Cypate‐Conjugated Porous Upconversion Nanocomposites for Programmed Delivery of Heat Shock Protein 70 Small Interfering RNA for Gene Silencing and Photothermal Ablation

Synergistic therapy is an accepted method of enhancing the efficacy of cancer therapies. In this study, cypate‐conjugated porous NaLuF₄ doped with Yb³⁺, Er³⁺, and Gd³⁺ is synthesized and its potential for upconversion luminescence/magnetic resonance dual‐modality molecular imaging for guiding oncotherapy is tested. Loading cypate‐conjugated upconversion nanoparticles (UCNP‐cy) with small interfering RNA gene against heat shock protein 70 (UCNP‐cy‐siRNA) enhances the cell damage. UCNP‐cy‐siRNA exhibits remarkable antitumor efficacy in vivo as a result of the synergistic effects of gene silencing and photothermal therapy, with low drug dose and minimal side effects. This result thus provides an explicit strategy for developing next‐generation multifunctional nanoplatforms for multimodal imaging‐guided synergistic oncotherapy.     

Tantalum Sulfide Nanosheets as a Theranostic Nanoplatform for Computed Tomography Imaging‐Guided Combinatorial Chemo‐Photothermal Therapy

Near‐infrared (NIR)‐absorbing metal‐based nanomaterials have shown tremendous potential for cancer therapy, given their facile and controllable synthesis, efficient photothermal conversion, capability of spatiotemporal‐controlled drug delivery, and intrinsic imaging function. Tantalum (Ta) is among the most biocompatible metals and arouses negligible adverse biological responses in either oxidized or reduced forms, and thus Ta‐derived nanomaterials represent promising candidates for biomedical applications. However, Ta‐based nanomaterials by themselves have not been explored for NIR‐mediated photothermal ablation therapy. In this work, an innovative Ta‐based multifunctional nanoplatform composed of biocompatible tantalum sulfide (TaS₂) nanosheets (NSs) is reported for simultaneous NIR hyperthermia, drug delivery, and computed tomography (CT) imaging. The TaS₂ NSs exhibit multiple unique features including (i) efficient NIR light‐to‐heat conversion with a high photothermal conversion efficiency of 39%, (ii) high drug loading (177% by weight), (iii) controlled drug release triggered by NIR light and moderate acidic pH, (iv) high tumor accumulation via heat‐enhanced tumor vascular permeability, (v) complete tumor ablation and negligible side effects, and (vi) comparable CT imaging contrast efficiency to the widely clinically used agent iobitridol. It is expected that this multifunctional NS platform can serve as a promising candidate for imaging‐guided cancer therapy and selection of cancer patients with high tumor accumulation.     

Photosynthetic Biohybrid Nanoswimmers System to Alleviate Tumor Hypoxia for FL/PA/MR Imaging‐Guided Enhanced Radio‐Photodynamic Synergetic Therapy

Biohybrid microswimmers have recently shown to be able to actively perform in targeted delivery and in vitro biomedical applications. However, more envisioned functionalities of the microswimmers aimed at in vivo treatments are still challenging. A photosynthetic biohybrid nanoswimmers system (PBNs), magnetic engineered bacteria‐Spirulina platensis, is utilized for tumor‐targeted imaging and therapy. The engineered PBNs is fabricated by superparamagnetic magnetite (Fe₃O₄ NPs) via a dip‐coating process, enabling its tumor targeting ability and magnetic resonance imaging property after intravenous injection. It is found that the PBNs can be used as oxygenerator for in situ O₂ generations in hypoxic solid tumors through photosynthesis, modulating the tumor microenvironment (TME), thus improving the effectiveness of radiotherapy (RT). Furthermore, the innate chlorophyll released from the RT‐treated PBNs, as a photosensitizer, can produce cytotoxic reactive oxygen species under laser irradiation to achieve photodynamic therapy. Excellent tumor inhibition can be realized by the combined multimodal therapies. The PBNs also possesses capacities of chlorophyll‐based fluorescence and photoacoustic imaging, which can monitor the tumor therapy and tumor TME environment. These intriguing properties of the PBNs provide a promising microrobotic platform for TME hypoxic modulation and cancer theranostic applications.     

应用于早期乳腺肿瘤探测的小型化超宽带天线

设计了两款可以应用于早期乳腺肿瘤超宽带微波检测技术的超宽带天线。两款天线均为平面单极天线,分别由叉形、三角形金属贴片和槽口金属接地板构成,采用微带线对其进行馈电。经过仿真优化,两款天线的-10 dB回波损耗频率覆盖范围分别为4～10 GHz和5～10 GHz,且在此带宽内具有良好的全向性。对叉形极子天线进行了实物测量,试验数据与仿真结果相吻合。两款天线体积小、结构简单、加工简便,能够较好地满足微波成像检测乳腺肿瘤技术中天线阵列的设计要求。     

Single Molecule with Dual Function on Nanogold: Biofunctionalized Construct for In Vivo Photoacoustic Imaging and SERS Biosensing

Multimodal imaging provides complimentary information that is advantageous in studying both cellular and molecular mechanisms in vivo, which has tremendous potential in pre‐clinical research and clinical translational imaging. It is desirable to design probes for multimodal imaging that can be administered minimally but provides multifaceted information. Herein, we demonstrate the complementary dual functional ability of a nanoconstruct for molecular imaging in both photoacoustic (PA) and surface‐enhanced Raman scattering (SERS) biosensing simultaneously in tandem. To realize this, a group of NIR active organic molecules are designed and synthesized that possess both SERS and PA activity. Nanoconstructs realized by anchoring such molecules onto gold nanoparticles are demonstrated for targeting cancer biomarkers in vivo while providing complimentary information about biodistribution and targeting efficiency. In future, such nanoconstructs could play a major role in identifying surgical margins and also for disease monitoring in translational medicine.     

Imaging‐Guided Combined Photothermal and Radiotherapy to Treat Subcutaneous and Metastatic Tumors Using Iodine‐131‐Doped Copper Sulfide Nanoparticles

Combining different therapeutic strategies to treat cancer by overcoming limitations of conventional cancer therapies has shown great promise in both fundamental and clinical studies. Herein, by adding ¹³¹I when making iodine‐doped CuS nanoparticles, CuS/[¹³¹I]I nanoparticles are obtained, which after functionalization with polyethylene glycol (PEG) are used for radiotherapy (RT) and photothermal therapy (PTT), by utilizing their intrinsic high near‐infrared absorbance and the doped ¹³¹I‐radioactivity, respectively. The combined RT and PTT based on CuS/[¹³¹I]I‐PEG is then conducted, achieving remarkable synergistic therapeutic effects as demonstrated in the treatment of subcutaneous tumors. In the meanwhile, as revealed by bimodal nuclear imaging and computed tomography (CT) imaging, it is found that CuS/[¹³¹I]I‐PEG nanoparticles after being injected into primary solid tumors could migrate to and retain in their nearby sentinel lymph nodes. Importantly, the combined RT and PTT applied on those lymph nodes to assist surgical resection of primary tumors results in remarkably inhibited cancer metastasis and greatly prolonged animal survival. In vivo toxicology studies further reveal that our CuS/I‐PEG is not obviously toxic to animals at fourfold of the treatment dose. This work thus demonstrates the potential of combining RT and PTT using a single nanoagent for imaging‐guided treatment of metastatic tumors.     

Local Immune‐Triggered Surface‐Modified Stem Cells for Solid Tumor Immunotherapy

Here, described are additional treatment strategies that make use of human mesenchymal stem cell (hMSC)‐based local immunotherapeutic agents for the treatment of solid tumors. Dibenzocyclooctyne‐poly(ethylene glycol)‐pheophorbide A conjugates are engineered for cell surface conjugation by copper‐free click chemistry and are subsequently conjugated to hMSC (hMSC‐DPP). hMSC‐DPP can recognize and migrate toward cancer lesions, where they secrete pro‐inflammatory cytokines such as interleukin (IL)‐6, IL‐8, and heat shock protein 70 in pursuance of photodynamic therapy‐mediated cell death. The secreted immune factors trigger interferon gamma, IL‐2, IL‐4, IL‐12, and granulocyte‐macrophage colony‐stimulating factor, resulting in the local accumulation of T cells, B cells, natural killer cells, and antigen presenting cells at the tumor site. Treatment with hMSC‐DPP induces the accumulation of cytokines at the cancer site and minimizes systemic immune‐based side effects. This strategy is expected to increase the vulnerability of cancer cells to immune cells and cytokines, thus aiding in the development of a robust treatment platform for cancer immunotherapy.     

Effective and Selective Anti‐Cancer Protein Delivery via All‐Functions‐in‐One Nanocarriers Coupled with Visible Light‐Responsive,Reversible Protein Engineering

Efficient intracellular delivery of protein drugs and tumor‐specific activation of protein functions are critical toward anti‐cancer protein therapy. However, an omnipotent protein delivery system that can harmonize the complicated systemic barriers as well as spatiotemporally manipulate protein function is lacking. Herein, an “all‐functions‐in‐one” nanocarrier doped with photosensitizer (PS) is developed and coupled with reactive oxygen species (ROS)‐responsive, reversible protein engineering to realize cancer‐targeted protein delivery, and spatiotemporal manipulation of protein activities using long‐wavelength visible light (635 nm) at low power density (5 mW cm^?2). Particularly, RNase A is caged with H₂O₂‐cleavable phenylboronic acid to form 4‐nitrophenyl 4‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)benzyl carbonate (NBC)‐modified RNase (RNBC), which is encapsulated in acid‐degradable, ketal‐crosslinked PEI (KPEI)‐based nanocomplexes (NCs) coated with PS‐modified hyaluronic acid (HA). Such NCs harmonize the critical processes for protein delivery, wherein HA coating renders NCs with long blood circulation and cancer cell targeting, and KPEI enables endosomal escape as well as acid‐triggered intracellular RNBC release. Tumor‐specific light irradiation generates H₂O₂ to kill cancer cells and restore the protein activity, thus achieving synergistic anti‐cancer efficacy. It is the first time to photomanipulate protein functions by coupling ROS‐cleavable protein caging with PS‐mediated ROS generation, and the “all‐functions‐in‐one” nanocarrier represents a promising example for the programmed anti‐cancer protein delivery.     

NIR Light‐Triggered Degradable MoTe2 Nanosheets for Combined Photothermal and Chemotherapy of Cancer

Telluride molybdenum (MoTe₂) nanosheets with wide near‐infrared (NIR) absorbance are functionalized with polyethylene glycol‐cyclic arginine‐glycine‐aspartic acid tripeptide (PEG‐cRGD). After loading a chemotherapeutic drug (doxorubicin, DOX), MoTe₂‐PEG‐cRGD/DOX is used for combined photothermal therapy and chemotherapy. With the high photothermal conversion efficiency, MoTe₂‐PEG‐cRGD/DOX exhibits favorable cells killing ability under NIR irradiation. Owing to the cRGD‐mediated specific tumor targeting, MoTe₂‐PEG‐cRGD/DOX shows efficient accumulation in tumors to induce a strong tumor ablation effect. MoTe₂‐PEG‐cRGD nanosheets, which are relatively stable in the circulation, could be degraded under NIR ray. The in vitro and in vivo experimental results demonstrate that this theranostic nanoagent, which could accumulate in tumors to allow photothermal imaging and combined therapy, is readily degradable in normal organs to enable rapid excretion and avoid long‐term retention/toxicity, holding great potential to treat tumor effectively.     

LSM下乳癌,乳腺囊性增生症早期恶变及乳腺增生细胞荧光特性的观察

本文报道了乳癌、乳腺囊性增生症早期恶变及乳腺增生细胞在单色激光激发下的自体荧光。结果发现乳癌细胞浆内荧光最强，囊性增生早期恶变细胞次之而乳腺增生细胞浆无荧光。这一荧江特征可为肿瘤早期诊断提供重要依据。