ABSTRACT
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.
Subject(s)
Anti-Infective Agents , Chitosan , Diabetes Mellitus, Experimental , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Anti-Infective Agents/pharmacology , Chitosan/chemistry , Hydrogels/chemistry , Hypoxia , Mice , Molecular Probes , Optical Imaging , OxygenABSTRACT
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.
Subject(s)
Drug Delivery Systems/methods , Lipopeptides/chemistry , Mammary Neoplasms, Experimental/drug therapy , Mitochondria/metabolism , Photosensitizing Agents/administration & dosage , Amidohydrolases , Animals , Cell Line, Tumor/transplantation , Female , Guanidine/chemistry , Humans , Hydrogen-Ion Concentration , Indocyanine Green/administration & dosage , Indocyanine Green/pharmacokinetics , Liposomes , Mammary Neoplasms, Experimental/pathology , Mice , Mitochondrial Membranes/drug effects , Mitochondrial Membranes/metabolism , Organophosphorus Compounds/chemistry , Photochemotherapy/methods , Photosensitizing Agents/pharmacokinetics , Photothermal Therapy/methods , Tissue DistributionABSTRACT
The efficiency of photodynamic therapy (PDT) highly depends on the tumor oxygenation state. However, PDT itself can not only cause oxygen depletion but also prevent oxygen supply in tumors. Such self-confinement effect significantly limits the efficacy of PDT, especially fractionated PDT (fPDT). Herein, we proposed a multifunctional nanoparticle system having a four-pronged pipelined therapeutic scheme to address this issue. It performed in situ oxygen supply and tumor microenvironment modulation together to effectively maintain tumor oxygenation even after multiple PDT fractions. It also introduced a new photosensitizer that not only was highly efficient in producing ROS but also could visually report tumor oxygenation state in a real-time fashion. All these functions were integrated into a single nanoparticulate system to obtain pipeline-style teamwork, which was then applied for the fPDT on a mice tumor model, and achieved significantly better tumor oxygenation even after multiple PDT fractions, ending up with a better tumor inhibition efficiency.
Subject(s)
Nanoparticles , Photochemotherapy , Animals , Cell Line, Tumor , Mice , Photosensitizing Agents/pharmacology , Tumor MicroenvironmentABSTRACT
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.