A dual-in-dual synergistic strategy was proposed based on the self-assembly of combinatorial nanocapsules (NCs) from Janus camptothecin-floxuridine (CF) conjugate and the near-infrared absorber of 1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide (DiR) by introducing PEGylated phospholipid of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycerol)-2000] to increase the blood circulation time of NCs. Due to the use of amphiphilic CF and DiR themselves to form liposome-like nanocapsules, the obtained CF-DiR NCs owned a significantly high loading content, a stable co-delivery drug combinations, a no premature release, and an excellent photothermal conversion efficiency. The in vivo fluorescence imaging indicated that CF-DiR NCs could achieve a high tumor accumulation after an intravenous injection. The dual drugs of camptothecin and floxuridine could be coordinately released due to the hydrolysis of the ester bond by the esterase in tumor. The in vivo experiments showed that more cytotoxicity of the CF-DiR NCs-mediated chemo- and photothermal dual therapy to tumor cells could be clearly observed than the chemotherapy or photothermal therapy alone due to the synergistic effect, leading to no recurrence in the entire treatment. All of the results highlighted that CF-DiR NCs were highly effective theranostic agents that could be used for imaging-guided cancer chemophotothermal therapy to conquer an intrinsic resistance to chemotherapeutics.

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Conventional phototherapies have been thought to destroy the malignant cells through apoptosis or necrosis, shut down tumor microvasculature, and activate the host immune system. Accumulating evidence indicates that photothermal agents stimulate both innate and adaptive arms of host immune systems by i) priming tumor antigen-specific T-cell responses, ii) attracting lymphocytes into the tumor site, and iii) modulation of the tumor microenvironment (TME). However, the salutary effect of traditional phototherapies is hindered by its limited penetration depth in tissues. Recent advances in cancer immunotherapies have significantly transformed the landscape of cancer treatment from conventional phototherapies to most standard cancer therapy regimen. Therefore, phototherapies synergized with immunotherapy, maximize the anticancer efficacy by overcoming immunosuppressive TME and elucidating immune responses outside the irradiation area. This synergism is further strengthened by nanomaterial-based strategies to form innovative nanocarriers for efficient and simultaneous delivery of photosensitizers and immunomodulators at the desired target. These nanocarriers can improve the accumulation and retention of both photosensitizer and immunomodulators within the target location, thereby enhancing safety and efficacy. Herein, the systematic effects of phototherapies on the immune system are summarized and the ways in which nanomaterial-based photoimmunotherapy can facilitate the eradication of both primary and metastatic tumors are discussed.

Acute occlusal interference following improper occlusal alteration in dental practice can induce chronic masticatory muscle pain. The underlying mechanism has not been clarified. Synaptic plasticity in the anterior cingulate cortex (ACC) plays a key role in the chronic pain state. This study investigated the role of synaptic plasticity in the ACC in acute occlusal interference–induced chronic masticatory muscle pain. A rat model of experimental occlusal interference (EOI) was established. In vivo local field potential (LFP) recording was conducted to evaluate the change of synaptic strength and plasticity from the medial thalamus (MT) to the ACC after EOI application. The effects of microdialysis of antagonists of glutamate receptors into the ACC on synaptic transmission from the MT to the ACC were examined. Furthermore, the influence of inhibiting glutamate receptors in the ACC on EOI-induced mechanical hyperalgesia in the masseter muscles of rats was investigated. The amplitude of LFP in the ACC evoked by MT stimulation was significantly potentiated since 14 d of EOI application. Long-term potentiation of LFP in the ACC was reliably induced by theta burst stimulation to the MT in control rats but was occluded in 14-d EOI rats. Microdialysis of AMPA/kainate receptor antagonist CNQX into the ACC attenuated LFP in the ACC evoked by stimulating the MT in control and EOI rats. Administration of NMDA receptor subunit NR2B antagonist Ro 25-6981 into the ACC significantly alleviated the potentiation of MT stimulation-evoked LFP in the ACC of EOI rats without affecting that in control rats. EOI-induced hyperalgesia in the bilateral masseter muscles of rats was dose-dependently relieved after microdialysis of Ro 25-6981 into ACC. These findings provide direct evidence that prolonged acute occlusal interference potentiates synaptic transmission in the ACC, which in turn mediates chronic masticatory muscle pain.