Scaffolds biomimicking macrophages for a glioblastoma NIR-Ib imaging guided photothermal therapeutic strategy by crossing Blood-Brain Barrier.

Glioblastoma (GBM) is one of the most malignant cancers, and Blood-Brain Barrier (BBB) is the main obstacle to diagnose and treat GBM, hence scientists are making great efforts to develop new drugs which can pass BBB and integrate diagnosis and therapeutics together. Here, we designed plasma membrane of macrophage camouflaged DSPE-PEG loaded near-infrared Ib (NIR-Ib) fluorescence dye IR-792 nanoparticles (MDINPs). MDINPs were able to penetrate BBB and selectively accumulate at tumor site, and then could be used as NIR-Ib fluorescence probes for targeted tumor imaging. At the same time, MDINPs could kill tumor cells by photothermal effect. Our results showed that MDINPs-mediated NIR-Ib fluorescence imaging could clearly observe orthotopic GBM, and the NIR-Ib imaging-guided photothermal therapy significantly suppressed the growth of GBM and prolonged the life of mice. This work not only provided a method to mimic the biological function of macrophage, but also provided an integrative strategy for diagnosis and treatment in GBM.

Dye-Anchored MnO Nanoparticles Targeting Tumor and Inducing Enhanced Phototherapy Effect via Mitochondria-Mediated Pathway.

Phototherapy is a promising treatment method for cancer therapy. However, the various factors have greatly restricted phototherapy development, including the poor accumulation of photosensitizer in tumor, hypoxia in solid tumor tissue and systemic phototoxicity. Herein, a mitochondrial-targeted multifunctional dye-anchored manganese oxide nanoparticle (IR808@MnO NP) is developed for enhancing phototherapy of cancer. In this nanoplatform, IR808 as a small molecule dye acts as a tumor targeting ligand to make IR808@MnO NPs with capacity to actively target tumor cells and relocate finally in the mitochondria. Meanwhile, continuous production of oxygen (O2 ) and regulation of pH induced by the high reactivity and specificity of MnO NPs toward mitochondrial endogenous hydrogen peroxide (H2 O2 ) could effectively modulate tumor hypoxia and lessen the tumor subacid environment. Large amounts of reactive oxide species (ROS) are generated during the reaction process between H2 O2 and MnO NPs. Furthermore, under laser irradiation, IR808 in IR808@MnO NPs turns O2 into a highly toxic singlet oxygen (1 O2 ) and generates hyperthermia. The results indicate that IR808@MnO NPs have the high efficiency of specific targeting of tumors, relieving tumor subacid environment, improving the tumor hypoxia environment, and generating large amounts of ROS to kill tumor cells. It is expected to have a wide application in treating cancer.

Hypoxia-triggered single molecule probe for high-contrast NIR II/PA tumor imaging and robust photothermal therapy.

Hypoxia is a common characteristic of solid tumors. This important feature is associated with resistance to radio-chemotherapy, which results in poor prognosis and probability of tumor recurrence. Taking advantage of background-free NIR II fluorescence imaging and deeper-penetrating photoacoustic (PA) imaging, we developed a hypoxia-triggered and nitroreductase (NTR) enzyme-responsive single molecule probe for high-contrast NIR II/PA tumor imaging and hypoxia-activated photothermal therapy (PTT), which will overcome cellular resistance during hypoxia. Methods: The single molecule probe IR1048-MZ was synthesized by conjugating a nitro imidazole group as a specific hypoxia trigger with an IR-1048 dye as a NIR II/PA signal reporter. We investigated the NIR II fluorescence, NIR absorbance and photothermal effect in different hypoxia conditions in vitro, and performed NIR II/PA tumor imaging and hypoxia-activated photothermal therapy in mice. Results: This versatile molecular probe IR1048-MZ not only realized high-contrast tumor visualization with a clear boundary by NIR II fluorescence imaging, but also afforded deep-tissue penetration at the centimeter level by 3D PA imaging. Moreover, after being activated by NTR that is overexpressed in hypoxic tumors, the probe exhibited a significant photothermal effect for curative tumor ablation with no recurrence. Conclusions: We have developed the first hypoxia-triggered and NTR enzyme-responsive single molecule probe for high-contrast NIR II/PA tumor imaging and hypoxia-activated photothermal therapy. By tracing the activity of NTR, IR1048-MZ may be a promising contrast agent and theranostic formulation for other hypoxia-related diseases (such as cancer, inflammation, stroke, and cardiac ischemia).

Dual-modal imaging-guided highly efficient photothermal therapy using heptamethine cyanine-conjugated hyaluronic acid micelles.

Targeted phototherapy and multi-modal imaging can effectively improve the therapeutic efficacy and reduce the side effects of theranostics. Herein, we constructed novel biocompatible cyanine dye IR808-conjugated hyaluronic acid nanoparticles (HAIR NPs) for photothermal therapy (PTT) with near-infrared fluorescence (FL) and photoacoustic (PA) dual-modal imaging. The nanoparticles formed stable nanostructures under aqueous conditions with uniform size distribution. The HAIR NPs were rapidly taken up by the human lung cancer cells A549 via CD44 (the hyaluronic acid receptor on the surface of tumor cells) receptor-mediated endocytosis. Upon laser irradiation, the HAIR NPs enabled good near-infrared fluorescence imaging and photoacoustic imaging in tumor-bearing mice. In addition, the tight nanostructure arising from the covalent link between HA and IR808 could significantly improve the light-thermal conversion efficiency of IR808. Under a low dose of laser power, the HAIR NPs presented more effective photothermal therapy for the suppression of tumor growth than free IR808 in vitro and in vivo. Overall, these results indicate that the HAIR NPs may be an extremely promising nanoplatform in cancer theranostics for targeted PTT under FL and PA dual-modal imaging.

Tumor-targeted small molecule for dual-modal imaging-guided phototherapy upon near-infrared excitation.

Near-infrared (NIR) organic dyes have received increasing attention in recent years as diagnostic and therapeutic agents in the field of tumor research. In this study, IR-822, a near-infrared fluorescence (NIRF) heptamethine cyanine dye, was chosen as a fluorophore due to its high extinction coefficients, and native preferential tumor accumulation property. To enhance its specificity in tumor imaging, N1-(pyridin-4-ylmethyl)ethane-1,2-diamine (PY) was conjugated to IR-822 as a pH-sensing receptor, forming a fluorophore-spacer-receptor molecular probe (IR-PY) that can modulate the fluorescence emission intensity through a fast photoinduced electron-transfer process, which allowed the probe to "switch on" significantly in an acidic tumor microenvironment and which realized enhanced NIRF imaging in vivo. Having a strong NIR absorption at 600-850 nm, this small-molecule IR-PY showed not only high spatial resolution photoacoustic (PA) imaging in mice, but also effective tumor photothermal ablation in vivo. After photothermal therapy (PTT) with IR-PY under NIR 808 nm laser irradiation, the mice exhibited remarkable ablation with no tumor recurrence after treatment. Therefore, a single smart small-molecule probe IR-PY has been designed, synthesized and verified as an "all in one" multifunctional agent, including pH sensitivity, tumor targeting, "switch-on" near-infrared fluorescence imaging, high-spatial-resolution PA imaging and efficient near-infrared photothermal therapy, which is promising for clinical application in NIRF/PA dual-modal imaging-guided cancer diagnosis and treatment.