Publications by authors named "Xing-Jie Liang"

264 Publications

Electromagnetic Field-Programmed Magnetic Vortex Nanodelivery System for Efficacious Cancer Therapy.

Adv Sci (Weinh) 2021 Jul 18:e2100950. Epub 2021 Jul 18.

Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi'an, Shaanxi, 710069, China.

Effective delivery of anticancer drugs into the nucleus for pharmacological action is impeded by a series of intratumoral transport barriers. Despite the significant potential of magnetic nanovehicles in electromagnetic field (EF)-activated drug delivery, modularizing a tandem magnetoresponsive activity in a one-nanoparticle system to meet different requirements at both tissue and cellular levels remain highly challenging. Herein, a strategy is described by employing sequential EF frequencies in inducing a succession of magnetoresponses in the magnetic nanovehicles that aims to realize cascaded tissue penetration and nuclear accumulation. This nanovehicle features ferrimagnetic vortex-domain iron oxide nanorings coated with a thermo-responsive polyethylenimine copolymer (PI/FVIOs). It is shown that the programmed cascading of low frequency (Lf)-EF-induced magnetophoresis and medium frequency (Mf)-EF-stimulated magneto-thermia can steer the Doxorubicin (DOX)-PI/FVIOs to the deep tissue and subsequently trigger intracellular burst release of DOX for successful nuclear entry. By programming the order of different EF frequencies, it is demonstrated that first-stage Lf-EF and subsequent Mf-EF operation enables DOX-PI/FVIOs to effectively deliver 86.2% drug into the nucleus in vivo. This nanodelivery system empowers potent antitumoral activity in various models of intractable tumors, including DOX-resistant MCF-7 breast cancer cells, triple-negative MDA-MB-231 breast cancer cells, and BxPC-3 pancreatic cancer cells with poor permeability.
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http://dx.doi.org/10.1002/advs.202100950DOI Listing
July 2021

Magnetothermal regulation of in vivo protein corona formation on magnetic nanoparticles for improved cancer nanotherapy.

Biomaterials 2021 Jul 10;276:121021. Epub 2021 Jul 10.

Key Laboratory of Synthetic and Natural Functional Molecule of the Ministry of Education, College of Chemistry and Materials Science, Northwest University, Xi'an, 710069, China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, The College of Life Sciences & School of Medicine, Northwest University, Xi'an, 710069, China. Electronic address:

Engineering the protein corona (PC) on nanodrugs is emerging as an effective approach to improve their pharmacokinetics and therapeutic efficacy, but conventional in vitro pre-programmed methods have shown great limitation for regulation of the PC in the complex and dynamic in vivo physiological environment. Here, we demonstrate an magnetothermal regulation approach that allows us to in situ modulate the in vivo PC composition on iron oxide nanoparticles for improved cancer nanotherapy. Experimental results revealed that the relative levels of major opsonins and dysopsonins in the PC can be tuned quantitatively by means of heat induction mediated by the nanoparticles under an alternating magnetic field. When the PC was magnetically optimized in vivo, the nanoparticles exhibited prolonged circulation and enhanced tumor delivery efficiency in mice, 2.53-fold and 2.02-fold higher respectively than the control. This led to a superior thermotherapeutic efficacy of systemically delivered nanoparticles. In vivo magnetothermal regulation of the PC on nanodrugs will find wide applications in biomedicine.
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http://dx.doi.org/10.1016/j.biomaterials.2021.121021DOI Listing
July 2021

Photo-responsive hydrogel facilitates nutrition deprivation by an ambidextrous approach for preventing cancer recurrence and metastasis.

Biomaterials 2021 Jun 24;275:120992. Epub 2021 Jun 24.

Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, College of Chemistry & Environmental Science, Chemical Biology Key Laboratory of Hebei Province, Institute of Life Science and Green Development, Hebei University, Baoding, 071002, PR China. Electronic address:

Postoperative recurrence at the primary site and distant metastasis remains the challenge in treating triple-negative breast cancer due to its unpredictable invasion into adjacent tissues. Although systemic chemotherapy has been extensively adopted to attenuate the recurrence and metastasis, the abundant nutrition supply by blood vessels would promote the rapid proliferation of tumor cells and angiogenesis. Herein, we reported a nutrition deprivation strategy by ambidextrously blocking the residual blood vessels and inhibiting angiogenesis to realize efficient treatment of triple-negative breast cancer. To this end, an injectable hydrogel with photo-responsive property was prepared by using polydopamine crosslinked collagen/silk fibroin composite to deliver thrombin for blocking blood vessels and angiogenesis. In the presence of NIR light, the locked thrombin was released into the blood vessels in the adjacent tissues to promote blood coagulation. In addition, the photothermal effect would reduce the secreting of VEGF for preventing angiogenesis in the adjacent tissues. The in vitro and in vivo results demonstrated that the permanent interruption of nutrient supply by blocking the blood vessels adjacent to the resected tumor and preventing angiogenesis is a promising strategy to prevent the recurrence and metastasis of TNBC.
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http://dx.doi.org/10.1016/j.biomaterials.2021.120992DOI Listing
June 2021

Advances in Application of Azobenzene as a Trigger in Biomedicine: Molecular Design and Spontaneous Assembly.

Adv Mater 2021 Jul 24;33(26):e2007290. Epub 2021 May 24.

Department of Chemistry and Nanoscience, Ewha Womans University, Seoul, 03760, Korea.

Azobenzene is a well-known derivative of stimulus-responsive molecular switches and has shown superior performance as a functional material in biomedical applications. The results of multiple studies have led to the development of light/hypoxia-responsive azobenzene for biomedical use. In recent years, long-wavelength-responsive azobenzene has been developed. Matching the longer wavelength absorption and hypoxia-response characteristics of the azobenzene switch unit to the bio-optical window results in a large and effective stimulus response. In addition, azobenzene has been used as a hypoxia-sensitive connector via biological cleavage under appropriate stimulus conditions. This has resulted in on/off state switching of properties such as pharmacology and fluorescence activity. Herein, recent advances in the design and fabrication of azobenzene as a trigger in biomedicine are summarized.
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http://dx.doi.org/10.1002/adma.202007290DOI Listing
July 2021

Pyroelectric Catalysis-Based "Nano-Lymphatic" Reduces Tumor Interstitial Pressure for Enhanced Penetration and Hydrodynamic Therapy.

ACS Nano 2021 06 21;15(6):10488-10501. Epub 2021 May 21.

State Key Laboratory of Metastable Materials Science and Technology, Applying Chemistry Key Lab of Hebei Province, Yanshan University, Qinhuangdao 066004, China.

Because of the deficiency of lymphatic reflux in the tumor, the retention of tumor interstitial fluid causes aggravation of the tumor interstitial pressure (TIP), which leads to unsatisfactory tumor penetration of nanomedicine. It is the main inducement of tumor recurrence and metastasis. Herein, we design a pyroelectric catalysis-based "Nano-lymphatic" to decrease the TIP for enhanced tumor penetration and treatments. It realizes photothermal therapy and decomposition of tumor interstitial fluid under NIR-II laser irradiation after reaching the tumor, which reduces the TIP for enhanced tumor penetration. Simultaneously, reactive oxygen species generated during the pyroelectric catalysis can further damage deep tumor stem cells. The results indicate that the "Nano-lymphatic" relieves 52% of TIP, leading to enhanced tumor penetration, which effectively inhibits the tumor proliferation (93.75%) and recurrence. Our finding presents a rational strategy to reduce TIP by pyroelectric catalysis for enhanced tumor penetration and improved treatments, which is of great significance for drug delivery.
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http://dx.doi.org/10.1021/acsnano.1c03048DOI Listing
June 2021

Gold-based nanomaterials for the treatment of brain cancer.

Cancer Biol Med 2021 May 18. Epub 2021 May 18.

CAS Center for Excellence in Nanoscience, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, Beijing 100190, China.

Brain cancer, also known as intracranial cancer, is one of the most invasive and fatal cancers affecting people of all ages. Despite the great advances in medical technology, improvements in transporting drugs into brain tissue have been limited by the challenge of crossing the blood-brain barrier (BBB). Fortunately, recent endeavors using gold-based nanomaterials (GBNs) have indicated the potential of these materials to cross the BBB. Therefore, GBNs might be an attractive therapeutic strategy against brain cancer. Herein, we aim to present a comprehensive summary of current understanding of the critical effects of the physicochemical properties and surface modifications of GBNs on BBB penetration for applications in brain cancer treatment. Furthermore, the most recent GBNs and their impressive performance in precise bioimaging and efficient inhibition of brain tumors are also summarized, with an emphasis on the mechanism of their effective BBB penetration. Finally, the challenges and future outlook in using GBNs for brain cancer treatment are discussed. We hope that this review will spark researchers' interest in constructing more powerful nanoplatforms for brain disease treatment.
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http://dx.doi.org/10.20892/j.issn.2095-3941.2020.0524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185869PMC
May 2021

Effect of physicochemical properties on fate of nanoparticle-based cancer immunotherapies.

Acta Pharm Sin B 2021 Apr 9;11(4):886-902. Epub 2021 Mar 9.

Laboratory of Controllable Nanopharmaceuticals, Chinese Academy of Sciences (CAS) Center for Excellence in Nanoscience and CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, Beijing 100190, China.

Current advances of immunotherapy have greatly changed the way of cancer treatment. At the same time, a great number of nanoparticle-based cancer immunotherapies (NBCIs) have also been explored to elicit potent immune responses against tumors. However, few NBCIs are nearly in the clinical trial which is mainly ascribed to a lack understanding of fate of nanoparticles (NPs) for cancer immunotherapy. NPs for cancer immunotherapy mainly target the immune organs or immune cells to enable efficient antitumor immune responses. The physicochemical properties of NPs including size, shape, elasticity and surface properties directly affect their interaction with immune systems as well as their fate and therapeutic effect. Hence, systematic analysis of the physicochemical properties and their effect on fate is urgently needed. In this review, we first recapitulate the fundamentals for the fate of NBCIs including physio-anatomical features of lymphatic system and strategies to modulate immune responses. Moreover, we highlight the effect of physicochemical properties on their fate including lymph nodes (LNs) drainage, cellular uptake and intracellular transfer. Challenges and opportunities for rational design of NPs for cancer immunotherapy are also discussed in detail.
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http://dx.doi.org/10.1016/j.apsb.2021.03.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105773PMC
April 2021

Recent progress in mitochondria-targeting-based nanotechnology for cancer treatment.

Nanoscale 2021 Apr 12;13(15):7108-7118. Epub 2021 Apr 12.

Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China.

Mitochondria play critical roles in the regulation of the proliferation and apoptosis of cancerous cells. Nanosystems for targeted delivery of cargos to mitochondria for cancer treatment have attracted increasing attention in the past few years. This review will summarize the state of the art of design and construction of nanosystems used for mitochondria-targeted delivery. The use of nanotechnology for cancer treatment through various pathways such as energy metabolism interference, reactive oxygen species (ROS) regulation, mitochondrial protein targeting, mitochondrial DNA (mtDNA) interference, mitophagy inducing, and combination therapy will be discussed. Finally, the major challenges and an outlook in this field will also be provided.
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http://dx.doi.org/10.1039/d1nr01068aDOI Listing
April 2021

Exploiting the acquired vulnerability of cisplatin-resistant tumors with a hypoxia-amplifying DNA repair-inhibiting (HYDRI) nanomedicine.

Sci Adv 2021 Mar 26;7(13). Epub 2021 Mar 26.

Laboratory of Controllable Nanopharmaceuticals, Chinese Academy of Sciences (CAS) Center for Excellence in Nanoscience and CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, Beijing 100190, P. R. China.

Various cancers treated with cisplatin almost invariably develop drug resistance that is frequently caused by substantial DNA repair. We searched for acquired vulnerabilities of cisplatin-resistant cancers to identify undiscovered therapy. We herein found that cisplatin resistance of cancer cells comes at a fitness cost of increased intracellular hypoxia. Then, we conceived an inspired strategy to combat the tumor drug resistance by exploiting the increased intracellular hypoxia that occurs as the cells develop drug resistance. Here, we constructed a hypoxia-amplifying DNA repair-inhibiting liposomal nanomedicine (denoted as HYDRI NM), which is formulated from a platinum(IV) prodrug as a building block and payloads of glucose oxidase (GOx) and hypoxia-activatable tirapazamine (TPZ). In studies on clinically relevant models, including patient-derived organoids and patient-derived xenograft tumors, the HYDRI NM is able to effectively suppress the growth of cisplatin-resistant tumors. Thus, this study provides clinical proof of concept for the therapy identified here.
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http://dx.doi.org/10.1126/sciadv.abc5267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997498PMC
March 2021

Temperature-Sensitive Lipid-Coated Carbon Nanotubes for Synergistic Photothermal Therapy and Gene Therapy.

ACS Nano 2021 04 22;15(4):6517-6529. Epub 2021 Mar 22.

Key Laboratory of Biotechnology and Bioresources Utilization of Ministry of Education, Dalian Minzu University, Dalian 116600, China.

The combination of photothermal therapy (PTT) and gene therapy (GT) shows great potential to achieve synergistic anti-tumor activity. However, the lack of a controlled release of genes from carriers remains a severe hindrance. Herein, peptide lipid (PL) and sucrose laurate (SL) were used to coat single-walled carbon nanotubes (SCNTs) and multi-walled carbon nanotubes (MCNTs) to form bifunctional delivery systems (denoted SCNT-PS and MCNT-PS, respectively) with excellent temperature-sensitivity and photothermal performance. CNT/siRNA suppressed tumor growth by silencing survivin expression while exhibiting photothermal effects under near-infrared (NIR) light. SCNT-PS/siRNA showed very high anti-tumor activity, resulting in the complete inhibition of some tumors. It was highly efficient for systemic delivery to tumor sites and to facilitate siRNA release owing to the phase transition of the temperature-sensitive lipids, due to PL and SL coating. Thus, SCNT-PS/siRNA is a promising anti-tumor nanocarrier for combined PTT and GT.
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http://dx.doi.org/10.1021/acsnano.0c08790DOI Listing
April 2021

Nanoscale Detection of Subcellular Nanoparticles by X-Ray Diffraction Imaging for Precise Quantitative Analysis of Whole Cancer Cells.

Anal Chem 2021 03 9;93(12):5201-5210. Epub 2021 Mar 9.

School of Physical Science and Technology, ShanghaiTech University, Shanghai 201210, China.

Nanoparticles show great potential for drug delivery systems in cancer treatment and diagnosis, which mainly rely on the interaction between nanoparticles and living cells. However, there is still a lack of accurate and large field-of-view imaging techniques to reveal the aggregation and distribution behavior of nanoparticles in whole cancer cells without being destroyed. Here, we demonstrated quantitative imaging of unstained and intact mouse breast cancer cells (4T1) containing 50 nm gold nanoparticles ([email protected] NPs) using an X-ray scanning coherent diffraction imaging (ptychography) technique in a large field-of-view. A two-dimensional spatial resolution of 17 nm was achieved on the 4T1 cell. We combine X-ray ptychography and equally sloped tomography (EST) to perform three-dimensional structural mapping, distribution, and aggregation behavior of [email protected] NPs in cancer cells. By taking full advantage of the large field-of-view, high-resolution, and quantitative imaging technique, the single intracellular [email protected] NPs are observed and the amount of [email protected] NPs in aggregations can be accurately quantified. In addition, the morphological changes of lysosomes containing [email protected] NPs can be observed in the high-contrast mass density images. This study provides an approach for exploring quantitative analysis and physiological delivery of nanomaterials in intact cancer cells at nanoscale resolution, which may greatly benefit the interdisciplinary research of material science, nanomedicine, and nanotoxicology.
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http://dx.doi.org/10.1021/acs.analchem.0c05282DOI Listing
March 2021

X-ray-Based Techniques to Study the Nano-Bio Interface.

ACS Nano 2021 03 2;15(3):3754-3807. Epub 2021 Mar 2.

Mathematics, Informatics, and Natural Sciences (MIN) Faculty, University of Hamburg, 20354 Hamburg, Germany.

X-ray-based analytics are routinely applied in many fields, including physics, chemistry, materials science, and engineering. The full potential of such techniques in the life sciences and medicine, however, has not yet been fully exploited. We highlight current and upcoming advances in this direction. We describe different X-ray-based methodologies (including those performed at synchrotron light sources and X-ray free-electron lasers) and their potentials for application to investigate the nano-bio interface. The discussion is predominantly guided by asking how such methods could better help to understand and to improve nanoparticle-based drug delivery, though the concepts also apply to nano-bio interactions in general. We discuss current limitations and how they might be overcome, particularly for future use .
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http://dx.doi.org/10.1021/acsnano.0c09563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992135PMC
March 2021

Core Role of Hydrophobic Core of Polymeric Nanomicelle in Endosomal Escape of siRNA.

Nano Lett 2021 04 17;21(8):3680-3689. Epub 2021 Feb 17.

School of Life Science, Advanced Research Institute of Multidisciplinary Science, Institute of Engineering Medicine, Key Laboratory of Molecular Medicine and Biotherapy, Beijing Institute of Technology, Beijing 100081, China.

Efficient endosomal escape is the most essential but challenging issue for siRNA drug development. Herein, a series of quaternary ammonium-based amphiphilic triblock polymers harnessing an elaborately tailored pH-sensitive hydrophobic core were synthesized and screened. Upon incubating in an endosomal pH environment (pH 6.5-6.8), mPEG-P(DPA--DMAEMA)-PT (PDDT, the optimized polymer) nanomicelles (PDDT-Ms) and PDDT-Ms/siRNA polyplexes rapidly disassembled, leading to promoted cytosolic release of internalized siRNA and enhanced silencing activity evident from comprehensive analysis of the colocalization and gene silencing using a lysosomotropic agent (chloroquine) and an endosomal trafficking inhibitor (bafilomycin A1). In addition, PDDT-Ms/siPLK1 dramatically repressed tumor growth in both HepG2-xenograft and highly malignant patient-derived xenograft models. PDDT-Ms-armed siPD-L1 efficiently blocked the interaction of PD-L1 and PD-1 and restored immunological surveillance in CT-26-xenograft murine model. PDDT-Ms/siRNA exhibited ideal safety profiles in these assays. This study provides guidelines for rational design and optimization of block polymers for efficient endosomal escape of internalized siRNA and cancer therapy.
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http://dx.doi.org/10.1021/acs.nanolett.0c04468DOI Listing
April 2021

Mannose-Derived Carbon Dots Amplify Microwave Ablation-Induced Antitumor Immune Responses by Capturing and Transferring "Danger Signals" to Dendritic Cells.

ACS Nano 2021 02 1;15(2):2920-2932. Epub 2021 Feb 1.

Department of Interventional Ultrasound, Chinese PLA General Hospital, 100853 Beijing, China.

Hepatocellular carcinoma recurrence and metastasis after microwave ablation (MWA) are challenges in the clinic. This study showed that mannose-derived carbon dots (Man-CDs) could effectively capture several "danger signals" (DS) after MWA treatment and then deliver DS specifically to dendritic cells (DCs). This improved delivery of DS to DCs enhanced the processing and presentation of tumor-associated antigens by DCs. The results demonstrated that intratumoral injection of Man-CDs after MWA therapy elicited a potent tumor-specific immune response and finally led to the effective suppression of both primary and distant tumors. MWA + Man-CD treatment could efficiently reject tumor cell rechallenge . This study demonstrated that Man-CD nanoparticles are effective adjuvants that can improve MWA therapy by eliciting a tumor-specific immune response.
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http://dx.doi.org/10.1021/acsnano.0c09120DOI Listing
February 2021

Protein-Activatable Diarylethene Monomer as a Smart Trigger of Noninvasive Control Over Reversible Generation of Singlet Oxygen: A Facile, Switchable, Theranostic Strategy for Photodynamic-Immunotherapy.

J Am Chem Soc 2021 02 28;143(5):2413-2422. Epub 2021 Jan 28.

Department of Chemistry and Nanoscience, Ewha Womans University, Seoul 120-750, Korea.

The development of activatable photosensitizers to allow for the reversible control of singlet oxygen (O) production for photodynamic therapy (PDT) faces great challenges. Fortunately, the flourishing field of supramolecular biotechnology provides more effective strategies for activatable PDT systems. Here, we developed a new reversible PDT on a switch that controls the O generation of self-assembled albumin nanotheranostics in vitro and in vivo. A new molecular design principle of aggregation-induced self-quenching photochromism and albumin on-photoswitching was demonstrated using a new asymmetric, synthetic diarylethene moiety . The photosensitizer porphyrin and were incorporated as building blocks in a glutaraldehyde-induced covalent albumin cross-linking nanoplatform, (NPs). More importantly, the excellent photoswitching property of enables the resultant nanoplatform to act as a facile, switchable strategy for photodynamic-immunotherapy.
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http://dx.doi.org/10.1021/jacs.0c12851DOI Listing
February 2021

Nano-herb medicine and PDT induced synergistic immunotherapy for colon cancer treatment.

Biomaterials 2021 02 5;269:120654. Epub 2021 Jan 5.

School of Life Sciences, Tianjin University, Tianjin Engineering Center of Micro Nano Biomaterials and Detection Treatment Technology, Collaborative Innovation Center of Chemical Science and Engineering, Tianjin, 300072, China. Electronic address:

A variety of therapies have been developed and used for the treatment of colon cancer, however, the high mortality rate remains high and more effective strategies are still in urgent needs. In this study, an immunotherapy approach that is composed of innate immune activator Astragaloside III (As) and the photodynamic therapy (PDT) reagent chlorine e6 (Ce6) ((As + Ce6)@MSNs-PEG), was developed for colon cancer treatment. We showed that (As + Ce6)@MSNs-PEG could effectively activate NK cells and inhibit the proliferation of tumor cells in vitro. It could also effectively reach tumor sites, induce infiltration of immune cells into the tumor, and enhance the cytotoxicity of natural killer cells and CD8 T cells in vivo. Without obvious side effects, (As + Ce6)@MSNs-PEG treatment significantly inhibited tumor growth and extended the lifespan of tumor-bearing mice. Further results revealed that treatment of (As + Ce6)@MSNs-PEG led to enhanced IFN secretion by immune cells and increased T-box transcription factor (T-bet), which is highly expressed by T cells. Therefore, (As + Ce6)@MSNs-PEG may serve as an effective and safe platform for combinatory use with nano-herb medicine and PDT to provide a new therapy for colon cancer treatment.
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http://dx.doi.org/10.1016/j.biomaterials.2021.120654DOI Listing
February 2021

Self-Propelled and Near-Infrared-Phototaxic Photosynthetic Bacteria as Photothermal Agents for Hypoxia-Targeted Cancer Therapy.

ACS Nano 2021 01 25;15(1):1100-1110. Epub 2020 Nov 25.

College of Chemistry & Environmental Science, Analytical Chemistry Key Laboratory of Hebei Province, Hebei University, Baoding 071002, P.R. China.

Hypoxia can increase the resistance of tumor cells to radiotherapy and chemotherapy. However, the dense extracellular matrix, high interstitial fluid pressure, and irregular blood supply often serve as physical barriers to inhibit penetration of drugs or nanodrugs across tumor blood microvessels into hypoxic regions. Therefore, it is of great significance and highly desirable to improve the efficiency of hypoxia-targeted therapy. In this work, living photosynthetic bacteria (PSB) are utilized as hypoxia-targeted carriers for hypoxic tumor therapy due to their near-infrared (NIR) chemotaxis and their physiological characteristics as facultative aerobes. More interestingly, we discovered that PSB can serve as a kind of photothermal agent to generate heat through nonradiative relaxation pathways due to their strong photoabsorption in the NIR region. Therefore, PSB integrate the properties of hypoxia targeting and photothermal therapeutic agents in an "all-in-one" manner, and no postmodification is needed to achieve hypoxia-targeted cancer therapy. Moreover, as natural bacteria, noncytotoxic PSB were found to enhance immune response that induced the infiltration of cytotoxicity T lymphocyte. Our results indicate PSB specifically accumulate in hypoxic tumor regions, and they show a high efficiency in the elimination of cancer cells. This proof of concept may provide a smart therapeutic system in the field of hypoxia-targeted photothermal therapeutic platforms.
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http://dx.doi.org/10.1021/acsnano.0c08068DOI Listing
January 2021

Proton-driven transformable nanovaccine for cancer immunotherapy.

Nat Nanotechnol 2020 12 26;15(12):1053-1064. Epub 2020 Oct 26.

Laboratory of Controllable Nanopharmaceuticals, Chinese Academy of Sciences (CAS) Center for Excellence in Nanoscience and CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, Beijing, China.

Cancer vaccines hold great promise for improved cancer treatment. However, endosomal trapping and low immunogenicity of tumour antigens usually limit the efficiency of vaccination strategies. Here, we present a proton-driven nanotransformer-based vaccine, comprising a polymer-peptide conjugate-based nanotransformer and loaded antigenic peptide. The nanotransformer-based vaccine induces a strong immune response without substantial systemic toxicity. In the acidic endosomal environment, the nanotransformer-based vaccine undergoes a dramatic morphological change from nanospheres (about 100 nanometres in diameter) into nanosheets (several micrometres in length or width), which mechanically disrupts the endosomal membrane and directly delivers the antigenic peptide into the cytoplasm. The re-assembled nanosheets also boost tumour immunity via activation of specific inflammation pathways. The nanotransformer-based vaccine effectively inhibits tumour growth in the B16F10-OVA and human papilloma virus-E6/E7 tumour models in mice. Moreover, combining the nanotransformer-based vaccine with anti-PD-L1 antibodies results in over 83 days of survival and in about half of the mice produces complete tumour regression in the B16F10 model. This proton-driven transformable nanovaccine offers a robust and safe strategy for cancer immunotherapy.
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http://dx.doi.org/10.1038/s41565-020-00782-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719078PMC
December 2020

Light-activatable liposomes for repetitive on-demand drug release and immunopotentiation in hypoxic tumor therapy.

Biomaterials 2021 01 15;265:120456. Epub 2020 Oct 15.

Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China. Electronic address:

External stimuli-responsive nanomedicine with desirable repetitive on-demand drug release character is postulated to greatly accommodate patients' flexible medication regime. To this object, light-activatable liposomes (Pt/Ce6-LP) integrated with both a Ce6 photodynamic component and a tetravalent platinum prodrug (Pt(IV)) chemotherapeutic component are engineered. This multifunctional system was rationally designed using unsaturated phospholipid to achieve repetitive on-demand drug release under discontinuous light irradiation, thus performing chemo-photodynamic therapy effect and immunopotentiation in hypoxic tumor. Furthermore, glutathione (GSH) consumption during transformation from Pt(IV) prodrug to Pt(II) can avoid depletion of reactive oxygen species (ROS) in photodynamic therapy (PDT). Note this positive feedback loop appears to remodel the redox balance of HO and GSH in tumors, alleviating the hypoxic tumor microenvironment. The alleviated hypoxia is found to be critical to the enhancement of PDT efficacy, reversal of cisplatin resistance in tumors, and polarization of tumor-associated macrophages (TAMs) to the immunocompetent M1-phynotype. Pt/Ce6-LP with light radiation demonstrates significant antitumor effect and persistent post-medication inhibition in patient-derived tumor xenograft model of hepatocellular carcinoma.
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http://dx.doi.org/10.1016/j.biomaterials.2020.120456DOI Listing
January 2021

Near-Infrared Light Irradiation Induced Mild Hyperthermia Enhances Glutathione Depletion and DNA Interstrand Cross-Link Formation for Efficient Chemotherapy.

ACS Nano 2020 11 21;14(11):14831-14845. Epub 2020 Oct 21.

Beijing National Laboratory for Molecular Sciences, State Key Laboratory of Polymer Physics and Chemistry, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China.

DNA alkylating agents generally kill tumor cells by covalently binding with DNA to form interstrand or intrastrand cross-links. However, in the case of cisplatin, only a few DNA adducts (<1%) are highly toxic irreparable interstrand cross-links. Furthermore, cisplatin is rapidly detoxified by high levels of intracellular thiols such as glutathione (GSH). Since the discovery of its mechanism of action, people have been looking for ways to directly and efficiently remove intracellular GSH and increase interstrand cross-links to improve drug efficacy and overcome resistance, but there has been little breakthrough. Herein, we hypothesized that the anticancer efficiency of cisplatin can be enhanced through iodo-thiol click chemistry mediated GSH depletion and increased formation of DNA interstrand cross-links mild hyperthermia triggered by near-infrared (NIR) light. This was achieved by preparing an amphiphilic polymer with platinum(IV) (Pt(IV)) prodrugs and pendant iodine atoms (iodides). The polymer was further used to encapsulate IR780 and assembled into Pt-I-IR780 nanoparticles. Induction of mild hyperthermia (43 °C) at the tumor site by NIR light irradiation had three effects: (1) it accelerated the GSH-mediated reduction of Pt(IV) in the polymer main chain to platinum(II) (Pt(II)); (2) it boosted the iodo-thiol substitution click reaction between GSH and iodide, thereby attenuating the GSH-mediated detoxification of cisplatin; (3) it increased the proportion of highly toxic and irreparable Pt-DNA interstrand cross-links. Therefore, we find that mild hyperthermia induced NIR irradiation can enhance the killing of cancer cells and reduce the tumor burden, thus delivering efficient chemotherapy.
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http://dx.doi.org/10.1021/acsnano.0c03781DOI Listing
November 2020

Artificial Nanotargeted Cells with Stable Photothermal Performance for Multimodal Imaging-Guided Tumor-Specific Therapy.

ACS Nano 2020 10 1;14(10):12652-12667. Epub 2020 Oct 1.

Department of Ultrasound, Chongqing Key Laboratory of Ultrasound Molecular Imaging, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China.

Organic-inorganic hybrid materials have drawn increasing attention as photothermal agents in tumor therapy due to the advantages of green synthesis, high loading efficiency of hydrophobic drugs, facile incorporation of theranostic iron, and excellent photothermal efficiency without inert components or additives. Herein, we proposed a strategy for biomimetic engineering-mediated enhancement of photothermal performance in the tumor microenvironment (TME). This strategy is based on the specific characteristics of organic-inorganic hybrid materials and endows these materials with homologous targeting ability and photothermal stability in the TME. The hybrid materials perform the functions of cancer cells to target homolytic tumors (acting as "artificial nanotargeted cells (ANTC)"). Inspired by the pH-dependent disassembly behaviors of tannic acid (TA) and ferric ion (Fe) and subsequent attenuation of photothermal performance, cancer cell membranes were self-deposited onto the surfaces of protoporphyrin-encapsulated TA and Fe nanoparticles to achieve ANTC with TME-stable photothermal performance and tumor-specific phototherapy. The resulting ANTC can be used as contrast agents for concurrent photoacoustic imaging, magnetic resonance imaging, and photothermal imaging to guide the treatment. Importantly, the high loading efficiency of protoporphyrin enables the initiation of photodynamic therapy to enhance photothermal therapeutic efficiency, providing antitumor function with minimal side effects.
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http://dx.doi.org/10.1021/acsnano.0c00771DOI Listing
October 2020

Fighting against Drug-Resistant Tumors using a Dual-Responsive Pt(IV)/Ru(II) Bimetallic Polymer.

Adv Mater 2020 Oct 22;32(43):e2004766. Epub 2020 Sep 22.

CAS Key Laboratory of Soft Matter Chemistry, Hefei National Laboratory for Physical Sciences at the Microscale, Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei, 230026, China.

Drug resistance is a major problem in cancer treatment. Herein, the design of a dual-responsive Pt(IV)/Ru(II) bimetallic polymer (PolyPt/Ru) to treat cisplatin-resistant tumors in a patient-derived xenograft (PDX) model is reported. PolyPt/Ru is an amphiphilic ABA-type triblock copolymer. The hydrophilic A blocks consist of biocompatible poly(ethylene glycol) (PEG). The hydrophobic B block contains reduction-responsive Pt(IV) and red-light-responsive Ru(II) moieties. PolyPt/Ru self-assembles into nanoparticles that are efficiently taken up by cisplatin-resistant cancer cells. Irradiation of cancer cells containing PolyPt/Ru nanoparticles with red light generates O , induces polymer degradation, and triggers the release of the Ru(II) anticancer agent. Meanwhile, the anticancer drug, cisplatin, is released in the intracellular environment via reduction of the Pt(IV) moieties. The released Ru(II) anticancer agent, cisplatin, and the generated O have different anticancer mechanisms; their synergistic effects inhibit the growth of drug-resistant cancer cells. Furthermore, PolyPt/Ru nanoparticles inhibit tumor growth in a PDX mouse model because they circulate in the bloodstream, accumulate at tumor sites, exhibit good biocompatibility, and do not cause side effects. The results demonstrate that the development of stimuli-responsive multi-metallic polymers provides a new strategy to overcome drug resistance.
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http://dx.doi.org/10.1002/adma.202004766DOI Listing
October 2020

Real-Time Pharmaceutical Evaluations of Near-Infrared II Fluorescent Nanomedicine Bound Polyethylene Glycol Ligands for Tumor Photothermal Ablation.

ACS Nano 2020 10 17;14(10):13681-13690. Epub 2020 Sep 17.

Translational Medicine Center, Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences & The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, P. R. China.

Pharmaceutical evaluations of nanomedicines are of great significance for their further launch into industry and clinic. Near-infrared (NIR) fluorescence imaging plays essential roles in preclinical drug development by providing important insights into the biodistributions of drugs with deep tissue penetration and high spatiotemporal resolution. However, NIR-II fluorescence imaging has rarely been exploited for real-time pharmaceutical evaluations of nanomedicine. Herein, we developed a highly emissive NIR-II luminophore to establish a versatile nanoplatform to noninvasively monitor the metabolism of nanomedicines bound various polyethylene glycol (PEG) ligands in a real-time manner. An alternative D-A-D conjugated oligomer (DTTB) was synthesized to achieve NIR-II emission peaked at ∼1050 nm with high fluorescence QYs of 13.4% and a large absorption coefficient. By anchoring with the DTTB molecule, intrinsically fluorescent micelles were fabricated and bound with PEG ligands at various chain lengths. NIR-II fluorescence and photoacoustic imaging results revealed that an appropriate PEG chain length could effectively contribute to the longer blood circulation and better tumor targeting. therapeutic experiments also confirmed the optimized nanomedicines have efficient photothermal elimination of tumors and good biosafety. This work offered an alternative highly fluorescent NIR-II material and demonstrated a promising approach for real-time pharmaceutical evaluation of nanomedicine .
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http://dx.doi.org/10.1021/acsnano.0c05885DOI Listing
October 2020

Nanoscale drug delivery systems for controllable drug behaviors by multi-stage barrier penetration.

J Control Release 2021 03 29;331:282-295. Epub 2020 Aug 29.

CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, No. 11, First North Road, Zhongguancun, Beijing 100190, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China. Electronic address:

Due to the poor physicochemical properties of drugs and multi-stage biological barriers in vivo, drugs at action site cannot reach up to sufficient concentration to acquire expected therapeutic outcomes, which may conversely lead to side effects to normal tissues and organs. In recent years, nanoscale drug delivery systems (NDDS) have developed rapidly to effectively deliver drugs to target site. In addition to avoiding drug degradation and preserving drug physicochemical properties, NDDS with controllable drug behaviors on tissues, cells, and organelles can be applied to break through multi-stage barriers and manipulate drug metabolism. But poor knowledge of various biological barriers still hinders the development of NDDS. Hence, this review is to dissect the vital influence of biological barriers in pharmaceutical research and introduce strategies for manipulating drug behaviors by crossing multi-stage biological barriers. Moreover, setbacks faced in the development of nanotechnology-based formulations are analyzed, which brings systematic thinking in the field of drug delivery. By addressing these barriers and understanding the principles behind, the current review provides a new insight into the rational design of NDDS and promotes the development of nanomedicine.
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http://dx.doi.org/10.1016/j.jconrel.2020.08.045DOI Listing
March 2021

Efficient hepatic delivery and protein expression enabled by optimized mRNA and ionizable lipid nanoparticle.

Bioact Mater 2020 Dec 13;5(4):1053-1061. Epub 2020 Jul 13.

School of Life Science, Advanced Research Institute of Multidisciplinary Science, Institute of Engineering Medicine, Key Laboratory of Molecular Medicine and Biotherapy, Beijing Institute of Technology, Beijing, 100081, China.

mRNA is a novel class of therapeutic modality that holds great promise in vaccination, protein replacement therapy, cancer immunotherapy, immune cell engineering However, optimization of mRNA molecules and efficient delivery are quite important but challenging for its broad application. Here we present an ionizable lipid nanoparticle (iLNP) based on iBL0713 lipid for and expression of desired proteins using codon-optimized mRNAs. mRNAs encoding luciferase or erythropoietin (EPO) were prepared by transcription and formulated with proposed iLNP, to form iLP171/mRNA formulations. It was revealed that both luciferase and EPO proteins were successfully expressed by human hepatocellular carcinoma cells and hepatocytes. The maximum amount of protein expression was found at 6 h post-administration. The expression efficiency of EPO with codon-optimized mRNA was significantly higher than that of unoptimized mRNA. Moreover, no toxicity or immunogenicity was observed for these mRNA formulations. Therefore, our study provides a useful and promising platform for mRNA therapeutic development.
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http://dx.doi.org/10.1016/j.bioactmat.2020.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7355334PMC
December 2020

Prodrug-Based Nanoreactors with Tumor-Specific Activation for Multisynergistic Cancer Therapy.

ACS Appl Mater Interfaces 2020 Aug 22;12(31):34667-34677. Epub 2020 Jul 22.

Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, Chemical Biology Key Laboratory of Hebei Province, Hebei University, Baoding 071002, China.

Efficient drug delivery into tumor cells while bypassing many biological barriers is still a challenge for cancer therapy. By taking advantage of the palladium (Pd)-mediated activation of a prodrug and the glucose oxidase (GOD)-based β-d-glucose oxidation reaction, we developed a multisynergistic cancer therapeutic platform that combined doxorubicin (DOX)-induced chemotherapy with GOD-mediated cancer-orchestrated oxidation therapy and cancer starvation therapy. In the present work, we first synthesized DOX prodrugs (pDOXs) and temporarily assembled them with β-cyclodextrins to reduce their toxic side effects. Then, a nanoreactor was constructed by synthesizing Pd nanoparticles within the pores of mesoporous silica nanoparticles for the conversion of pDOX into the active anticancer drug. Furthermore, GOD was introduced to decrease the pH of the tumor microenvironment and induce cancer-orchestrated oxidation/starvation therapy by catalyzing β-d-glucose oxidation to form hydrogen peroxide (HO) and gluconic acid. Our study provides a new strategy that employs a cascade chemical reaction to achieve combined orchestrated oxidation/starvation/chemotherapy for the synergistic killing of cancer cells and the suppression of tumor growth.
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http://dx.doi.org/10.1021/acsami.0c09489DOI Listing
August 2020

Superhydrophilic fluorinated polymer and nanogel for high-performance F magnetic resonance imaging.

Biomaterials 2020 10 17;256:120184. Epub 2020 Jun 17.

Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300192, PR China. Electronic address:

F magnetic resonance imaging (F MRI), a kind of non-invasive and non-radioactive diagnostic technique with no endogenous background signals, opens up new research avenues for accurate molecular imaging studies. However, F MRI is manily limited by the performance of contrast agents. Here, for the first time, we presented the zwitterionic fluorinated polymer and nanogel as new types of superhydrophilic, sensitive and ultra-stable F MRI contrast agents. The superhydrophilicity of carboxybetaine zwitterionic structure completely overcame the hydrophobic aggregation-induced signal attenuation associated with amphiphilic fluorinated polymer-based nanoprobes. In addition, the superhydrophilic contrast agent exhibited distinct advantages, including high F-content (19.1 wt%), superior resistance to protein adsorption, constant MR properties and F MRS-based quantitative determination in complex biological fluids, and intense F MRI signals in the whole-body images after intravenous injection. In combination with angiogenesis targeting ligand, the superhydrophilic contrast agent was applied for the unambiguous detection of tumor. Importantly, computational algorithm was established for the directly quantitative determination of bioavailability and tumor-to-whole body ratio (TBR) from the in vivoF MRI dataset, providing real-time information with non-invasive manner. Finally, crosslinked nanogels were developed with significantly prolonged systemic circulation, of which intense F MRI signals nonspecifically distributed in the aortaventralis and blood-rich organs, instead of being trapped steadily in liver as with the state-of-the-art superhydrophobic perfluocarbon nanoemulsions. Overall, this kind of superhydrophilic, zwitterionic fluorinated polymer and nanogel could be defined as a new generation of high-performance F MRI contrast agents, which hold great potential for image-based unambiguous disease detection and computational quantification.
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http://dx.doi.org/10.1016/j.biomaterials.2020.120184DOI Listing
October 2020

Dually Enzyme- and Acid-Triggered Self-Immolative Ketal Glycoside Nanoparticles for Effective Cancer Prodrug Monotherapy.

Nano Lett 2020 07 23;20(7):5465-5472. Epub 2020 Jun 23.

Key Laboratory of Functional Polymer Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Institute of Polymer Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China.

The use of glycoside prodrugs is a promising strategy for developing new targeted medicines for chemotherapy. However, the utility of such prodrugs is hindered by insufficient activation and the lack of convenient synthetic methods. We have developed an innovative strategy for synthesizing ketal glycoside prodrugs that are unique in being activated by a dual enzyme- and acid-triggered self-immolative mechanism. Amphiphilic glucosyl acetone-based ketal-linked etoposide glycoside prodrug isomers were synthesized and fabricated into excipient-free nanoparticles for effective cancer prodrug monotherapy. Hydrolysis of the glycosidic linkage or the ketal linkage triggered hydrolysis of the other linkage, which resulted in spontaneous self-immolative hydrolysis of the prodrugs. Nanoparticles of the prodrug isomer that was the most labile in a lysosome-mimicking environment displayed high intratumoral accumulation and strong antitumor activity in an A549 xenograft mouse model. Our strategy may be useful for the development of stimulus-responsive self-immolative prodrugs and their nanomedicines.
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http://dx.doi.org/10.1021/acs.nanolett.0c01973DOI Listing
July 2020

Therapeutic siRNA: state of the art.

Signal Transduct Target Ther 2020 06 19;5(1):101. Epub 2020 Jun 19.

Chinese Academy of Sciences (CAS), Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, 100190, Beijing, People's Republic of China.

RNA interference (RNAi) is an ancient biological mechanism used to defend against external invasion. It theoretically can silence any disease-related genes in a sequence-specific manner, making small interfering RNA (siRNA) a promising therapeutic modality. After a two-decade journey from its discovery, two approvals of siRNA therapeutics, ONPATTRO (patisiran) and GIVLAARI™ (givosiran), have been achieved by Alnylam Pharmaceuticals. Reviewing the long-term pharmaceutical history of human beings, siRNA therapy currently has set up an extraordinary milestone, as it has already changed and will continue to change the treatment and management of human diseases. It can be administered quarterly, even twice-yearly, to achieve therapeutic effects, which is not the case for small molecules and antibodies. The drug development process was extremely hard, aiming to surmount complex obstacles, such as how to efficiently and safely deliver siRNAs to desired tissues and cells and how to enhance the performance of siRNAs with respect to their activity, stability, specificity and potential off-target effects. In this review, the evolution of siRNA chemical modifications and their biomedical performance are comprehensively reviewed. All clinically explored and commercialized siRNA delivery platforms, including the GalNAc (N-acetylgalactosamine)-siRNA conjugate, and their fundamental design principles are thoroughly discussed. The latest progress in siRNA therapeutic development is also summarized. This review provides a comprehensive view and roadmap for general readers working in the field.
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http://dx.doi.org/10.1038/s41392-020-0207-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305320PMC
June 2020
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