Hypoxia not only promotes tumor metastasis but also strengthens tumor resistance to therapies that demand the involvement of oxygen, such as radiation therapy and photodynamic therapy (PDT). Herein, taking advantage of the high reactivity of manganese dioxide (MnO2) nanoparticles toward endogenous hydrogen peroxide (H2O2) within the tumor microenvironment to generate O2, multifunctional chlorine e6 (Ce6) loaded MnO2 nanoparticles with surface polyethylene glycol (PEG) modification (Ce6@MnO2‐PEG) are formulated to achieve enhanced tumor‐specific PDT. In vitro studies under an oxygen‐deficient atmosphere uncover that Ce6@MnO2‐PEG nanoparticles could effectively enhance the efficacy of light‐induced PDT due to the increased intracellular O2 level benefited from the reaction between MnO2 and H2O2, the latter of which is produced by cancer cells under the hypoxic condition. Owing to the efficient tumor homing of Ce6@MnO2‐PEG nanoparticles upon intravenous injection as revealed by T1‐weighted magnetic resonance imaging, the intratumoral hypoxia is alleviated to a great extent. Thus, in vivo PDT with Ce6@MnO2‐PEG nanoparticles even at a largely reduced dose offers remarkably improved therapeutic efficacy in inhibiting tumor growth compared to free Ce6. The results highlight the promise of modulating unfavorable tumor microenvironment with nanotechnology to overcome current limitations of cancer therapies.
Extensive efforts have been directed at the discovery, investigation and clinical monitoring of targeted therapeutics. These efforts may be facilitated by the convenient access of the genetic, proteomic, interactive and other aspects of the therapeutic targets. Here, we describe an update of the Therapeutic target database (TTD) previously featured in NAR. This update includes: (i) 2000 drug resistance mutations in 83 targets and 104 target/drug regulatory genes, which are resistant to 228 drugs targeting 63 diseases (49 targets of 61 drugs with patient prevalence data); (ii) differential expression profiles of 758 targets in the disease-relevant drug-targeted tissue of 12 615 patients of 70 diseases; (iii) expression profiles of 629 targets in the non-targeted tissues of 2565 healthy individuals; (iv) 1008 target combinations of 1764 drugs and the 1604 target combination of 664 multi-target drugs; (v) additional 48 successful, 398 clinical trial and 21 research targets, 473 approved, 812 clinical trial and 1120 experimental drugs, and (vi) ICD-10-CM and ICD-9-CM codes for additional 482 targets and 262 drugs against 98 disease conditions. This update makes TTD more useful for facilitating the patient focused research, discovery and clinical investigations of the targeted therapeutics. TTD is accessible at http://bidd.nus.edu.sg/group/ttd/ttd.asp.
Cancer combination therapy to treat tumors with different therapeutic approaches can efficiently improve treatment efficacy and reduce side effects. Herein, we develop a theranostic nano-platform based on polydopamine (PDA) nanoparticles, which then are exploited as a versatile carrier to allow simultaneous loading of indocyanine green (ICG), doxorubicin (DOX) and manganese ions (PDA-ICG-PEG/DOX(Mn)), to enable imaging-guided chemo & photothermal cancer therapy. In this system, ICG acts as a photothermal agent, which shows red-shifted near-infrared (NIR) absorbance and enhanced photostability compared with free ICG. DOX, a model chemotherapy drug, is then loaded onto the surface of PDA-ICG-PEG with high efficiency. With Mn 2+ ions intrinsically chelated, PDA-ICG-PEG/DOX(Mn) is able to offer contrast under T1-weighted magnetic resonance (MR) imaging. In a mouse tumor model, the MR imaging-guided combined chemo-& photothermal therapy achieves a remarkable synergistic therapeutic effect compared with the respective single treatment modality. This work demonstrates that PDA nanoparticles could serve as a versatile molecular loading platform for MR imaging guided combined chemo-& photothermal therapy with minimal side effects, showing great potential for cancer theranostics.
Nanoscale metal-organic particles (NMOPs) are constructed from metal ions and organic bridging ligands via the self-assembly process. Herein, we fabricate NMOPs composed of Mn(2+) and a near-infrared (NIR) dye, IR825, obtaining Mn-IR825 NMOPs, which are then coated with a shell of polydopamine (PDA) and further functionalized with polyethylene glycol (PEG). While Mn(2+) in such Mn-IR825@PDA-PEG NMOPs offers strong contrast in T1-weighted magnetic resonance (MR) imaging, IR825 with strong NIR optical absorbance shows efficient photothermal conversion with great photostability in the NMOP structure. Upon intravenous injection, Mn-IR825@PDA-PEG shows efficient tumor homing together with rapid renal excretion behaviors, as revealed by MR imaging and confirmed by biodistribution measurement. Notably, when irradiated with an 808 nm laser, tumors on mice with Mn-IR825@PDA-PEG injection are completely eliminated without recurrence within 60 days, demonstrating the high efficacy of photothermal therapy with this agent. This study demonstrates the use of NMOPs as a potential photothermal agent, which features excellent tumor-targeted imaging and therapeutic functions, together with rapid renal excretion behavior, the latter of which would be particularly important for future clinical translation of nanomedicine.
Skeletal muscle fitness and plasticity is an important determinant of human health and disease. Mitochondria are essential for maintaining skeletal muscle energy homeostasis by adaptive re-programming to meet the demands imposed by a myriad of physiologic or pathophysiological stresses. Skeletal muscle mitochondrial dysfunction has been implicated in the pathogenesis of many diseases, including muscular dystrophy, atrophy, type 2 diabetes, and aging-related sarcopenia. Notably, exercise counteracts the effects of many chronic diseases on skeletal muscle mitochondrial function. Recent studies have revealed a finely tuned regulatory network that orchestrates skeletal muscle mitochondrial biogenesis and function in response to exercise and in disease states. In addition, increasing evidence suggests that mitochondria also serve to "communicate" with the nucleus and mediate adaptive genomic re-programming. Here we review the current state of knowledge relevant to the dynamic remodeling of skeletal muscle mitochondria in response to exercise and in disease states.
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