Nanodrug Carrier Based on Poly(Ursolic Acid) with Self‐Anticancer Activity against Colorectal Cancer

As the second most common cause of cancer‐related death worldwide, colorectal cancer (CRC) requires novel therapy strategies. Biodegradable polymers are used as drug carriers for treating CRC and other cancers. However, one of the limitations for the polymeric drug carriers is that they do not directly involve the treating procedure. Herein, to develop a polymeric drug delivery system with additional therapeutic effect from that of the polymer itself, poly(ursolic acid) (PUA) is, for the first time, simply synthesized via polycondensation of ursolic acid (UA), a bioactive ingredient widely distributed in herbal medicine. PUA can self‐assemble into nanoparticles (PUA‐NPs) with a diameter of ≈122 nm and an effective load of ≈10.1%, and deliver drugs, such as paclitaxel (PUA‐NPs@PTX). In vitro studies show that PUA‐NPs@PTX have strong cytotoxicity against colorectal cancer CT26 cells, while in vivo results indicate that these NPs have a prolonged blood circulation time, enhanced tumor accumulation, and significantly improved antitumor efficacy in CT26 tumor‐bearing mice. Furthermore, both in vitro and in vivo results confirm that the PUA‐NPs themselves have therapeutic effects on CT26 cells, without causing obvious toxicity to main organs, such as bledding or necrosis. In summary, such a therapeutic polymer platform provides a new therapeutic strategy for treating cancer.     

Calcium Phosphate Mineralized Black Phosphorous with Enhanced Functionality and Anticancer Bioactivity

Biodegradable inorganic nanomaterials have opened new perspectives for cancer therapy due to their inherent anticancer activity. Black phosphorus nanosheets (BPs) with their unique bioactivity have recently been identified as promising cancer therapeutic agents but their application is hampered by the difficulty in surface functionalization. Herein, an in situ calcium phosphate (CaP) mineralization strategy is described to enhance the anticancer activity of BPs. By using BPs as the phosphate sources and growth templates, the synthesized CaP‐mineralized BPs (CaBPs) retain the intrinsic properties of BPs and at the same time have high loading capacities for various fluorophores to enable effective bioimaging and tracing. Compared to BPs, CaBPs exhibit enhanced and selective anticancer bioactivity due to the improved pH‐responsive degradation behavior and intracellular Ca²⁺ overloading in cancer cells. Furthermore, CaBPs specifically target mitochondria and cause structural damage, thus leading to mitochondria‐mediated apoptosis in cancer cells. After intravenous injection, CaBPs target orthotopic breast cancer cells to inhibit tumor growth without giving rise to adverse effects or toxicity. The results demonstrate the great potential of CaBPs as targeted anticancer agents and the CaP mineralization approach provides a versatile surface functionalization strategy for nanotherapeutic agents.     

Ultrashort electrical pulses open a new gateway into biological cells

An electrical model for biological cells predicts that for pulses with durations shorter than the charging time of the outer membrane, there is an increasing probability of electric field interactions with intracellular structures. Experimental studies in which human cells were exposed to pulsed electric fields of up to 300-kV/cm amplitude, with durations as short as 10 ns, have confirmed this hypothesis. The observed effects include the breaching of intracellular granule membranes without permanent damage to the cell membrane, abrupt rises in intracellular free calcium levels, and enhanced expression of genes. At increased electric fields, the application of submicrosecond pulses induces apoptosis (programmed cell death) in biological cells, an effect that has been shown to reduce the growth of tumors. Possible applications of the intracellular electroeffect are enhancing gene delivery to the nucleus, controlling cell functions that depend on calcium release (causing cell immobilization), and treating tumors.     

Multiple Layer‐by‐Layer Lipid‐Polymer Hybrid Nanoparticles for Improved FOLFIRINOX Chemotherapy in Pancreatic Tumor Models

The FOLFIRINOX regimen, a combination of three chemotherapy agents (5‐fluorouracil, irinotecan, oxaliplatin) and folinic acid (a vitamin B derivatives reducing the side effect of 5‐fluorouracil), has proved to be effective in the treatment of pancreatic cancer, and is more efficacious than the long‐term reference standard, gemcitabine. However, the FOLFIRINOX is associated with high‐grade toxicity, which markedly limits its clinical application. Encapsulation of drugs in nanocarriers that selectively target cancer cells promises to be an effective method for co‐delivery of drug combinations and to mitigate the side effects of conventional chemotherapy. Here we reported the development of multiple layer‐by‐layer lipid‐polymer hybrid nanoparticles with targeting capability that show excellent biocompatibility and synergistically combine the favorable properties of liposomes and polymer nanoparticles. Relative to nanoparticles consisting of polymer alone, these novel nanocarriers have a long half‐life in vivo and a higher stability in serum. The nanocarriers were loaded with the three active antitumor constituents of FOLFIRINOX regimen. Little drugs were released from the nanoparticles in phosphate buffered saline (PBS) solution, but the cargoes were quickly released after the nanoparticles were taken up by tumor cells. These innovative drug‐loaded nanoparticles achieved higher antitumor efficacy and showed minimal side effects compared with the FOLFIRINOX regimen alone. Our study suggested that the multiple layer‐by‐layer hybrid nanoparticles have great potential for improving the chemotherapeutic efficacy for the patients with pancreatic cancer. This platform also provides new opportunities for tailored design of nanoparticles that may offer therapeutics benefits for a range of other tumors.     

Nanopoxia: Targeting Cancer Hypoxia by Antimonene-Based Nanoplatform for Precision Cancer Therapy

Most anticancer drugs with broad toxicities are systematically administrated to cancer patients and their distribution in tumors is extremely low owing to hypoxia, which compromises the therapeutic efficacies of these cancer drugs. Consequently, a preponderant proportion of cancer drugs is distributed in off-target-healthy tissues, which often causes severe adverse effects. Precision cancer therapy without overdosing patients with drugs remains one of the most challenging issues in cancer therapy. Here, a novel concept of nanopoxia is presented, which is a tumor-hypoxia-based photodynamic nanoplatform for the release of therapeutic agents to achieve precision cancer therapy. Under tumor hypoxia, exposure of tumors to laser irradiation induces the fracture of polymer outer shell and produces anticancer reactive oxygen species, and switches 2D antimonene (Sb) nanomaterials to cytotoxic trivalent antimony to synergistically kill tumors. In preclinical cancer models, delivery of Sb nanomaterials to mice virtually ablates tumor growth without producing any detectable adverse effects. Mechanistically, the tumor hypoxia-triggered generation of trivalent antimony displays direct damaging effects on cancer cells and suppression of tumor angiogenesis. Together, the study provides a proof-of-concept of hypoxia-based precision cancer therapy by developing a novel nanoplatform that offers multifarious mechanisms of cancer eradication.     

Multifunctional DNA Polycatenane Nanocarriers for Synergistic Targeted Therapy of Multidrug‐Resistant Human Leukemia

Chemotherapy, as one of the principal modalities for cancer therapy, is limited by its inefficient delivery, serious side effects as well as multidrug resistance (MDR). Herein, multifunctional aptamer‐tethered deoxyribonucleic acids (DNA) polycatenanes (AptDPCs) is reported to combat MDR human leukemia. By rational design, the DNA polycatenanes (DPCs) are first constructed by a one‐step self‐assembly approach, during which DPCs are incorporated with fluorophores for bioimaging, abundant doxorubicin (DOX) intercalation sites for drug delivery, and antisense oligonucleotides (AS ODNs) for inhibiting the expression of P‐glycoprotein (P‐gp) and further reversing MDR. In addition, to endow the DPCs with specific recognition toward the target cancer cells and high purity, aptamers are tethered to the DPCs via the magnetic separation method based on the toehold‐mediated strand displacement (TMSD) reaction, which not only improves the purity and reproducibility of the AptDPCs, but also realizes the recycle of magnetic carriers. The results confirm that the AptDPCs can deliver drugs and AS ODNs into the target cancer cells and synergistically inhibit the MDR tumor growth without apparent systematic toxicity. The proposed AptDPC‐based drug delivery system can effectively reduce side effects and reverse MDR, which provides a promising platform for codelivery of therapeutic genes and chemodrugs in targeted cancer therapy.     

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.     

Ultrasmall Confined Iron Oxide Nanoparticle MSNs as a pH‐Responsive Theranostic Platform

A unique mesoporous silica nanoparticles (MSNs)‐based theranostic platform with ultrasmall iron oxide nanoparticles (NPs) confined within mesopore network has been developed by a facile but efficient physical‐vapor‐infiltration (PVI) method. The highly dispersed Fe species within mesopore channels can synchronously function as the non‐toxic contrast agents for highly efficient T₁‐weighted MR imaging, and as anchoring sites for anti‐cancer drug molecule loading and pH‐responsive release based on the special metal‐ligand coordination bonding between the Fe species and drug molecules. Moreover, the obtained Fe‐MSNs exhibit favorable biocompatibility, enhanced chemotherapeutic efficacy and concurrently diminished side effects due to the non‐specific attack of chemotherapeutic drugs, as well as the capability in circumventing the multidrug resistance (MDR) of cancer cells and suppressing the metastasis of tumor cells in vitro and in vivo. This pH‐resoponsive theranostic agent provides a new promising MSNs‐based anti‐cancer nanomedicine for future biomedical application.     

Synergistic Enhancement of Lung Cancer Therapy Through Nanocarrier‐Mediated Sequential Delivery of Superantigen and Tyrosin Kinase Inhibitor

Gefitinib (GFT) and other tyrosine kinase inhibitors (TKIs) have been widely used for the treatment of advanced or metastatic lung cancer due to their reduced side effects when compared to classic cytotoxic chemotherapeutic agents. However, both intrinsic and acquired resistance often hinders the effectiveness of TKIs. Based on recent findings that the outcome of chemotherapy can be influenced by the host immune system at multiple levels, an exploration of whether activating antitumor immunity improves the efficacy of the targeted cancer therapy of TKIs is undertaken. To this end, a cationic carrier is used to deliver superantigen and GFT in a simultaneous or sequential manner. The sequential delivery of superantigen and GFT can significantly enhance T cell immunity, promote cytokine production, inhibit tumor growth, and prolong survival time in tumor models with lung carcinoma xenografts. Most importantly, dual sequential treatment reveals a synergistic effect on tumor inhibition, which is much more effective than the monotherapy of either GFT or pTSA, as well as the combined treatment through simultaneous codelivery of pTSA and GFT together. This study demonstrates the important contribution of immunotherapy to targeted molecular therapy and opens up new possibilities for treating a wide spectrum of cancers.     

Artificial Immunogenic Cell Death Lipid Nanoparticle Functions as a Therapeutic Vaccine for Cancer

Anticancer drug-mediated induction of immunogenic cell death (ICD) blocks metastasis or recurrence in cancer cells by promoting specific immune activity against cancer antigens. However, this strategy has failed to afford adequate treatment efficiency. Overcoming the failure of ICD-mediated cancer therapy, lipid nanoparticles (LNPs) containing cancer cell surface proteins are synthesized using sonication and extrusion without microfluidics. In addition, these LNPs are decorated with high-mobility group box 1 protein and calreticulin, indicators of ICD, and named artificial ICD LNPs (AiLNPs). Administration of AiLNPs effectively targets dendritic cells (DCs) and induces DC activation in mice. Moreover, treating CT-26 tumor-bearing mice with AiLNPs inhibits tumor growth by inducing CT-26 antigen-specific T-cell immunity. Furthermore, AiLNPs containing Lewis lung carcinoma (LLC1) membrane proteins can prevent metastatic LLC1 tumor growth in the lung via LLC1 antigen-specific T-cell activation. Finally, AiLNPs synthesized with human breast cancer membrane proteins activate DC-mediated antigen-specific T-cell immunity, effectively killing tumor cells. Therefore, AiLNPs are expected to be developed as a patient-specific cancer treatment to prevent cancer recurrence and metastasis.     

Segmentation of Lung Lobes in High-Resolution Isotropic CT Images

Modern multislice computed tomography (CT) scanners produce isotropic CT images with a thickness of 0.6 mm. These CT images offer detailed information of lung cavities, which could be used for better surgical planning of treating lung cancer. The major challenge for developing a surgical planning system is the automatic segmentation of lung lobes by identifying the lobar fissures. This paper presents a lobe segmentation algorithm that uses a two-stage approach: 1) adaptive fissure sweeping to find fissure regions and 2) wavelet transform to identify the fissure locations and curvatures within these regions. Tested on isotropic CT image stacks from nine anonymous patients with pathological lungs, the algorithm yielded an accuracy of 76.7%–94.8% with strict evaluation criteria. In comparison, surgeons obtain an accuracy of 80% for localizing the fissure regions in clinical CT images with a thickness of 2.5–7.0 mm. As well, this paper describes a procedure for visualizing lung lobes in three dimensions using software—amira—and the segmentation algorithm. The procedure, including the segmentation, needed about 5 min for each patient. These results provide promising potential for developing an automatic algorithm to segment lung lobes for surgical planning of treating lung cancer.      

基于虚拟气体传感器阵列的肺癌检测电子鼻

提出了一种无创电子鼻诊断肺癌的新方法。该方法结合虚拟声表面波(SAW)传感器阵列的概念和图像识别方法,对肺癌病人、正常人和老慢支病人的呼出气体进行了检测,确定11种挥发性有机成分(VOCs)为肺癌特征气体。此外,在细胞水平上进行研究,证明了肺癌细胞培养液中存在的特征性VOCs是肺癌细胞新陈代谢的产物,可以作为判定特定肺癌细胞的依据,为确定肺癌病人呼吸中的特征性气体提供病理根据。     

肺癌患者胸水中腺癌细胞的超微病理诊断

探讨肺癌患者胸水中腺癌细胞的超微结构特点及与反应性间皮细胞的鉴别,分别对41例肺腺癌患者胸水中的癌细胞和对照组10例胸水中反应性间皮细胞进行超微结构对比观察.肺腺癌细胞表面的微绒毛、核凹陷和胞浆内的分泌颗粒、连接复合体及板层小体等超微结构均有助于与反应性间皮细胞的鉴别,其中短棒状微绒毛作为腺癌细胞形态特征标志,检出率为92.7%,如果再结合观察细胞间的连接复合体,其检出率高达95.1%.在常规细胞病理学诊断的基础上,再进行电镜观察,对肺癌患者胸水中腺癌细胞的诊断及鉴别诊断具有重要的临床应用价值.     

Pulmonary Targeting Crosslinked Cyclodextrin Metal–Organic Frameworks for Lung Cancer Therapy

Lung cancer is a serious threat to human health with the highest morbidity and mortality; metastatic lung cancer accounts for a majority of cancer-related deaths. Hence, there is considerable interest in developing efficient lung-targeted drug delivery systems to improve overall survival and quality of life of lung cancer patients. Based on the lung-targeting characteristics of cubic crosslinked cyclodextrin metal–organic framework (CDF) nanoparticles, this study shows the synthesis of a nanoplatform using RGD-functionalized CDF to co-deliver low-molecular-weight heparin (LMWH) and doxorubicin (DOX) for treatment of lung cancer. Rational design of the DOX-loaded RGD-CDF-LMWH nanoplatform (RCLD) is carried out. RCLD nanoparticles are efficiently targeted to lung tumors following intravenous administration; RCLD accumulation in the lung is 5.8 times greater than that in the liver. Moreover, RCLD inhibits migration and invasion of cancer cells in vitro and significantly diminishes lung tumor nodule count and area of spread in human A549 and murine B16F10 lung cancer models in vivo. Furthermore, RCLD does not show serum enzyme or histopathologic indicators of tissue damage or adverse hematologic effects. Therefore, the multiple antitumor activities of this novel RCLD nanoplatform, alongside its safety profile for normal tissues, strongly support its use for targeted treatment of lung cancer.     

A Redox‐Triggered Bispecific Supramolecular Nanomedicine Based on Peptide Self‐Assembly for High‐Efficacy and Low‐Toxic Cancer Therapy

Polo‐like kinase 1 (PLK1) and polo‐like kinase 4 (PLK4) are closely associated with the progression of several cancers, and their bispecific inhibitors can kill tumor cells effectively. Herein, a redox‐responsive bispecific supramolecular nanomedicine based on the self‐assembly of a cyclic peptide, termed as C‐1, targeting both PLK1 and PLK4 as a potent anticancer agent is reported. C‐1 is a cyclic peptide in response to reducing agents such as glutathione (GSH), which is constructed by a combined approach of pharmacophore modeling, molecular docking, and reversible cyclization. After entering the cytosol of cancer cell, the disulfide linkage is reduced by intracellular GSH, with the resulting linear conformation self‐assembling into bispecific nanofibers. C‐1 can lead to apoptotic cell death by inducing caspase‐3 activation and PARP cleavage in HeLa cells. Moreover, it suppresses the growth of HeLa cells in cell assays, and inhibits the progression of HeLa cells‐induced xenografts in nude mice without inducing notable side effects. This work provides a successful example of developing the redox‐responsive bispecific nanomedicine for high‐efficacy and low‐toxic cancer therapy.     

Bioinspired Nanoparticles with NIR‐Controlled Drug Release for Synergetic Chemophotothermal Therapy of Metastatic Breast Cancer

Optimal nanosized drug delivery systems (NDDS) require long blood circulation and controlled drug release at target lesions for efficient anticancer therapy. Red blood cell (RBC) membrane‐camouflaged nanoparticles (NPs) can integrate flexibility of synergetic materials and highly functionality of RBC membrane, endowed with many unique advantages for drug delivery. Here, new near‐infrared (NIR)‐responsive RBC membrane‐mimetic NPs with NIR‐activated cellular uptake and controlled drug release for treating metastatic breast cancer are reported. An NIR dye is inserted in RBC membrane shells, and the thermoresponsive lipid is employed to the paclitaxel (PTX)‐loaded polymeric cores to fabricate the RBC‐inspired NPs. The fluorescence of dye in the NPs can be used for in vivo tumor imaging with an elongated circulating halftime that is 12.3‐folder higher than that of the free dye. Under the NIR laser stimuli, the tumor cellular uptake of NPs is significantly enhanced to 2.1‐fold higher than that without irradiation. The structure of the RBC‐mimetic NPs can be destroyed by the light‐induced hyperthermia, triggered rapid PTX release (45% in 30 min). These RBC‐mimetic NPs provide a synergetic chemophotothermal therapy, completely inhibited the growth of the primary tumor, and suppress over 98% of lung metastasis in vivo, suggesting it to be an ideal NDDS to fight against metastatic breast cancer.     

Self‐Doped Conjugated Polymeric Nanoassembly by Simplified Process for Optical Cancer Theragnosis

To access smart optical theragnosis for cancer, an easily processable heterocyclic conjugated polymer (poly(sodium3‐((3‐methyl‐3,4‐dihydro‐2H‐thieno[3,4‐b][1,4]dioxepin‐3‐yl)methoxy)propane‐1‐sulfonate), PPDS) nanoassembly is fabricated by a surfactant‐free one‐step process, without the laborious ordinary multicoating process. The conjugated nanoassembly, with a self‐doped structure, provides strong absorbance in the near‐infrared (NIR) range even in a neutral pH medium and exhibits excellent stability (>six months). In addition, the prepared PPDS nanoassembly shows a high photothermal conversion efficiency of 31.4% in organic photothermal nanoparticles. In particular, the PPDS nanoassembly is stably suspended in the biological medium without any additives. Through a simple immobilization with the anti‐CD44 antibody, the prepared biomarker‐targetable PPDS nanoassembly demonstrates specific targeting toward CD44 (expressed in stem‐like cancer cells), allowing NIR absorbance imaging and the efficient targeted photothermal damaging of CD44‐expressing cancer cells, from in vitro 3D mammospheres (similar to the practical structure of tumor in the body) to in vivo xenograft mice tumor models (breast cancer and fibrosarcoma). In this study, the most simplified preparation method is for this organic conjugated polymer‐based nanoassembly by a molecular approach is reported, and demonstrated as a highly promising optical nanoagent for optical cancer theragnosis.     

基于VQ的病症脉象识别系统的实现

结合传统中医理论和现代信号处理技术以脉象信号的LPC系数、LPC倒谱系数和MEL频率倒谱参数作为识别的特征矢量,运用VQ模型对胃癌、肺癌、乳腺癌等病症患者的脉象信号进行建模以及识别的研究.此研究为病症脉象识别和辅助诊断疾病提供了一种有效的方法.     

Nitric Oxide Modulating Calcium Store for Ca2+-Initiated Cancer Therapy

Ions are essential to body, but sometimes can evolve into weapons to attack and destroy cells without systematic toxicity and drug resistance. Inspired by nitric oxygen as neurotransmitter in mediating Ca²⁺ release, NO nanodonors with high photoreactivity and stability are constructed with upconversion nanoparticles (UCNPs) coated by zeolitic nitro-/nitrile-imidazole framework-82 (ZIF-82), capable of near-infrared light (NIR) triggered NO generation and berbamine (BER) release, to achieve cancer therapy with the stored Ca²⁺ in cells. The spatial confinement effect of 2-nitroimidazole in ZIF-82 enables NO-releasing with tunable release kinetics. NO turns on the ryanodine receptors overexpressed in cancer cells for abrupt Ca²⁺ elevation; meanwhile, berbamine (BER) turns Ca²⁺-excretion pumps off to inhibit calcium efflux, resulting in intracellular Ca²⁺ overload induced apoptosis. This work provides the first example of regulating endogenous ions for cell killing, which holds promise as an effective cancer therapeutics that is complementary to traditional chemotherapeutics.     

X‐Ray‐Induced Persistent Luminescence Promotes Ultrasensitive Imaging and Effective Inhibition of Orthotopic Hepatic Tumors

Persistent luminescence imaging is accompanied by continuous illumination after the removal of excitation light, which can successfully prevent the generation of autofluorescence. In this study, a mesoporous silica template method is used to prepare uniform and monodisperse porous nanophosphors that can generate X‐ray‐excited persistent luminescence (XEPL). By loading photosensitizers, XEPL effectively excites the photosensitizers to produce reactive oxygen species for killing cancer cells. Imaging of orthotopic hepatic tumors in vivo shows that nanophosphors accumulate in the liver tumors through a passive targeting mechanism, as confirmed by the co‐imaging of bioluminescence and X‐ray‐excited luminescence. Under image‐guidance, X‐ray‐induced photodynamic therapy effectively inhibits the growth of orthotopic hepatic tumors with negligible side effects. Overall, X‐ray‐induced persistent luminescence promotes ultrasensitive imaging and effective inhibition of orthotopic hepatic tumors.