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Photothermal therapy (PTT) is a promising cancer treatment modality, but PTT generally requires direct access to the source of light irradiation, thus precluding its utility against disseminated, metastatic tumors. Here, we demonstrate that PTT combined with chemotherapy can trigger potent anti-tumor immunity against disseminated tumors. Specifically, we have developed polydopamine-coated spiky gold nanoparticles as a new photothermal agent with extensive photothermal stability and efficiency. Strikingly, a single round of PTT combined with a sub-therapeutic dose of doxorubicin can elicit robust anti-tumor immune responses and eliminate local as well as untreated, distant tumors in >85% of animals bearing CT26 colon carcinoma. We also demonstrate their therapeutic efficacy against TC-1 submucosa-lung metastasis, a highly aggressive model for advanced head and neck squamous cell carcinoma (HNSCC). Our study sheds new light on a previously unrecognized, immunological facet of chemo-photothermal therapy and may lead to new therapeutic strategies against advanced cancer.

We report a new nanoparticle system for chemoimmunotherapy that elicits robust antitumor immunity against established tumors.

Polymeric gene delivery vectors show great potential for the construction of the ideal gene delivery system. These systems harness their ability to incorporate versatile functional traits to overcome most impediments encountered in gene delivery: from the initial complexation to their target-specific release of the therapeutic nucleic acids at the cytosol. Among the numerous multifunctional polymers that have been designed and evaluated as gene delivery vectors, polymers with redox-sensitive (or bioreducible) functional domains have gained great attention in terms of their structural and functional traits. The redox environment plays a pivotal role in sustaining cellular homeostasis and natural redox potential gradients exist between extra- and intracellular space and between the exterior and interior of subcellular organelles. In some cases, researchers have designed the polymeric delivery vectors to exploit these gradients. For example, researchers have taken advantage of the high redox potential gradient between oxidizing extracellular space and the reducing environment of cytosolic compartments by integrating disulfide bonds into the polymer structure. Such polymers retain their cargo in the extracellular space but selectively release the therapeutic nucleic acids in the reducing space within the cytosol. Furthermore, bioreducible polymers form stable complex with nucleic acids, and researchers can fabricate these structures to impart several important features such as site-, timing-, and duration period-specific gene expression. Additionally, the introduction of disulfide bonds within these polymers promotes their biodegradability and limits their cytotoxicity. Many approaches have demonstrated the versatility of bioreducible gene delivery, but the underlying biological rationale of these systems remains poorly understood. The process of disulfide reduction depends on multiple variables in the cellular redox environment. Therefore, the quest to unravel various issues such as the site and time of disulfide bond reduction during the cellular uptake and trafficking have stimulated a number of interesting studies which have employed disulfide compounds with a variety of reducible linkers. Such studies help researchers understand not only how modifications made to disulfides can alter their thiol-disulfide exchange characteristics but also to decipher the effect of the induced changes on the dynamics of the redox environment. This Account discusses current research trends and recent progress in the disulfide chemistry enabling novel and versatile designs of reducible polymeric gene delivery systems. We present strategies for the introduction of disulfide bonds into polymers. These representative examples and their respective outcomes elaborate the benefit and efficiency of disulfides at the individual stages of gene delivery.

The non-invasive photodynamic therapy has been limited to treat superficial tumours, primarily ascribed to poor tissue penetration of light as the energy source. Herein, we designed a long-circulating hydrophilized titanium dioxide nanoparticle (HTiO2 NP) that can be activated by ultrasound to generate reactive oxygen species (ROS). When administered systemically to mice, HTiO2 NPs effectively suppressed the growth of superficial tumours after ultrasound treatments. In tumour tissue, the levels of proinflammatory cytokines were elevated several fold and intense vascular damage was observed. Notably, ultrasound treatments with HTiO2 NPs also suppressed the growth of deeply located liver tumours at least 15-fold, compared to animals without ultrasound treatments. This study provides the first demonstration of the feasibility of using HTiO2 NPs as sensitizers for sonodynamic therapy in vivo.

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ObjectiveTo evaluate the effect of extracorporeal shock wave therapy (ESWT) on lower limb spasticity in subacute stroke patients.MethodsWe studied thirty hemiplegic subacute stroke patients with ankle plantar flexor spasticity. ESWT was applied for 1 session/week, with a total of 3 sessions at the musculotendinous junction of medial and lateral gastrocnemius muscles. Patients were evaluated both clinically and biomechanically at baseline, after sham stimulation, and at immediately 1 week and 4 weeks after ESWT. For clinical assessment, Modified Ashworth Scale (MAS), clonus score, passive range of motion of ankle, and Fugl-Myer Assessment for the lower extremity were used. A biomechanical assessment of spasticity was conducted by an isokinetic dynamometer. Two parameters, peak eccentric torque (PET) and torque threshold angle (TTA), were analyzed at the velocities of 60°/sec, 180°/sec, and 240°/sec.ResultsAfter sham stimulation, there were no significant changes between each assessment. MAS and PET (180°/sec and 240°/sec) were significantly improved immediately and 1 week after ESWT. However, these changes were not significant at 4 weeks after ESWT. PET (60°/sec) and TTA (60°/sec, 180°/sec, and 240°/sec) were significantly improved immediately after ESWT. Yet, these changes were not significant at 1 week and 4 weeks after ESWT as well.ConclusionLower limb spasticity in subacute stroke patients was significantly improved immediately after ESWT. Although the therapeutic effect of ESWT reduced with time and therefore was not significant at 4 weeks after ESWT, the degree of spasticity was lower than that of the baseline. Future studies with a larger sample of patients are warranted in order to verify the protocols which can optimize the effect of ESWT on spasticity.

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