Dynamic monitoring of the fibrosis disease by a collagen targeting near infrared probe.

The deposition of the extracellular matrix, especially collagen, and the elevated expression levels of reactive oxygen species, including H2O2, are the main features of fibrosis. Fibrosis can occur in many tissues, such as tumor and liver tissues. The deposition of collagen in the location of lesions not only leads to immunological rejection and supports liver fibrosis and tumor progression, but also provides unique physiological signals with the progression of fibrosis and tumor. However, at present, the detection of fibrosis, especially real time detection, is greatly difficult, making it important to develop noninvasive probes for the dynamic monitoring of fibrosis progression. Herein, we propose a H2O2 responsive macromolecular probe for collagen imaging with high sensitivity and specificity. This probe consists of a collagen-targeting peptide and a H2O2-sensitive and near-infrared (NIR)-emitting macromolecular optical probe, which could effectively bind to collagen both in vitro and in vivo in the region of tumor or fibrotic liver tissues, allowing for high sensitivity and noninvasive visualization of fibrotic tissues and real time monitoring of collagen degradation after anti-fibrotic drug treatment.

Smart Lipid Nanoparticle that Remodels Tumor Microenvironment for Activatable H2S Gas and Photodynamic Immunotherapy.

Hydrogen sulfide (H2S) has shown promise for gas therapy. However, it is still controversial whether H2S can remodel the tumor microenvironment (TME) and induce robust antitumor immunity. Here, a tumor-targeting and TME-responsive "smart" lipid nanoparticle (1-JK-PS-FA) is presented, which is capable of delivering and releasing H2S specifically in tumor tissues for on-demand H2S gas and photodynamic immunotherapy. 1-JK-PS-FA enables a burst release of H2S in the acidic TME, which promptly reduces the embedded organic electrochromic materials and consequently switches on near-infrared fluorescence and photodynamic activity. Furthermore, we found that high levels of H2S can reprogram the TME by reducing tumor interstitial fluid pressure, promoting angiogenesis, increasing vascular permeability, ameliorating hypoxia, and reducing immunosuppressive conditions. This leads to increased tumor uptake of 1-JK-PS-FA, thereby enhancing PDT efficacy and eliciting strong immunogenic cell death during 808 nm laser irradiation. Therefore, 1-JK-PS-FA permits synergistic H2S gas and photodynamic immunotherapy, effectively eradicating orthotopic breast tumors and preventing tumor metastasis and recurrence. This work showcases the capacity of H2S to reprogram the TME to enhance H2S gas and immunotherapy.

Acid and Hypoxia Tandem-Activatable Deep Near-Infrared Nanoprobe for Two-Step Signal Amplification and Early Detection of Cancer.

The early detection of cancers can significantly change outcomes even with existing treatments. However, ~50% of cancers still cannot be detected until they reach an advanced stage, highlighting the great challenges in the early detection. Here, an ultrasensitive deep near-infrared (dNIR) nanoprobe that is successively responsive to tumor acidity and hypoxia is reported. It is demonstrated that the new nanoprobe specifically detects tumor hypoxia microenvironment based on deep NIR imaging in ten different types of tumor models using cancer cell lines and patient-tissue derived xenograft tumors. By combining the acidity and hypoxia specific two-step signal amplification with a deep NIR detection, the reported nanoprobe enables the ultrasensitive visualization of hundreds of tumor cells or small tumors with a size of 260 µm in whole-body imaging or 115 µm metastatic lesions in lung imaging. As a result, it reveals that tumor hypoxia can occur as early as the lesions contain only several hundred cancer cells.

Light-Driven Self-Recruitment of Biomimetic Semiconducting Polymer Nanoparticles for Precise Tumor Vascular Disruption.

Tumor vascular disrupting therapy has offered promising opportunities to treat cancer in clinical practice, whereas the overall therapeutic efficacy is notably limited due to the off-target effects and repeated dose toxicity of vascular disrupting agents (VDAs). To tackle this problem, a VDA-free biomimetic semiconducting polymer nanoparticle (SPNP ) is herein reported for precise tumor vascular disruption through two-stage light manipulation. SPNP consists of a semiconducting polymer nanoparticle as the photothermal agent camouflaged with platelet membranes that specifically target disrupted vasculature. Upon the first photoirradiation, SPNP administered in vivo generates mild hyperthermia to trigger tumor vascular hemorrhage, which activates the coagulation cascade and recruits more SPNP to injured blood vessels. Such enhanced tumor vascular targeting of photothermal agents enables intense hyperthermia to destroy the tumor vasculature during the second photoirradiation, leading to complete tumor eradication and efficient metastasis inhibition. Intriguingly, the mechanism study reveals that this vascular disruption strategy alleviates splenomegaly and reverses the immunosuppressive tumor microenvironment by reducing myeloid-derived suppressor cells. Therefore, this study not only illustrates a light-driven self-recruitment strategy to enhance tumor vascular disruption via a single dose of biomimetic therapeutics but also deciphers the immunotherapeutic role of vascular disruption therapy that is conducive to clinical studies.

The relationship between MUC19 copy number variation and growth traits of Chinese cattle.

Copy number variation (CNV), as one of the important variations in the biological genome, refers to the deletion and duplication of genomic segments between 1 kb and 50 kb caused by genomic rearrangements. Currently, many copy number variations have been found to be significantly associated with important economic traits such as growth, development and reproduction of cattle. However, the study of MUC19 gene has not been reported. In this study, we detected an appropriate correlation between MUC19 gene and growth traits of Chinese cattle. We detected the distribution of MUC19-CNV across Qinchuan cattle (QC), Pinan cattle (PN), Xianan cattle (XN), Yunling cattle (YL), Guyuan cattle (GY), Jiaxian cattle (JX), and analyzed the association between types of MUC19-CNV and growth traits through SPSS20.0 software and method of ANOVA. The results showed that various types of CNV were present in each breed of cattle, but there were discrepancies in the distribution of copy number variant types. The Association analysis result showed that CNV of MUC19 gene showed a postive effect in cattle growth traits: the copy number of MUC19 was significantly correlated with hip width of PN cattle (P < 0.01), height at hip cross and withers height of PN cattle (P < 0.05), hip width and body length of JX cattle (P < 0.05), Huckle bone width of YL cattle (P < 0.05).

Dendritic lipopeptide liposomes decorated with dual-targeted proteins.

Due to their homing effects, cell and cell membrane-derived nanocarriers have been widely used to enhance drug target delivery. Inspired by the protein-anchored cell membrane architecture, we here report a tumor-targeted liposome, dtDLP, which was constructed through the electrostatic interaction between dendritic lipopeptide liposomes and a dual-targeted recombinant protein, achieving superior tumor homing, cellular endocytotic and penetration abilities. The dual-targeted recombinant protein consists of an anti-epidermal growth factor receptor single domain antibody and a peptide ligand for the integrin αvß3. dtDLPs substantially reduced macrophage phagocytosis and increased drug internalization in both 4T1 cells and HeLa cells by providing more endocytic pathways. In addition, the dtDLPs showed great penetration ability in both multicellular spheroids and tumor tissues. Due to the improved cancer cellular uptake and tumor penetration, the dtDLPs exhibited a superior anticancer effect in both HeLa and 4T1 tumor-bearing mice. This work will be helpful for the design of cell-specific liposomes with admirable tumor targeting, endocytotic and penetration abilities.

Cascade Downregulation of the HER Family by a Dual-Targeted Recombinant Protein-Drug Conjugate to Inhibit Tumor Growth and Metastasis.

Human epidermal growth factor receptor type 2 (HER2)-targeted therapy can significantly improve the outcome of patients with HER2 positive cancer. However, relapse after this treatment remains a great challenge in the clinic due to tumor resistance, in which the HER network induces constitutive signal transduction. In addition, integrin receptors in the tumor extracellular matrix can mitigate the therapeutic effect of inhibitors to the growth factors receptors and tyrosine kinases. Here, the development of a recombinant protein (RP-HI) and its drug conjugates (RPDC-HI) to target both HER2 and integrin is reported. When simultaneously blocking HER2 and integrin by RP-HI, functions of the HER family and their interactions with the integrin are disrupted by downregulated expressions of HER family members, leading to inhibition of several downstream signal pathways. In combination with targeted delivery of the anticancer agent, doxorubicin (DOX), RPDC-HI significantly improves the tumor inhibition efficacy to 97.5% in treating HER2-positive breast cancer, comparing to 34.3% for free DOX. RPDC-HI shows even better antitumor efficiency than a monoclonal antibody, trastuzumab, when treating larger tumors. The developed dual-targeted RPDC platform offers a new and promising strategy for treating HER2-positive patients with synergistic therapeutic effects against tumor resistance to the conventional HER2-targeted treatment.

An oxygen-sensitive probe and a hydrogel for optical imaging and photodynamic antimicrobial chemotherapy of chronic wounds.

A small molecular probe (Ir-fliq) and a macromolecular optical probe (Ir-fliq-PVP) based on an iridium complex are designed for hypoxia imaging and antibacterial chemotherapy in this work. The existence of both isoquinoline and fluorene moieties in the probe structure extends the phosphorescence emission to the red-wavelength region. The rigid large conjugated structure of the ligand can also reduce the packing caused by intermolecular interactions and suppress the self-quenching, thus improving the phosphorescence efficiency. The hydrophilic Ir-fliq-PVP has a good ability to generate singlet oxygen and can be used for photodynamic antimicrobial chemotherapy (PACT). Moreover, the small molecular probe Ir-fliq is further cross-linked with carboxymethyl chitosan (CMCS) and sodium alginate (SA) to form a CSGI hydrogel. The biocompatibility, mechanical properties, antibacterial properties and hypoxic imaging ability of the CSGI hydrogel have been evaluated in chronic wound models of diabetic mice. It shows that the CSGI hydrogel can effectively inhibit the growth of bacteria in wounds through PACT under light irradiation, promote the healing of chronic wounds in diabetic mice, and record the hypoxia process of mouse wounds.

Enhancing Penetration Ability of Semiconducting Polymer Nanoparticles for Sonodynamic Therapy of Large Solid Tumor.

Sonodynamic therapy (SDT) holds growing promise in deep-seated or large solid tumor treatment owing to its high tissue penetration depth ability; however, its therapeutic efficacy is often compromised due to the hypopermeable and hypoxic characteristics in the tumor milieu. Herein, a semiconducting polymer nanoparticle (SPNC) that synergistically enhances tumor penetration and alleviates tumor hypoxia is reported for sonodynamic therapy of large solid tumors. SPNC comprises a semiconducting polymer nanoparticle core as a sonodynamic converter coated with a poly (ethylene glycol) corona. An oxygen-modulating enzyme, catalase, is efficiently conjugated to the surface of nanoparticles via the coupling reaction. Superior to its counterpart SPNCs (SPNC2 (84 nm) and SPNC3 (134 nm)), SPNC with the smallest size (SPNC1 (35 nm)) can efficiently penetrate throughout the tumor interstitium to alleviate whole tumor hypoxia in a large solid tumor model. Upon ultrasound (US) irradiation, SPNC1 can remotely generate sufficient singlet oxygen to eradicate tumor cells at a deep-tissue depth. Such a single treatment of SPNC1-medicated sonodynamic therapy effectively inhibits tumor growth in a large solid tumor mouse model. Therefore, this study provides a generalized strategy to synergistically overcome both poor penetration and hypoxia of large tumors for enhanced cancer treatment.

Mitochondrion-specific dendritic lipopeptide liposomes for targeted sub-cellular delivery.

The mitochondrion is an important sub-cellular organelle responsible for the cellular energetic source and processes. Owing to its unique sensitivity to heat and reactive oxygen species, the mitochondrion is an appropriate target for photothermal and photodynamic treatment for cancer. However, targeted delivery of therapeutics to mitochondria remains a great challenge due to their location in the sub-cellular compartment and complexity of the intracellular environment. Herein, we report a class of the mitochondrion-targeted liposomal delivery platform consisting of a guanidinium-based dendritic peptide moiety mimicking mitochondrion protein transmembrane signaling to exert mitochondrion-targeted delivery with pH sensitive and charge-reversible functions to enhance tumor accumulation and cell penetration. Compared to the current triphenylphosphonium (TPP)-based mitochondrion targeting system, this dendritic lipopeptide (DLP) liposomal delivery platform exhibits about 3.7-fold higher mitochondrion-targeted delivery efficacy. Complete tumor eradication is demonstrated in mice bearing 4T1 mammary tumors after combined photothermal and photodynamic therapies delivered by the reported DLP platform.

Phenothiazine versus Phenoxazine: Structural Effects on the Photophysical Properties of NIR-II AIE Fluorophores.

Aggregation-induced emission (AIE) fluorophores with second near-infrared window (NIR-II) fluorescence are very promising for in vivo imaging because they emit fluorescence in an aggregated state and provide desirable imaging resolution and depth. Up to now, only a limited number of NIR-II AIE fluorophores have been developed. Therefore, synthesizing novel NIR-II AIE fluorophores and investigating structural effects on their photophysical properties are very important for the development of AIE probes. In this work, we synthesized two donor-acceptor-donor-type NIR fluorophores with emissions extending into the NIR-II window named DPTQ-PhPTZ and DPTQ-PhPXZ with phenothiazine (PTZ) and phenoxazine (PXZ) derivatives as the electron donors, respectively, and studied their photophysical properties via theoretical and experimental approaches as well as the properties in NIR-II in vivo imaging. The PTZ and PXZ moieties provided typical AIE characteristics. Despite the very similar chemical structures of PTZ and PXZ, DPTQ-PhPTZ and DPTQ-PhPXZ exhibited rather different photophysical properties, for example, compared to DPTQ-PhPTZ, DPTQ-PhPXZ had higher quantum yield (QY) both in solution and in the aggregated state and its QY was less sensitive to solvent polarity. After being coated with an amphiphilic copolymer F-127, the fluorophores maintained fluorescence, and the formed fluorescent polymer nanoparticles (NPs) had satisfactory tumor accumulation and biocompatibility, implying that they are applicable for in vivo tumor detection.

A Dendron-Based Fluorescence Turn-On Probe for Tumor Detection.

Specifically amplifying the emission signals of optical probes in tumors is an effective way to improve the tumor-imaging sensitivity and contrast. In this paper, the first case of dendron-based fluorescence turn-on probes mediated by a Förster resonance energy transfer (FRET) mechanism is reported. Dendrons up to the fourth generation with a hydrophilic oligo(ethylene glycol) scaffold are synthesized by a solid-phase synthesis strategy, and show precise and defect-free chemical structures. To construct the fluorescence turn-on probe, one Cy5.5 molecule is conjugated to the focal of a G3 dendron through a robust linkage and eight Black Hole Quencher 3 (BHQ-3) molecules are conjugated to its periphery through a PEG chain bearing a reductively cleavable disulfide linkage. By in vitro and in vivo experiments, it is demonstrated that the fluorescence of the dendron-based probe can be activated effectively and rapidly in the reductive environments of tumor cells and tissues, and the probe thus exhibits amplified tumor signals and weak normal tissue signals. Compared with the reported nanoscale turn-on probes, the dendron-based probe has several significant advantages, such as well-defined chemical structure, precisely controllable fluorophore/quencher conjugation sites and ratio, desirable chemical stability, and reproducible pharmacokinetic and pharmacological profiles, and is very promising in tumor detection.

Improving Quantum Yield of a NIR-II Dye by Phenylazo Group.

Understanding structure-fluorescence correlation is very helpful for the design of fluorescent probes. In this paper, a donor-acceptor-donor (D-A-D) type NIR-II fluorophore with benzobisthiadiazole as the acceptor and triphenyl amine as the donor, and its three derivatives bearing respectively amino, tert-butyloxycarbonyl amino and phenylazo groups in donor moieties, are synthesized. Their electronic structures and optical properties are investigated via theoretical and experimental studies. It is found that all the three types of substituents significantly influence its fluorescent properties and the phenylazo groups dramatically enhance its quantum yield (QY). To achieve biological applications and maintain high QY in aqueous environments, the phenylazo-containing fluorophore is encapsulated in polystyrene-co-poly(ethylene glycol) micelles. The obtained fluorescent micelles have a QY of ≈3.51% in 1000-1500 nm in aqueous medium that is among the highest of the organic NIR-II probes reported so far for biological imaging. The high QY enables the in vivo imaging of the micelle-administered mice to be conducted with high speed and quality. As an application example, ultrafast NIR-II imaging of intravenously injected mice is performed and used to determine their cardiac cycle and heart rate. The micelles also significantly accumulate in tumors after tail-vein injection and exhibit great application potentials in tumor detection.

Target-Amplified Drug Delivery of Polymer Micelles Bearing Staudinger Ligation.

Bioorthogonal chemistry together with biomarker-installing techniques is very promising in the amplification of the tumor targeting efficiency of nanomedicine. In this work, we newly synthesized an amphiphilic block copolymer polyoxazoline-block-polycaprolactone (POX-PCL) in which a certain number of amino groups were dangled in the side chain of the POX block and then functionalized into triarylphosphine groups for active tumor targeting via Staudinger ligation. By using the block copolymer self-assembly, the Staudinger ligation reagent-containing and drug-loaded reactive micelles were prepared with a hydrodynamic diameter of ∼74 nm. Such drug-loaded reactive POX-PCL micelles exhibited significant tumor target ability through the Staudinger ligation between the micelles and the tumors metabolically labeled with azide group, as demonstrated by a series of in vitro and in vivo evaluations. In this work, a novel method was proposed for the application of Staudinger ligation in the nanomedicine for amplifying the tumor targeting ability and antitumor activity of nanodrugs.

Oxygen-Sensing Probes and Bandage for Optical Detection of Inflammation.

Small-molecular and macromolecular optical probes based on an iridium complex chromophore were designed for detecting hypoxic inflammation in this work. The optical probes had a large conjugated ligand that could extend its phosphorescence emission to the red-wavelength region, thus increasing the tissue penetration depth of the optical signal. Due to good water solubility, the macromolecular optical probe could image both monolayer cells and three-dimensional multicellular spheroids. Moreover, this macromolecular probe was able to effectively image inflammation and distinguish healthy and inflammatory regions in a mouse model of lipopolysaccharide (LPS)-induced inflammation with low background interference. Furthermore, we integrated the hydrophobic small-molecular probe into the polyurethane thin film, and the resulting film successfully monitored the inflammation of chronic wounds in a mouse model. This work demonstrated the great potential of the iridium complex in optical imaging hypoxia and hypoxia-associated inflammation and will have significant impact on the design of high-sensitivity sensors for the detection of hypoxia.

Translatable High Drug Loading Drug Delivery Systems Based on Biocompatible Polymer Nanocarriers.

Most nanocarriers possess low drug loading, resulting in frequently repeated administration and thereby high cost and increased side effects. Furthermore, the characteristics of nanocarrier materials, especially the drug loading capacity, plays a vital role in the drug delivery efficacy. In this review, we focus on the readily translatable polymeric drug delivery systems with high drug loading, which are comprised of biocompatible polymers such as poly(ethylene glycol), poly( N-vinylpyrrolidone), polyoxazoline, natural proteins like albumin and casein, non-natural proteins such as recombinant elastin-like polypeptides, as well as nucleic acids. At the end of this review, applications of these polymeric nanocarriers on the delivery of proteins and gene drugs are also briefly discussed.

Dendritic phospholipid-based drug delivery systems.

A class of new dendritic phospholipid compounds with different hydrophilic dendritic poly(l-lysine) peripheries from generations 1 (G1) to 3 (G3) (DPL-1 to DPL-3) were synthesised and nano-drug delivery systems based on these compounds were prepared (DPN-2 and DPN-3). DPL-1 couldn't self-assemble into nanocarriers. The size, TEM image, and the CD spectrum of DPN-2 and DPN-3 were experimentally examined. The effect of the peripheral structure of dendritic phospholipid-based nanocarriers on their biological performance and drug delivery efficiency was studied. In vitro cytotoxicity studies demonstrated that the DOX-loaded DPN-3 shows higher cytotoxicity against 4T1 cells and BGC823 cells than DPN-2. DOX-loaded DPN-3 also showed excellent behaviours in cell internalization and 4T1 multicellular spheroid penetration. The composition of the hydrophilic block in dendritic phospholipids affected the self-assembly behaviour, properties and delivery efficiency of the formed nanocarriers. This work will be helpful for building drug delivery systems with characteristics of high delivery efficiency and low cytotoxicity for clinical applications.