A TME-enlightened protein-binding photodynamic nanoinhibitor for highly effective oncology treatment.

The efficiency of photodynamic therapy (PDT) is greatly dependent on intrinsic features of photosensitizers (PSs), but most PSs suffer from narrow diffusion distances and short life span of singlet oxygen (1O2). Here, to conquer this issue, we propose a strategy for in situ formation of complexes between PSs and proteins to deactivate proteins, leading to highly effective PDT. The tetrafluorophenyl bacteriochlorin (FBC), a strong near-infrared absorbing photosensitizer, can tightly bind to intracellular proteins to form stable complexes, which breaks through the space-time constraints of PSs and proteins. The generated singlet oxygen directly causes the protein dysfunction, leading to high efficiency of PSs. To enable efficient delivery of PSs, a charge-conversional and redox-responsive block copolymer POEGMA-b-(PAEMA/DMMA-co-BMA) (PB) was designed to construct a protein-binding photodynamic nanoinhibitor (FBC@PB), which not only prolongs blood circulation and enhances cellular uptake but also releases FBC on demand in tumor microenvironment (TME). Meanwhile, PDT-induced destruction of cancer cells could produce tumor-associated antigens which were capable to trigger robust antitumor immune responses, facilitating the eradication of residual cancer cells. A series of experiments in vitro and in vivo demonstrated that this multifunctional nanoinhibitor provides a promising strategy to extend photodynamic immunotherapy.

Tumor Microenvironment-Triggered Self-Adaptive Polymeric Photosensitizers for Enhanced Photodynamic Therapy.

Photodynamic therapy (PDT) employs photosensitizers to convert nearby oxygen into toxic singlet oxygen (1O2) upon laser light irradiation, showing great potential as a noninvasive approach for tumor ablation. However, the therapeutic efficacy of PDT is essentially impeded by π-π stacking and the aggregation of photosensitizers. Herein, we propose a tumor microenvironment-triggered self-adaptive nanoplatform to weaken the aggregation of photosensitizers by selenium-based oxidation at the tumor site. The selenide units in a selenium-based porphyrin-containing amphiphilic copolymer (PSe) could be oxidized into hydrophilic selenoxide units, leading to the nanoplatform self-expansion and stretching of the distance between intramolecular porphyrin units. This process could provide a better switch to greatly reduce the aggregation of photosensitive porphyrin units, generating more 1O2 upon laser irradiation. As verified in a series of in vitro and in vivo studies, PSe could be efficiently self-adapted at tumor sites, thus significantly enhancing the PDT therapeutic effect against solid tumors and minimizing side effects.

Reactive oxygen species (ROS)-mediated M1 macrophage-dependent nanomedicine remodels inflammatory microenvironment for osteoarthritis recession.

Osteoarthritis (OA) is a common chronic inflammatory disorder. Effective remodeling of inflammatory microenvironment in the joint is a promising strategy to prevent OA. However, current drugs remain unsatisfactory due to a lack of targeted and effective ways for relieving inflammatory conditions in OA joints. Bortezomib (BTZ), a proteasome inhibitor, could effectively inhibit proinflammatory cytokines but with poor accumulation in the inflammatory tissues. To overcome the shortcomings of BTZ delivery and to improve the efficacy of OA therapy, herein, we designed a novel nanomedicine (denoted as BTZ@PTK) by the co-assembly of BTZ and an amphiphilic copolymer (denoted as PTK) with ROS-cleaved thioketal (TK) linkages. The TK units in BTZ@PTK are first cleaved by the excessive ROS at OA sites, and then triggered the controlled release of BTZ, resulting in the accurate delivery and the inflammatory microenvironment remodeling. Accordingly, BTZ@PTK suppressed ROS generation and proinflammatory cytokines while promoting M1 macrophage apoptosis in lipopolysaccharide (LPS)-activated RAW264.7 macrophages or LPS/IFN-γ-treated primary macrophages, which leads to a better effect than BTZ. In OA mice, BTZ@PTK passively accumulates into inflamed joints to attenuate pain sensitivity and gait abnormality. Importantly, BTZ@PTK treatment successfully ameliorates synovitis with the reduction of synovial hyperplasia and synovitis scores by suppressing M1 macrophage polarization and promoting M1 macrophage apoptosis in the synovium, thereby delaying cartilage damage. Collectively, BTZ@PTK can effectively modulate inflammatory microenvironment for OA recession by activating M1 macrophage apoptosis and inhibiting M1macrophage-mediated inflammatory response.

Thermosensitive Capturer Coupled with the CD63 Aptamer for Highly Efficient Isolation of Exosomes.

Exosomes are bioactive substances secreted by various cells that play a crucial role in cell communication. Due to their nanoscale size and interference from nonexosome proteins, the rapid capture and nondestructive release of exosomes remain a technical challenge which significantly hinders their biomedical application. To overcome this obstacle, we have designed a CD63 aptamer-based thermosensitive copolymer for the effective isolation of exosomes from mesenchymal stem cells (MSCs). A thermal-responsive copolymer, poly(N-isopropylacrylamide-co-butyl methacrylate-co-N-hydroxysuccinimide methacrylate) P(NIPAM-co-BMA-co-NHSMA, PNB), was prepared, which could realize reversible hydrophilic/hydrophobic phase transition by varying temperature. Then, CD63 aptamers were further modified to the copolymer to form the PNB-aptamer, where the aptamer units, acting as a "lock and key", specifically bind exosomes. Under the low critical solution temperature (LCST) of the PNB-aptamer, it can maintain a hydrophilic state, capturing exosomes from the cell culture medium. Subsequently, exosome-carrying PNB-aptamers can endure from hydrophilic to hydrophobic phase transition by increasing the temperature above its LCST, and then they can be collected after centrifugation. By introducing the complementary sequence of the CD63 aptamer, the stronger binding affinity between the complementary sequence and the aptamers facilitates the release of exosomes from the PNB-aptamer. The yield of exosome samples captured from a MSC culture medium by the PNB-aptamer system (around 62%) is considerably higher than that obtained by the current "gold standard" ultrafiltration (UC) approach (around 42%). Thus, the PNB-aptamer capturer provides a potential strategy for highly efficient exosome isolation.

Inflammation specific environment activated methotrexate-loaded nanomedicine to treat rheumatoid arthritis by immune environment reconstruction.

Rheumatoid arthritis (RA), as an autoimmune inflammatory disease, is featured by enhanced vascular permeability, irreversible cartilage destroys and bone erosion. Although the pathogenesis of RA is still unclear, the immune environment, particularly the lymphatic system, which is instrumental to immune cell surveillance and interstitial fluid balance, plays vital roles in the process of RA. Herein, an inflammation specific environment activated methotrexate-encapsulated nanomedicine (MTX@NPs) was constructed for RA treatment, which accumulated in inflamed joints, and released MTX in the specific RA microenvironment. Notably, MTX@NPs could regulate the immune environment including reducing the expressions of inflammatory cytokines of macrophages and the inflammatory level of lymphatic epithelial cells (LECs), and ameliorating the lymphatic vessel contraction and drainage. In vitro and In vivo studies illustrated that MTX@NPs exhibited a high RA therapeutic efficacy and insignificant systemic toxicity owing to the suppression of the inflammation response and the improved lymphatic functions of RA joints. It suggests that the nanomedicine paves a potential way to the clinical practice of autoimmune diseases treatments via the regulation of immune environment and lymphatic functions. STATEMENT OF SIGNIFICANCE: Although 1.0% of the population in the world suffers from rheumatoid arthritis (RA), the pathogenesis of RA is still unclear and the therapeutic effect of the first-line clinical drugs is relatively low. Herein, we propose a specific RA-microenvironment triggered nanomedicine (MTX@NPs), which enhances RA treatment of a first-line antirheumatic drug (methotrexate, MTX) by immune environment reconstruction. The nanomedicine exhibits RA joints accumulation by EPR effect, and releases MTX under the specific RA environment, leading to the dramatical drop of M1-type macrophages and acceleration of lymphatic vessel contraction and drainage. Finally, the inflammatory cytokines in RA immune environment are reduced sharply, indicating the outstanding therapeutic efficacy of MTX@NPs to RA.

Mitochondria-targeting and ROS-sensitive smart nanoscale supramolecular organic framework for combinational amplified photodynamic therapy and chemotherapy.

Owing to their reversibly dynamic features, and the regularity of their architectures, supramolecular organic frameworks (SOFs) have attracted attention as new porous materials. Herein, we propose a smart SOF platform for enhanced photodynamic therapy, where the SOF with a superior mitochondria-targeting capability could be cleaved by reactive oxygen species (ROS) produced by itself for highly enhancing PDT. Moreover, it can further work as a platform for carrying chemo-therapeutic drug doxorubicin for synergistic chemo-photodynamic therapy. The SOF is constructed by combining a tetra-ß-cyclodextrin-conjugated porphyrin photosensitizer and a ROS-sensitive thioketal linked adamantane dimer utilizing a host-guest supramolecular strategy. The unique supramolecular framework not only completely resolves the aggregation caused quenching of porphyrin photosensitizers but also endows them with significantly enhanced water-solubility. The in vitro and in vivo results demonstrate that the SOF could be targeted onto mitochondria by confocal imaging, and dissociated by ROS generated by itself, leading to autonomous release of porphyrin photosensitizers and DOX for high anti-cancer activity. It is believed that the strategy using a SOF has the potential of being used to construct versatile agents for combined therapies. STATEMENT OF SIGNIFICANCE: Photosensitizers are the essential element in photodynamic therapy. However, typical photosensitizers commonly encounter poor water-solubility, non-specific tumor-targeting, aggregation-caused quenching (ACQ), which seriously reduce PDT efficacy. A mitochondria-targeting and ROS-sensitive supramolecular organic framework (SOF) is designed for photodynamic therapy in cancer treatment, which could completely overcome the bottleneck in the applications of photosensitizers (PSs). The SOF is constructed by combining a tetra-ß-cyclodextrin-conjugated porphyrin photosensitizer and a ROS-sensitive thioketal linked adamantane dimer unit utilizing a host-guest supramolecular strategy. The unique supramolecular framework not only completely resolves the aggregation caused quenching of porphyrin photosensitizers but also endows them with significantly enhanced water-solubility. Moreover, the SOF can be readily functionalized to incorporate the anti-cancer agent Doxorubicin and mitochondria targeting molecules through respective physical encapsulation and host-guest interactions.

New Molecular Ferroelectrics Accompanied by Ultrahigh Second-Harmonic Generation.

Second-harmonic generation (SHG) is one of the outstanding properties for practical applications. However, the great majority of molecular ferroelectric materials have very low nonlinear optical coefficients, attenuating their attractive performance. Here we synthesized (4-amino-2-bromopyridinium)(4-amino-2-bromopyridine)tetrafluoroborate (1), whose second-order nonlinear optical coefficient reaches up to 2.56 pm V(-1), 2.67 times of that of KDP, and (4-amino-2-bromopyridinium)tetrafluoroborate (2), possessing a more incredible large second-order nonlinear optical coefficient as high as 10.24 pm V(-1), 10.67 times that of KDP. The compound 1 undergoes two reversible phase transitions at around T1 = 244.1 K and T2 = 154.6 K, caused by dramatic changes of the protonated cations and order-disorder of anions, which was disclosed by differential scanning calorimetry, heat capacity, dielectric anomalies, SHG, and single-crystal X-ray diffraction analysis. The pyroelectric measurements reveal that compound 1 is a Rochelle salt type ferroelectric, which has a large spontaneous polarization of about 3 µC/cm(2).

The growth mechanism and ferroelectric domains of diisopropylammonium bromide films synthesized via 12-crown-4 addition at room temperature.

Diisopropylammonium bromide (DIPAB) has attracted great attention as a molecular ferroelectric with large spontaneous polarization and high Curie temperature. It is hard to grow the ferroelectric phase DIPAB because of the appearance of the non-ferroelectric phase DIPAB at room temperature. Here, a ferroelectric thin film of DIPAB was successfully fabricated on a Si substrate using a spin coating method from aqueous solution via 12-crown-4 addition at room temperature. The ferroelectric DIPAB film with a thickness of hundreds of nanometers is distributed discontinuously on the substrate in narrow strips. The direction of polarization is along the narrow strip. Piezoresponse force microscopy (PFM) shows that the ferroelectric films have two kinds of domain structures: noncharged antiparallel stripe domains and charged head-to-head (H-H)/tail-to-tail (T-T) type domains. 12-crown-4 has been proved to play important roles in forming the H-H/T-T type domains. The Chynoweth method shows that the DIPAB films synthesized in this way show a better pyroelectric effect than DIPAB crystals.