square acid acceptor. As a result, the fluorescence spectrum of acceptor-engineered squaraine dye SQ1 exhibits a significant red-shift into NIR-II window. To translate NIR-II fluorophores SQ1 into effective theranostic agents, fibronectin-targeting SQ1 nanoprobe was constructed and showed excellent NIR-II imaging performance in angiography and tumor imaging, including lung metastatic foci in deep tissue. Furthermore, SQ1 nanoprobe can be used for photoacoustic imaging and photothermal ablation of tumors. This research demonstrates that the donor-acceptor engineering strategy is feasible and effective to develop NIR-II squaraine dyes.

Triple-negative breast cancer (TNBC), as the most tough subtype in breast cancer, has the worst outcome, and developing effective and safe strategies for patients undergone TNBC are urgently needed. Recently, phototheranostics, including optical imaging and phototherapy have shown a great potential in TNBC management. However, most of the phototheranostic probes, as ‘always-on’ agents, lead to high imaging background and nonspecific phototoxicity in adjacent healthy tissues. Herein, a toolbox of wavelength-adjustable butterfly molecules and gold nanorods (GNRs)-based peptide nanoassemblies (GPNAs) were achieved through simple synthesis and stepwise self-assembly for the targeted optical imaging and phototherapeutic of TNBC. Specifically, the self-assembled GPNAs were not only nonfluorescent but also photodynamic-inactivated, which significantly reduces background fluorescence and phototoxicity in adjacent healthy tissue. Extradomain-B fibronectin, as a biomarker of TNBC, can selectively disassemble peptide-conjugated butterfly molecules (ZD2-SQ) from GPNAs and liberate extremely bright NIR fluorescence in high signal-to-background ratio (SBR) and specific photodynamic therapy (PDT) capability while GNRs hold robust photoacoustic (PA) and CT imaging signals as internal reference and convert NIR light into heat energy for photothermal therapy (PTT) of TNBC. This research offers a novel general strategy for the development of activated molecular probes for specific phototheranostics of TNBC.

Peptide functionalized polydiacetylene (PDA) micelles encapsulated with camptothecin (CPT) kill ovarian cancer cells by the lysosome release of anticancer drug CPT. Moreover, the sub-30 nm PDA micelles penetrate efficiently into a tumor for enhanced therapeutic efficacy.

An aggregation-induced emission (AIE) dye-powered afterglow luminogen has been designed for in vivo tumor imaging. The underlying afterglow mechanism can be described as a closed-loop of “photon–1O2–SP intermediates–photon”., Semiconducting polymer (SP)-based afterglow luminogens are showing increasing potential for in vivo imaging because of their long-life luminescence and the associated benefits (e.g., zero-autofluorescence background and high signal-to-noise ratio). However, such organic afterglow luminescence agents are still rare and their application is usually limited by their relatively low afterglow intensity and short afterglow duration. Herein, we report an aggregation-induced emission (AIE) dye-powered SP afterglow luminogen by leveraging on the unique characteristics of an AIE dye to circumvent the concentration-quenching effect, enhance afterglow intensity and prolong afterglow duration. The underlying working mechanism is investigated by a series of experiments and it is found that the AIE dye provides sufficient 1O2 to excite SPs and form massive amounts of high-energy intermediates, and then the SP intermediates emit photons that can activate the AIE dye to generate 1O2 and simultaneously trigger the energy transfer process between the SPs and AIE dye, resulting in a deep-red emission. It is this closed-loop of “photon–1O2–SP intermediates–photon” that provides the afterglow emission even after the cessation of the excitation light. The as-prepared luminogen shows good performance in in vivo tumour imaging. This study demonstrates the advantages of AIE-facilitated afterglow luminescence and discloses its mechanism, and hopefully it could inspire the development of other innovative designs for cancer theranostics.

Lysophosphatidic acid (LPA, cutoff values ≥ 1.5 μM) is an effective biomarker for early stage ovarian cancer. The development of selective probes for LPA detection is therefore critical for early clinical diagnosis. Although current methods have been developed for the detection of LPA in solution, they cannot be used for tracking LPA in vivo. Here, we report a near-infrared (NIR) fluorescent probe that can selectively respond to LPA based on polarity-sensitive emission at a very low detection limit of 0.5 μM in situ. This probe exhibits a marked increase of fluorescence at 720 nm upon binding to LPA, allowing the direct visualization of LPA in vitro and in vivo without interference from other biomolecules. Moreover, the probe containing two arginine-glycine-aspartic acid units can be efficiently taken up by cancer cells based on an αvβ3 integrin receptor targeting mechanism. It also exhibits excellent biocompatibility and high pH stability in live cells and in vivo. Confocal laser scanning microscopy and flow cytometric imaging of SKOV-3 cells have confirmed that our probe can be used to image LPA in live cells. In particular, its NIR turn-on fluorescence can be used to effectively monitor LPA imaging in a SKOV-3 tumor-bearing mouse model. Our probe may pave the way for the detection of cancer-related biomarkers and even for early stage cancer diagnosis.

We describe an enzyme-regulated liberation strategy to in situ generate AIEgen nanoaggregates for on-site sensing and long-term tracking of β-galactosidase in ovarian cancer cells., Development of fluorescent probes for on-site sensing and long-term tracking of specific biomarkers is particularly desirable for the early detection of diseases. However, available small-molecule probes tend to facilely diffuse across the cell membrane or remain at the activation site but always suffer from the aggregation-caused quenching (ACQ) effect. Here we report an enzyme-activatable aggregation-induced emission (AIE) probe QM–βgal, which is composed of a hydrophilic β-galactosidase (β-gal)-triggered galactose moiety and a hydrophobic AIE-active fluorophore QM–OH. The probe is virtually non-emissive in aqueous media, but when activated by β-gal, specific enzymatic turnover would liberate hydrophobic AIE luminogen (AIEgen) QM–OH, and then highly fluorescent nanoaggregates are in situ generated as a result of the AIE process, allowing for on-site sensing of endogenous β-gal activity in living cells. Notably, taking advantage of the improved intracellular retention of nanoaggregates, we further exemplify QM–βgal for long-term (∼12 h) visualization of β-gal-overexpressing ovarian cancer cells with high fidelity, which is essential for biomedicine and diagnostics. Thus, this enzyme-activatable AIE probe not only is a potent tool for elucidating the roles of β-gal in biological systems, but also offers an enzyme-regulated liberation strategy to exploit multifunctional probes for preclinical applications.

A peptide-modified gold nanoparticle was developed for tumour-targeted therapy. Triggered by alkaline phosphatase, the CREKA-YPFFK(Nph) peptide can self-assemble and further result in accumulation of gold nanoparticles in tumour cells. The large-sized gold nanoparticle aggregates cannot escape from the tumour tissue, therefore realizing the goal of tumour-specific targeting, enhanced retention and photothermal effects.

Polydiacetylene (PDA) micelles have been widely used to deliver anticancer drugs in the treatment of a variety of tumours and for imaging living cells. In this study, we developed an effective strategy to directly conjugate magainin II (MGN-II) to the surface of PDA micelles using a fluorescent dye. These stable and well-defined PDA micelles had high cytotoxicity in cancer cell lines, and were able to reduce the tumour size in mice. The modified PDA micelles improved the anticancer effects of MGN-II in the A549 cell line only at a concentration of 16.0 μg mL(-1) (IC50). In addition, following irradiation with UV light at 254 nm, the PDA micelles gave rise to an energy transfer from the fluorescent dye to the backbone of PDA micelles to enhance the imaging of living cells. Our results demonstrate that modified PDA micelles can not only be used in the treatment of tumors in vitro and in vivo in a simple and directed way, but also offer a new platform for designing functional liposomes to act as anticancer agents.