Chemiluminescent Conjugated Polymer Nanoparticles for Deep-Tissue Inflammation Imaging and Photodynamic Therapy of Cancer.

Deep-tissue optical imaging and photodynamic therapy (PDT) remain a big challenge for the diagnosis and treatment of cancer. Chemiluminescence (CL) has emerged as a promising tool for biological imaging and in vivo therapy. The development of covalent-binding chemiluminescence agents with high stability and high chemiluminescence resonance energy transfer (CRET) efficiency is urgent. Herein, we design and synthesize an unprecedented chemiluminescent conjugated polymer PFV-Luminol, which consists of conjugated polyfluorene vinylene (PFV) main chains and isoluminol-modified side chains. Notably, isoluminol groups with chemiluminescent ability are covalently linked to main chains by amide bonds, which dramatically narrow their distance, greatly improving the CRET efficiency. In the presence of pathologically high levels of various reactive oxygen species (ROS), especially singlet oxygen (1O2), PFV-Luminol emits strong fluorescence and produces more ROS. Furthermore, we construct the PFV-L@PEG-NPs and PFV-L@PEG-FA-NPs nanoparticles by self-assembly of PFV-Luminol and amphiphilic copolymer DSPE-PEG/DSPE-PEG-FA. The chemiluminescent PFV-L@PEG-NPs nanoparticles exhibit excellent capabilities for in vivo imaging in different inflammatory animal models with great tissue penetration and resolution. In addition, PFV-L@PEG-FA-NPs nanoparticles show both sensitive in vivo chemiluminescence imaging and efficient chemiluminescence-mediated PDT for antitumors. This study paves the way for the design of chemiluminescent probes and their applications in the diagnosis and therapy of diseases.

Conjugated Polymer Composite Nanoparticles Augmenting Photosynthesis-Based Light-Triggered Hydrogel Promotes Chronic Wound Healing.

Diabetic chronic wounds are characterized by local hypoxia, impaired angiogenesis, and bacterial infection. In situ, self-supply of dissolved oxygen combined with the elimination of bacteria is urgent and challenging for chronic nonhealing wound treatment. Herein, an oxygen-generating system named HA-L-NB/PFE@cp involving biological photosynthetic chloroplasts (cp)/conjugated polymer composite nanoparticles (PFE-1-NPs@cp) and light-triggered hyaluronic acid-based (HA-L-NB) hydrogel for promoting diabetic wound healing is introduced. Briefly, conjugated polymer nanoparticles (PFE-1-NPs) possess unique light harvesting ability, which accelerates the electron transport rates in photosystem II (PS II) by energy transfer, elevating photosynthesis beyond natural chloroplasts. The enhanced release of oxygen can greatly relieve hypoxia, promote cell migration, and favor antibacterial photodynamic therapy. Additionally, the injectable hydrogel precursors are employed as a carrier to deliver PFE-1-NPs@cp into the wound. Under light irradiation, they quickly form a gel by S-nitrosylation coupling reaction and in situ anchor on tissues through amine-aldehyde condensation. Both in vitro and in vivo assays demonstrate that the oxygen-generating system can simultaneously relieve wound hypoxia, eliminate bacteria, and promote cell migration, leading to the acceleration of wound healing. This study provides a facile approach to develop an enhanced oxygen self-sufficient system for promoting hypoxic tissue, especially diabetic wound healing.

Bioactive Conjugated Polymer-Based Biodegradable 3D Bionic Scaffolds for Facilitating Bone Defect Repair.

Bone defect regeneration is one of the great clinical challenges. Suitable bioactive composite scaffolds with high biocompatibility, robust new-bone formation capability and degradability are still required. This work designs and synthesizes an unprecedented bioactive conjugated polymer PT-C3 -NH2 , demonstrating low cytotoxicity, cell proliferation/migration-promoting effect, as well as inducing cell differentiation, namely regulating angiogenesis and osteogenesis to MC3T3-E1 cells. PT-C3 -NH2 is incorporated into polylactic acid-glycolic acid (PLGA) scaffolds, which is decorated with caffeic acid (CA)-modified gelatin (Gel), aiming to improve the surface water-wettability of PLGA and also facilitate to the linkage of conjugated polymer through catechol chemistry. A 3D composite scaffold PLGA@GC-PT is then generated. This scaffold demonstrates excellent bionic structures with pore size of 50-300 µm and feasible biodegradation ability. Moreover, it also exhibites robust osteogenic effect to promote osteoblast proliferation and differentiation in vitro, thus enabling the rapid regeneration of bone defects in vivo. Overall, this study provides a new bioactive factor and feasible fabrication approach of biomimetic scaffold for bone regeneration.

Polymer Nanoparticles Overcome Drug Resistance by a Dual-Targeting Apoptotic Signaling Pathway in Breast Cancer.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) activating therapy has received wide attention due to its capacity to precisely induce cancer cell apoptosis. However, drug resistance and the poor pharmacokinetic properties of TRAIL protein are obstacles in TRAIL-based therapy for cancer. Herein, a strategy is developed to remotely control and specifically initiate TRAIL-mediated apoptotic signaling to promote TRAIL-resistant cancer cell apoptosis using near-infrared (NIR) light-absorbing conjugated polymer nanoparticles (CPNs). Upon 808 nm laser excitation, the promoter 70 kilodalton heat shock protein (HSP70) initiates transcription of the TRAIL gene in response to heat shock, thereby expressing TRAIL protein in breast cancer cells, which activates the TRAIL-mediated apoptosis signaling pathway. Simultaneously, the CPNs locally release W-7, which targets calmodulin (CaM) and further promotes caspase-8 cleavage and enhances cancer cell apoptosis. Both in vitro and in vivo results demonstrate that CPNs/W-7/pTRAIL produces an excellent synergistic therapeutic effect on breast cancer upon near-infrared light with low toxicity. Therefore, this work provides a strategy for overcoming drug resistance through dual-targeting TRAIL-mediated apoptotic signaling in breast cancer.

Bioactive Composite Nanoparticles for Effective Microenvironment Regulation, Neuroprotection, and Cell Differentiation.

Brain injuries typically result in neural tissue damage and trigger a permanent neurologic deficit. Current methods exhibit limited effects due to the harsh microenvironment of injury regions rich in reactive oxygen species (ROS). Herein, a microenvironment regulation combined with cellular differentiation strategy is designed for repairing injured nerves. We prepare PMNT/F@D-NP nanoparticles comprising a bioactive polythiophene derivative (PMNT) and fullerenol as a multifunctional theranostic nanoplatform. PMNT/F@D-NPs can significantly reduce the accumulation of ROS in the simulated ischemic brain injury trial and inhibit cell apoptosis due to the effective free radical scavenging ability of fullerenol. Interestingly, the bioactive PMNT/F@D-NPs can promote the proliferation and differentiation of neurons, confirmed by immunofluorescence and western blotting studies. This newly developed strategy exhibits a combinatorial therapeutic effect by promoting nerve cell survival and differentiation while improving the microenvironment in the damaged area, which paves the way for the rational design of multifunctional agents for brain injury therapy.

A Ratiometric Fluorescent Conjugated Oligomer for Amyloid ß Recognition, Aggregation Inhibition, and Detoxification.

The sensitive recognition and effective inhibition of toxic amyloid ß protein (Aß) aggregates play a critical role in early diagnosis and treatment of neurodegenerative diseases. In this work, a new conjugated oligo(fluorene-co-phenylene) (OFP) modified with 1,8-naphthalimide (NA) derivative OFP-NA-NO2 is designed and synthesized as a ratiometric fluorescence probe for sensing Aß, inhibiting the assembly of Aß, and detoxicating the cytotoxicity of Aß aggregates. In the presence of Aß, the active ester group on the side chain of OFP-NA-NO2 can covalently react with the amino group on Aß, effectively inhibiting the formation of Aß aggregates and degrading the preformed fibrils. In this case, the fluorescence intensity ratio of NA to OFP (INA /IOFP ) increases greatly. The detection limit is calculated to be 89.9 nM, presenting the most sensitive ratiometric recognition of Aß. Interestingly, OFP-NA-NO2 can dramatically recover the cell viability of PC-12 and restore the Aß-clearing ability of microglia. Therefore, this ratiometric probe exhibits the targeted recognition of Aß, effective inhibition of Aß aggregates, and detox effect, which is potential for early diagnosis and treatment of neurodegenerative diseases.

Near-Infrared Light Regulation of Tumor PI3K/Akt Signaling Pathway for Enhancing Cancer Cell Apoptosis through Conjugated Polymer Nanoparticles.

Calmodulin (CaM), as a calcium binding protein involved in the signal pathways of many life activities such as cell proliferation and apoptosis, can be regulated with the near-infrared (NIR) light-based photothermal conversion. Here, we build a conjugated polymer nanoparticle (CPNs-C) by assembling polypyrrole dione and dipalmitoyl phosphatidylethanolamine-polyethylene glycol-maleimide with a calmodulin antibody modified on the surface, which is NIR light-responsive for photothermally inducing apoptosis of cancer cells. Under near-infrared light irradiation, protein kinase B (Akt) and phosphatidylinositol 3-kinase, which bind to CaM, reduce the degree of phosphorylation due to the photothermal effect of CPNs-C, thus inhibiting the recruitment of Akt on the cell membrane. Therefore, the phosphorylation of GSK-3ß downstream of the signaling pathway is reduced, and the phosphorylation of FoxO3a is enhanced, which can promote apoptosis of cancer cells. Compared with the photothermal effect of traditional CPNs, CPNs-C exhibits higher efficiency to regulate signaling pathways to promote cancer cells toward apoptosis. This strategy of utilizing NIR light to regulate the tumor apoptotic signaling pathway provides an effective way to enhance cancer cell apoptosis with high efficiency.