Project description:Nanomedicine holds promise to enhance cancer immunotherapy; however, its potential to elicit highly specific anti-tumor immunity without compromising immune tolerance has yet to be fully unlocked. This study develops deep-tissue activatable cancer sono-immunotherapy based on the discovery of a semiconducting polymer that generates sonodynamic singlet oxygen (1O2) substantially higher than other sonosensitizers. Conjugation of two immunomodulators via 1O2-cleavable linkers onto this polymer affords semiconducting polymer immunomodulatory nanoparticles (SPINs) whose immunotherapeutic actions are largely inhibited. Under ultrasound irradiation, SPINs generate 1O2 not only to directly debulk tumors and reprogram tumor microenvironment to enhance tumor immunogenicity, but also to remotely release the immunomodulators specifically at tumor site. Such a precision sono-immunotherapy eliminates tumors and prevents relapse in pancreatic mouse tumor model. SPINs show effective antitumor efficacy even in a rabbit tumor model. Moreover, the sonodynamic activation of SPINs confines immunotherapeutic action primarily to tumors, reducing the sign of immune-related adverse events.
Project description:Due to the complicated tumor microenvironment that compromises the efficacies of various therapies, the effective treatment of pancreatic cancer remains a big challenge. Sono-activatable semiconducting polymer nanoreshapers (SPNDN H) are constructed to multiply remodel tumor microenvironment of orthotopic pancreatic cancer for potent immunotherapy. SPNDN H contain a semiconducting polymer, hydrogen sulfide (H2 S) donor, and indoleamine 2,3-dioxygenase (IDO) inhibitor (NLG919), which are encapsulated by singlet oxygen (1 O2 )-responsive shells with modification of hyaluronidase (HAase). After accumulation in orthotopic pancreatic tumor sites, SPNDN H degrade the major content of tumor microenvironment hyaluronic acid to promote nanoparticle enrichment and immune cell infiltration, and also release H2 S to relieve tumor hypoxia via inhibiting mitochondrion functions. Moreover, the relieved hypoxia enables amplified sonodynamic therapy (SDT) under ultrasound (US) irradiation with generation of 1 O2 , which leads to immunogenic cell death (ICD) and destruction of 1 O2 -responsive components to realize sono-activatable NLG919 release for reversing IDO-based immunosuppression. Through such a multiple remodeling mechanism, a potent antitumor immunological effect is triggered after SPNDN H-based treatment. Therefore, the growths of orthotopic pancreatic tumors in mouse models are almost inhibited and tumor metastases are effectively restricted. This study offers a sono-activatable nanoplatform to multiply remodel tumor microenvironment for effective and precise immunotherapy of deep-tissue orthotopic tumors.
Project description:Photosensitizers (PSs) are of particular importance for efficient photodynamic therapy (PDT). Challenges for PSs simultaneously possessing strong light-absorbing ability, high 1O2 generation by effective intersystem crossing from the singlet to the triplet state, good water-solubility and excellent photostability still exist. Reported here are a new kind of dual-emissive semiconducting polymer nanoparticles (SPNs) containing fluorescent BODIPY derivatives and near-infrared (NIR) phosphorescent iridium(iii) complexes. In the SPNs, the BODIPY units serve as the energy donors in the fluorescence resonance energy transfer (FRET) process for enhancing the light absorption of the SPNs. The NIR emissive iridium(iii) complexes are chosen as the energy acceptors and efficient photosensitizers. The ionized semiconducting polymers can easily self-assemble to form hydrophilic nanoparticles and homogeneously disperse in aqueous solution. Meanwhile, the conjugated backbone of SPNs provides effective shielding for the two luminophores from photobleaching. Thus, an excellent overall performance of the SPN-based PSs has been realized and the high 1O2 yield (0.97) resulting from the synergistic effect of BODIPY units and iridium(iii) complexes through the FRET process is among the best reported for PSs. In addition, owing to the phosphorescence quenching of iridium(iii) complexes caused by 3O2, the SPNs can also be utilized for O2 mapping in vitro and in vivo, which assists in the evaluation of the PDT process and provides important instructions in early-stage cancer diagnosis.
Project description:The integration of photoacoustic imaging (PAI) and photothermal therapy (PTT) within the second near-infrared (NIR-II) window, offering a combination of high-resolution imaging and precise non-invasive thermal ablation, presents an attractive opportunity for cancer treatment. Despite the significant promise, the development of this noninvasive phototheranostic nanomedicines encounters challenges that stem from tumor thermotolerance and limited therapeutic efficacy. In this contribution, we designed an amphiphilic semiconducting polymer brush (SPB) featuring a thermosensitive carbon monoxide (CO) donor (TDF-CO) for NIR-II PAI-assisted gas-augmented deep-tissue tumor PTT. TDF-CO nanoparticles (NPs) exhibited a powerful photothermal conversion efficiency (43.1%) and the capacity to trigger CO release after NIR-II photoirradiation. Notably, the liberated CO not only acts on mitochondria, leading to mitochondrial dysfunction and promoting cellular apoptosis but also hinders the overexpression of heat shock proteins (HSPs), enhancing the tumor's thermosensitivity to PTT. This dual action accelerates cellular thermal ablation, achieving a gas-augmented synergistic therapeutic effect in cancer treatment. Intravenous administration of TDF-CO NPs in 4T1 tumor-bearing mice demonstrated bright PAI signals and remarkable tumor ablation under 1064 nm laser irradiation, underscoring the potential of CO-mediated photothermal/gas synergistic therapy. We envision this tailor-made multifunctional NIR-II light-triggered SPB provides a feasible approach to amplify the performance of PTT for advancing future cancer phototheranostics.
Project description:BackgroundPancreatic ductal adenocarcinoma (PDAC) is a devastatingly malignant tumor with a high mortality. However, current strategies to treat PDAC generally have low efficacy and high side-effects, therefore, effective treatment against PDAC remains an urgent need.ResultsWe report a semiconducting polymer nano-radiopharmaceutical with intrinsic photothermal capability and labeling with therapeutic radioisotope 177Lu (177Lu-SPN-GIP) for combined radio- and photothermal therapy of pancreatic tumor. 177Lu-SPN-GIP endowed good stability at physiological conditions, high cell uptake, and long retention time in tumor site. By virtue of combined radiotherapy (RT) and photothermal therapy (PTT), 177Lu-SPN-GIP exhibited enhanced therapeutic capability to kill cancer cells and xenograft tumor in living mice compared with RT or PTT alone. More importantly, 177Lu-SPN-GIP could suppress the growth of the tumor stem cells and reverse epithelial mesenchymal transition (EMT), which may greatly reduce the occurrence of metastasis.ConclusionSuch strategy we developed could improve therapeutic outcomes over traditional RT as it is able to ablate tumor with relatively lower doses of radiopharmaceuticals to reduce its side effects.
Project description:Pyroptosis, an inflammatory cell death, has attracted great attention for potentiating a strong immune response against tumor cells. However, developing powerful pyroptosis inducers and then activating specific pyroptosis still remains challenging. Herein, a PEG-CuP-COF@∆St nanosystem is rationally designed, consisting of PEG-CuP-COF nanozyme pyroptosis inducers and tumor-targeting bacteria of the Salmonella Typhimurium strain VNP20009 (ΔSt), with an affinity for the tumor hypoxic microenvironment. The PEG-CuP-COF nanozymes possessed excellent sonodynamic performance and multienzyme-mimicking activities to generate reactive oxygen species (ROS) and then induce potent pyroptosis. The superoxide dismutase- and peroxidase-mimicking activities of PEG-CuP-COF catalytically produced hydrogen peroxide (H2O2) and hydroxyl radicals (•OH) which have important value in triggering acute inflammatory responses and pyroptosis. Moreover, PEG-CuP-COF showed outstanding glutathione peroxidase-mimicking activities, impairing the antioxidant defense in tumor cells and enhancing sonodynamic efficiency by making them more vulnerable to ROS-induced damage. During in vivo studies, PEG-CuP-COF@∆St nanosystem with its self-driven property exhibited impressive tumor-targeting capability and activated Caspase-3/gasdermin E-dependent pyroptosis to inhibit tumor growth. More importantly, it induced a powerful immune memory effect to prevent bone metastasis. In summary, this study introduces an innovative approach for combinatorial sono-catalytic immunotherapy using bacteria-mediated tumor-targeting delivery of nanozymes as specific pyroptosis inducers.
Project description:This work describes the preparation and validation of single-chain semiconducting polymer dots (sPdots), which were generated using a method based on surface immobilization, washing, and cleavage. The sPdots have an ultrasmall size of ∼3.0 nm as determined by atomic force microscopy, a size that is consistent with the anticipated diameter calculated from the molecular weight of the single-chain semiconducting polymer. sPdots should find use in biology and medicine as a new class of fluorescent probes. The FRET assay this work presents is a simple and rapid test to ensure methods developed for preparing sPdot indeed produced single-chain Pdots as designed.
Project description:Advances in photonics have stimulated significant progress in medicine, with many techniques now in routine clinical use. However, the finite depth of light penetration in tissue is a serious constraint to clinical utility. Here we show implantable light-delivery devices made of bio-derived or biocompatible, and biodegradable polymers. In contrast to conventional optical fibres, which must be removed from the body soon after use, the biodegradable and biocompatible waveguides may be used for long-term light delivery and need not be removed as they are gradually resorbed by the tissue. As proof of concept, we demonstrate this paradigm-shifting approach for photochemical tissue bonding (PTB). Using comb-shaped planar waveguides, we achieve a full thickness (>10 mm) wound closure of porcine skin, which represents ∼ 10-fold extension of the tissue area achieved with conventional PTB. The results point to a new direction in photomedicine for using light in deep tissues.
Project description:This communication describes an approach for preparing monovalent semiconducting polymer dots (mPdots) with a size of 5 nm where each mPdot was composed of precisely a single active functional group.