A Versatile Nanozyme-Based NADH Circulating Oxidation Reactor for Tumor Therapy through Triple Cellular Metabolism Disruption.

Nanozyme-based metabolic regulation triggered by tumor-specific endogenous stimuli has emerged as a promising therapeutic strategy for tumors. The current efficacy, however, is constrained by the limited concentration of endogenous substrates and the metabolic plasticity of tumors. Consequently, the implementation of efficient metabolic regulation in tumor therapy is urgently needed. Herein, a versatile nanozyme-based nicotinamide adenine dinucleotide (NADH) circulating oxidation nanoreactor is reported. First, the synthesized cobalt-doped hollow carbon spheres (Co-HCS) possess NADH oxidase (NOX)-mimicking activity for the NADH oxidation to disrupt oxidative phosphorylation (OXPHOS) pathway of tumor cells. Second, the substrate-cycle manner of Co-HCS can be used for NADH circulating oxidation to overcome the limitation of substrate deficiency. Finally, 2-Deoxy-D-glucose (2-DG) and 6-aminonicotinamide (6-AN) are introduced to block glycolysis and pentose phosphate pathway (PPP), thus creating a versatile nanozyme-based NADH circulating oxidation nanoreactor (Co-HCS/D/A) for tumor therapy through triple cellular metabolism disruption. In vitro and in vivo results demonstrate that the designed nanoreactor not only enhances the catalytic efficiency but also disrupts the tumor metabolic homeostasis, leading to efficient therapy outcome. This study develops a novel NADH circulating oxidation nanoreactor for tumor therapy through triple cellular metabolism disruption, which addresses the limitations of current nanozyme-based metabolism regulation for tumor therapy.

Metal-Organic Frameworks@Au Nanoreactor as an Oxidative Stress Amplifier for Enhanced Tumor Photodynamic Therapy through the Alleviation of Hypoxemia and the Depletion of Glutathione.

Recently, photodynamic therapy (PDT) based on the generation of cytotoxic reactive oxygen species (ROS) has drawn great attention in tumor treatment. However, the hypoxia tumor microenvironment (TME) inhibits the generation efficacy of ROS, and the high glutathione (GSH) level in TME could neutralize the generated ROS, both of which strongly reduce the therapeutic efficiency of PDT. In this work, we first constructed the porphyrinic metal-organic framework PCN-224. Then Au nanoparticles were decorated on the PCN-224 to obtain the PCN-224@Au. The decorated Au nanoparticles could not only produce O2 through the decomposition of H2O2 in tumor sites for enhancing the generation of 1O2 in PDT but also deplete glutathione through the strong interactions between Au and sulfhydryl groups on glutathione to weaken the antioxidant ability of tumor cells, thus amplifying the 1O2 damage to cancer cells. The in vitro and in vivo experiments totally exhibited that the as-prepared PCN-224@Au nanoreactor can be used as an oxidative stress amplifier for enhanced PDT, which provides a promising candidate to conquer the limitation of intratumor hypoxia and high GSH level on PDT of cancer.

Carbon dots nanophotosensitizers with tunable reactive oxygen species generation for mitochondrion-targeted type I/II photodynamic therapy.

Carbon dots (CDs) have emerged as promising nanomaterials for bioimaging-guided photodynamic therapy (PDT). However, designing red-emissive CDs (RCDs) with tunable type I and type II reactive oxygen species (ROS) generation to simultaneously meet PDT applications in aerobic and hypoxic scenarios still remain major challenges. Herein, three types of RCDs with maximum emission at approximately 680 nm are successfully prepared. It is noteworthy that they exhibit the adjustable ROS production with equal superoxide anion (via type I PDT) and incremental singlet oxygen (via type II PDT). Detailed structural and optical characterizations along with theoretical calculation reveal that the unique type I/II ROS formation mainly depends on the core sizes and surface states of RCDs, which determine their identical redox potentials and tapering energy gaps between singlet- and triplet states, respectively. Additionally, due to the inherent mitochondria targeting capability, RCDs enable themselves to induce cell programmed death via activating mitochondrion-mediated apoptotic pathways. This work exploits the unprecedented RCDs with tunable type I and type II ROS generation that could ensure highly efficient tumor eradication both in vitro and in vivo, even under the harsh tumor microenvironment, providing a new prospect for CDs as nanophotosensitizers to conquer the limitations of single type PDT.

Iron phthalocyanine-derived nanozyme as dual reactive oxygen species generation accelerator for photothermally enhanced tumor catalytic therapy.

Nanozymes are artificial enzymes that mimic natural enzyme-like activities and show great promise for tumor catalytic therapy. However, new nanozymes with multiple catalytic activities for multifunctional nanotheranostic use remain challenging to design. Herein, for the first time, iron phthalocyanine (Fe(II)Pc) was assembled with poly(l-lactide-co-glycolide)-block-poly(ethylene glycol) to prepare an Fe(II)Pc assembly (denoted as Fe(II)Pc-A). The obtained Fe(II)Pc-A could be applied as a smart near-infrared (NIR) light-responsive nanotheranostic for simultaneous photoacoustic imaging-guided photothermal therapy. Notably, Fe(II)Pc-A possessed peroxidase, catalase, and oxidase mimicking activities, which could not only catalyze the conversion of intratumoral H2O2 to •OH, but also degrade H2O2 to generate O2 and continuously catalyze the conversion of O2 to cytotoxic O2•-. Impressively, the dual reactive oxygen species (ROS) generation of Fe(II)Pc-A was further remarkably enhanced by the endogenous acidity of the tumor microenvironment and the exogenous NIR light-responsive photothermal effect. Moreover, the O2 self-supplying ability of Fe(II)Pc-A led to increased generation of O2•- for enhancing catalytic therapy in hypoxic tumor. These collective properties of Fe(II)Pc-A nanozyme enabled it to be a dual ROS generation accelerator for photothermally enhanced tumor catalytic therapy. Thus, a new type of high-performance nanozyme for multifunctional nanotheranostic use toward cancer was presented.

Red Emissive Carbon Dots Prepared from Polymers as an Efficient Nanocarrier for Coptisine Delivery in†vivo and in†vitro.

Negatively charged fluorescent carbon dots (CDs, Em =608 nm) were hydrothermally prepared from thiophene phenylpropionic acid polymers and then successfully loaded with the positively charged anticancer cargo coptisine, which suffers from poor bioavailability. The formed CD-coptisine complexes were thoroughly characterized by particle size, morphology, drug loading efficiency, drug release, cellular uptake and cellular toxicity in vitro and antitumor activities in vivo. In this nano-carrier system, red emissive CDs possess multiple advantages as follows: 1) high drug loading efficiency (>96 %); 2) sustained drug release; 3) enhanced drug efficacy towards cancer cells; 4) EPR effect; 5) drug release tracing with near-infrared imaging. These properties indicated that red emissive CDs prepared from polymers could be used as a novel drug delivery system with integrated therapeutic and imaging functions in cancer therapy, which are expected to have great potential in future clinical applications.

Hypocrellin Derivative-Loaded Calcium Phosphate Nanorods as NIR Light-Triggered Phototheranostic Agents with Enhanced Tumor Accumulation for Cancer Therapy.

Dopamine modified hypocrellin B (DAHB) derivative-loaded calcium phosphate nanorods (DAHB@CaP NRs) were prepared as a novel phototheranostic agent for effective tumor imaging and therapy. DAHB@CaP NRs were obtained through microwave treatment using DAHB, CaCl2 , NH3 ⋅H2 O, and H3 PO4 as precursors. The DAHB@CaP NRs possessed the following advantages: 1) efficient absorption in the near-infrared (NIR) region from 650 nm to 800 nm; 2) maximum NIR emission at approximately 735 nm; 3) enhanced cellular uptake efficiency in vitro and in vivo; and 4) efficient inhibition of tumor growth and low biotoxicity. These properties indicate the high capability of DAHB@CaP NRs for NIR fluorescence (FL) imaging-guided photodynamic therapy of cancer, thus offering promising new prospects for clinical applications.

Pheophytin Derived Near-Infrared-Light Responsive Carbon Dot Assembly as a New Phototheranotic Agent for Bioimaging and Photodynamic Therapy.

Carbon dots (CDs), a kind of phototheranostic agent with the capability of simultaneous bioimaging and phototherapy [i.e., photodynamic therapy (PDT) or photothermal therapy (PTT)], have received considerable attention because of their remarkable properties, including flexibility for surface modification, high biocompatibility, low toxicity and photo-induced activity for malignant tumor cells. Among numerous carbon sources, it has been found that natural biomass are good candidates for the preparation of CD phototheranostic agents. In this study, pheophytin, a type of Mg-free chlorophyll derivative and also a natural product with low toxicity, was used as a raw carbon source for the synthesis of CDs by using a microwave method. The obtained hydrophobic CDs exhibited a maximum near-infrared (NIR) emission peak at approximately 680 nm, and high singlet oxygen (1 O2 ) generation with a quantum yield of 0.62. The self-assembled CDs from the as-prepared CDs with DSPE-mPEG2000 retained efficient 1 O2 generation. The obtained carbon dot assembly was not only an efficient fluorescence (FL) imaging agent but also a smart PDT agent. Our studies indicated that the obtained hydrophilic CD assembly holds great potential as a new phototheranostic agent for cancer therapy. This work provides a new route for synthesis of CDs and proposes a readily available candidate for tumor treatment.

Biodegradable Natural Product-Based Nanoparticles for Near-Infrared Fluorescence Imaging-Guided Sonodynamic Therapy.

Natural products show high potential for clinical translation because of their specific biological activities and molecular structure diversities. Sonosensitizers that originate from natural products play a crucial role as anti-inflammatory and anticancer agents. Herein, hypocrellin-derivative nanoparticles (APHB NPs) were constructed for synchronous near-infrared fluorescence (NIR FL) imaging and sonodynamic therapy (SDT) for deep-seated tumors in vivo. The prepared APHB NPs exhibit excellent water solubility, FL in the NIR region, and effective reactive oxygen species generation under ultrasound stimulation. Furthermore, the APHB NPs show excellent biocompatibility, suitable biodegradation rate, and enhanced tumor accumulation. Therefore, the APHB NPs exhibit promising clinical potential as novel safe and precise NIR FL imaging and SDT agents for deep-seated tumor therapy.