A Biomimetic Polymer Magnetic Nanocarrier Polarizing Tumor‐Associated Macrophages for Potentiating Immunotherapy

The progress of antitumor immunotherapy is usually limited by tumor‐associated macrophages (TAMs) that account for the highest proportion of immunosuppressive cells in the tumor microenvironment, and the TAMs can also be reversed by modulating the M2‐like phenotype. Herein, a biomimetic polymer magnetic nanocarrier is developed with selectively targeting and polarizing TAMs for potentiating immunotherapy of breast cancer. This nanocarrier PLGA‐ION‐R837 @ M (PIR @ M) is achieved, first, by the fabrication of magnetic polymer nanoparticles (NPs) encapsulating Fe₃O₄ NPs and Toll‐like receptor 7 (TLR7) agonist imiquimod (R837) and, second, by the coating of the lipopolysaccharide (LPS)‐ treated macrophage membranes on the surface of the NPs for targeting TAMs. The intracellular uptake of the PIR @ M can greatly polarize TAMs from M2 to antitumor M1 phenotype with the synergy of Fe₃O₄ NPs and R837. The relevant mechanism of the polarization is deeply studied through analyzing the mRNA expression of the signaling pathways. Different from previous reports, the polarization is ascribed to the fact that Fe₃O₄ NPs mainly activate the IRF5 signaling pathway via iron ions instead of the reactive oxygen species‐induced NF‐κB signaling pathway. The anticancer effect can be effectively enhanced through potentiating immunotherapy by the polarization of the TAMs in the combination of Fe₃O₄ NPs and R837.     

Intra/Extracellular Lactic Acid Exhaustion for Synergistic Metabolic Therapy and Immunotherapy of Tumors

Regulating the tumor microenvironment (TME) has been a promising strategy to improve antitumor therapy. Here, a red blood cell membrane (mRBC)‐camouflaged hollow MnO₂ (HMnO₂) catalytic nanosystem embedded with lactate oxidase (LOX) and a glycolysis inhibitor (denoted as PMLR) is constructed for intra/extracellular lactic acid exhaustion as well as synergistic metabolic therapy and immunotherapy of tumor. Benefiting from the long‐circulation property of the mRBC, the nanosystem can gradually accumulate in a tumor site through the enhanced permeability and retention (EPR) effect. The extracellular nanosystem consumes lactic acid in the TME by catalyzing its oxidation reaction via LOX. Meanwhile, the intracellular nanosystem releases the glycolysis inhibitor to cut off the source of lactic acid, as well as achieve antitumor metabolic therapy through the blockade of the adenosine triphosphate (ATP) supply. Both the extracellular and intracellular processes can be sensitized by O₂, which can be produced during the decomposition of endogenous H₂O₂ catalyzed by the PMLR nanosystem. The results show that the PMLR nanosystem can ceaselessly remove lactic acid, and then lead to an immunocompetent TME. Moreover, this TME regulation strategy can effectively improve the antitumor effect of anti‐PDL1 therapy without the employment of any immune agonists to avoid the autoimmunity.     

反应挤出在聚乳酸合成及改性中的应用进展

综述了反应挤出技术的特点以及历史发展概况,主要从反应挤出聚合、反应挤出接枝以及反应挤出共混3个方面总结了反应挤出技术在聚乳酸材料的制备和改性中的应用情况,指出了其在聚乳酸材料领域的重要地位,并展望了其在未来的发展趋势.     

聚乳酸接枝硅烷偶联剂的制备及对聚乳酸/木粉复合材料的影响

通过反应挤出制备了聚乳酸接枝γ-(甲基丙烯酰氧基)丙基三甲氧基硅(PLA-g-MPS),研究其在聚乳酸/木粉(PLA/WF)复合材料中的偶联作用。核磁共振氢谱证实MPS已接枝到PLA上。使用溶剂洗脱复合材料粒子中的PLA相从而得到WF相,对其红外光谱的分析表明PLA-g-MPS可与WF发生共价键偶联作用。力学性能测试表明,在大分子偶联剂用量仅为3%时,相比未添加的复合材料,拉伸强度、弯曲强度和冲击强度分别提高17.5%,12.4%和88.4%。对复合材料的动态力学分析表明,添加大分子偶联剂会提升PLA与WF间相互作用力从而使材料在玻璃态下的储能模量升高。     

Inhibiting Solid Tumor Growth In Vivo by Non‐Tumor‐Penetrating Nanomedicine

Nanomedicine (NM) cannot penetrate deeply into solid tumors, which is partly attributed to the heterogeneous microenvironment and high interstitial fluid pressure of solid tumors. To improve NM efficacy, there has been tremendous effort developing tumor‐penetrating NMs by miniaturizing NM sizes or controlling NM surface properties. But progress along the direction of developing tumor penetrating nanoparticle has been slow and improvement of the overall antitumor efficacy has been limited. Herein, a novel strategy of inhibiting solid tumor with high efficiency by dual‐functional, nontumor‐penetrating NM is demonstrated. The intended NM contains 5,6‐dimethylxanthenone‐4‐acetic acid (DMXAA), a vascular‐disrupting agent, and doxorubicin (DOX), a cytotoxic drug. Upon arriving at the target tumor site, sustained release of DMXAA from NMs results in disruption of tumor vessel functions, greatly inhibiting the interior tumor cells by cutting off nutritional supply. Meanwhile, the released DOX kills the residual cells at the tumor exterior regions. The in vivo studies demonstrate that this dual‐functional, nontumor penetrating NM exhibits superior anticancer activity, revealing an alternative strategy of effective tumor growth inhibition.     

Hyaluronic Acid–Based Activatable Nanomaterials for Stimuli‐Responsive Imaging and Therapeutics: Beyond CD44‐Mediated Drug Delivery

There is a rapidly increasing interest in developing stimuli‐responsive nanomaterials for treating a variety of diseases. By enabling the activation of function locally at the sites of interest, it is possible to increase therapeutic efficacy significantly while simultaneously reducing adverse side effects. While there are many sophisticated nanomaterials available, they are often highly complex and not easily transferrable to industrial scales and clinical settings. However, nanomaterials based on hyaluronic acid offer a compelling strategy for reducing their complexity while retaining several desirable benefits such as active targeting and stimuli‐responsive degradation. Herein, the basic properties of hyaluronic acid, its binding partners, and natural routes for degradation by hyaluronidases—hyaluronic‐acid‐degrading enzymes—and oxidative stresses are discussed. Recent advances in designing hyaluronic acid–based, actively targeted, hyaluronidase‐ or reactive‐oxygen‐species‐responsive nanomaterials for both diagnostic imaging and therapeutic delivery, which go beyond merely the classical targeting of CD44, are summarized.     

聚乳酸复合纳米纤维创面敷料的制备及性能

采用静电纺丝技术制备了聚乳酸(PLLA)纳米纤维毡、壳聚糖/PLLA纳米纤维毡和明胶/PLLA纳米纤维毡。利用扫描电镜(SEM)、图像分析软件等手段研究了纳米纤维微观形貌,并研究各种创面敷料的吸水性、保水性和水蒸汽通透性等性能。结果表明,壳聚糖/PLLA、明胶/PLLA复合纳米纤维毡的吸水性和保水性有显著提高,水蒸汽通透性略有下降,是理想的创面敷料材料。     

Electrochemical Monitoring of Paclitaxel‐Induced ROS Release from Mitochondria inside Single Cells

Mitochondria are believed to be the major source of intracellular reactive oxygen species (ROS). However, in situ, real‐time and quantitative monitoring of ROS release from mitochondria that are present in their cytosolic environment remains a great challenge. In this work, a platinized SiC@C nanowire electrode is placed into a single cell for in situ detection of ROS signals from intracellular mitochondria, and antineoplastic agent (paclitaxel) induced ROS production is successfully recorded. Further investigations indicate that complex IV (cytochrome c oxidase, COX) is the principal site for ROS generation, and significantly more ROS are generated from mitochondria in cancer cells than that from normal cells. This work provides an effective approach to directly monitor intracellular mitochondria by nanowire electrodes, and consequently obtains important physiological evidence on antineoplastic agent‐induced ROS generation, which will be of great benefit for better understanding of chemotherapy at subcellular levels.     

Potent‐By‐Design: Amino Acids Mimicking Porous Nanotherapeutics with Intrinsic Anticancer Targeting Properties

Exogenous sources of amino acids are essential nutrients to fuel cancer growth. Here, the increased demand for amino acid displayed by cancer cells is unconventionally exploited as a design principle to replete cancer cells with apoptosis inducing nanoscopic porous amino acid mimics (Nano‐PAAM). A small library consisting of nine essential amino acids nanoconjugates (30 nm) are synthesized, and the in vitro anticancer activity is evaluated. Among the Nano‐PAAMs, l ‐phenylalanine functionalized Nano‐PAAM (Nano‐pPAAM) has emerged as a novel nanotherapeutics with excellent intrinsic anticancer and cancer‐selective properties. The therapeutic efficacy of Nano‐pPAAM against a panel of human breast, gastric, and skin cancer cells could be ascribed to the specific targeting of the overexpressed human large neutral amino acid transporter SLC7A5 (LAT‐1) in cancer cells, and its intracellular reactive oxygen species (ROS) inducing properties of the nanoporous core. At the mechanistic level, it is revealed that Nano‐pPAAM could activate both the extrinsic and intrinsic apoptosis pathways to exert a potent “double‐whammy” anticancer effect. The potential clinical utility of Nano‐pPAAM is further investigated using an MDA‐MB‐231 xenograft in NOD scid gamma mice, where an overall suppression of tumor growth by 60% is achieved without the aid of any drugs or application of external stimuli.     

基于聚乳酸两亲性共聚物的立构复合胶束与物理凝胶的研究进展

两亲性共聚物在水溶液中可形成胶束、物理凝胶等多层次自组装结构,疏水链段的结晶和立构复合是影响其胶束、物理凝胶形成的过程、结构与性能的重要因素。聚乳酸(PLA)是一种典型的生物基/生物可降解高分子,其2种对映体聚左旋乳酸(PLLA)与聚右旋乳酸(PDLA)之间可形成立构复合结晶。由于立构复合结晶中较强的链间相互作用,含PLLA和PDLA疏水链段的两亲性共聚物水溶液混合后,可形成立构复合胶束与物理凝胶,这为生物可降解、生物相容的胶束与物理凝胶材料的制备与性能调控提供了一种新方法,近年来该领域备受关注。文中介绍了基于PLA两亲性共聚物的立构复合胶束与物理凝胶的制备和性能,并从聚合物链拓扑结构设计出发,详细综述了近年来PLA立构复合胶束与物理凝胶的研究进展,以及聚合物相对分子质量、浓度、共聚组成、温度等因素对立构复合胶束和凝胶结构与性能的影响。     

ROS‐Sensitive Degradable PEG–PCL–PEG Micellar Thermogel

A reactive oxygen species (ROS)‐sensitive degradable polymer would be a promising material in designing a disease‐responsive system or accelerating degradation of polymers with slow hydrolysis kinetics. Here, a thermogelling poly(ethylene glycol)–polycaprolactone–poly(ethylene glycol) (PEG–PCL–PEG or EG₁₂–CL₂₀–EG₁₂) triblock copolymer with an oxalate group at the middle of the polymer is reported. The polymers form micelles with an average size of 100 nm in water. Thermogelation is observed in a concentration range of 8.0?37.0 wt%. In particular, the aqueous PEG–PCL–PEG triblock copolymer solutions are in a gel state at 37 °C in a concentration range of 25.0–37.0 wt%, whereas the aqueous PEG–PCL diblock copolymer solutions are in a sol state in the same concentration range at 37 °C. Thus, the gel depot could dissolve out once degradation of the triblock copolymers occurs at the oxalate group as confirmed by the in vitro experiment. In vivo gel formation is confirmed by injecting an aqueous PEG–PCL–PEG solution (36.0 wt%) into the subcutaneous layer of rats. The gel completely disappears in 21 d. A model polypeptide drug (cyclosporine A) is released over 21 d from the in situ formed gel. The micelle‐based thermogel of PEG–PCL–PEG with ROS‐triggering degradability is a promising injectable material for biomedical applications.     

Lanthanide Hydroxide Nanoparticles Induce Angiogenesis via ROS‐Sensitive Signaling

Recent studies suggest that the nanorods consisting of europium hydroxide could promote angiogenesis. In this study, it is sought to determine if additional types of nanoparticles are capable of enhancing angiogenesis and in addition, understand the underlying mechanisms. For this reason, a method is employed that combines a high throughput in vitro cell based screen coupled with an in vivo validation using vascular specific green fluorescent protein reporter transgenic zebrafish for examining proangiogenesis activity. After screening multiple types of nanoparticles, it is discovered that four of them, Eu^III(OH)₃ rods (Eu rods), Eu^III(OH)₃ spheres (Eu spheres), Tb^III(OH)₃ rods (Tb rods), and Tb^III(OH)₃ spheres (Tb spheres), are the most effective in promoting angiogenesis. It is also showed that ionic forms of europium nitrate [Eu(NO₃)₃] (Eu) and terbium nitrate [Tb(NO₃)₃] (Tb), the two lanthanide elements for these four nanoparticles, are also capable of enhancing angiogenesis. However, this effect is further enhanced by nanoparticle synthesis. Finally, it is demonstrated that reactive oxygen species H₂O₂ is a key factor in the process of proangiogenesis by lanthanide elemental nanoparticles.     

Depriving Bacterial Adhesion‐Related Molecule to Inhibit Biofilm Formation Using CeO2‐Decorated Metal‐Organic Frameworks

The formation of bacterial biofilm is one of the causes of antimicrobial resistance, often leading to persistent infections and a high fatality rate. Therefore, there is an urgent need to develop novel and effective strategies to inhibit biofilm formation. Adenosine triphosphate (ATP) plays an important role in bacterial adhesion and biofilm formation through stimulating cell lysis and extracellular DNA (eDNA) release. Herein, a simple and robust strategy for inhibiting biofilm formation is developed using CeO₂‐decorated porphyrin‐based metal‐organic frameworks (MOFs). The function of extracellular ATP (eATP) can be inhibited by CeO₂ nanoparticles, leading to the disruption of the initial adhesion of bacteria. Furthermore, planktonic bacteria can be killed by cytotoxic reactive oxygen species (ROS) generated by MOFs. As a consequence, the synergic effect of eATP deprivation and ROS generation presents excellent capacity to prevent biofilm formation, which may provide a new direction for designing flexible and effective biofilm‐inhibiting systems.     

Phthalocyanine–Virus Nanofibers as Heterogeneous Catalysts for Continuous‐Flow Photo‐Oxidation Processes

The generation of highly reactive oxygen species (ROS) at room temperature for application in organic synthesis and wastewater treatment represents a great challenge of the current chemical industry. In fact, the development of biodegradable scaffolds to support ROS‐generating active sites is an important prerequisite for the production of environmentally benign catalysts. Herein, the electrostatic cocrystallization of a cationic phthalocyanine (Pc) and negatively charged tobacco mosaic virus (TMV) is described, together with the capacity of the resulting crystals to photogenerate ROS. To this end, a novel peripherally crowded zinc Pc (1) is synthesized. With 16 positive charges, this photosensitizer shows no aqueous aggregation, and is able to act as a molecular glue in the unidimensional assembly of TMV. A step‐wise decrease of ionic strength in mixtures of both components results in exceptionally long fibers, constituted by hexagonally bundled viruses thoroughly characterized by electron and confocal microscopy. The fibers are able to produce ROS in a proof‐of‐concept microfluidic device, where they are immobilized and irradiated in several cycles, showing a resilient performance. The bottom‐up approach also enables the light‐triggered disassembly of fibers after use. This work represents an important example of a biohybrid material with projected application in light‐mediated heterogeneous catalysis.     

Dye‐Anchored MnO Nanoparticles Targeting Tumor and Inducing Enhanced Phototherapy Effect via Mitochondria‐Mediated Pathway

Phototherapy is a promising treatment method for cancer therapy. However, the various factors have greatly restricted phototherapy development, including the poor accumulation of photosensitizer in tumor, hypoxia in solid tumor tissue and systemic phototoxicity. Herein, a mitochondrial‐targeted multifunctional dye‐anchored manganese oxide nanoparticle (IR808@MnO NP) is developed for enhancing phototherapy of cancer. In this nanoplatform, IR808 as a small molecule dye acts as a tumor targeting ligand to make IR808@MnO NPs with capacity to actively target tumor cells and relocate finally in the mitochondria. Meanwhile, continuous production of oxygen (O₂) and regulation of pH induced by the high reactivity and specificity of MnO NPs toward mitochondrial endogenous hydrogen peroxide (H₂O₂) could effectively modulate tumor hypoxia and lessen the tumor subacid environment. Large amounts of reactive oxide species (ROS) are generated during the reaction process between H₂O₂ and MnO NPs. Furthermore, under laser irradiation, IR808 in IR808@MnO NPs turns O₂ into a highly toxic singlet oxygen (¹O₂) and generates hyperthermia. The results indicate that IR808@MnO NPs have the high efficiency of specific targeting of tumors, relieving tumor subacid environment, improving the tumor hypoxia environment, and generating large amounts of ROS to kill tumor cells. It is expected to have a wide application in treating cancer.