Surface Nanopore Engineering of 2D MXenes for Targeted and Synergistic Multitherapies of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is one of the most common and deadly gastrointestinal malignancies. Given its insensitivity to traditional systematic chemotherapy, new therapeutic strategies for efficient HCCs treatment are urgently needed. Here, the development of a novel 2D MXene‐based composite nanoplatform for highly efficient and synergistic chemotherapy and photothermal hyperthermia against HCC is reported. A surface‐nanopore engineering strategy is developed for the MXenes’ surface functionalization, which achieves the uniform coating of a thin mesoporous‐silica layer onto the surface of 2D Ti₃C₂ MXene (Ti₃C₂@mMSNs). This strategy endows MXenes with well‐defined mesopores for on‐demand drug release/delivery, enhanced hydrophilicity/dispersity, and abundant surface chemistry for targeting engineering. Systematic in vitro and in vivo evaluations have demonstrated the high active‐targeting capability of arginine‐glycine‐aspartic acid (RGD)‐targeting Ti₃C₂@mMSNs into tumor, and the synergistic chemotherapy (contributed by the mesoporous shell) and photothermal hyperthermia (contributed by the Ti₃C₂ MXene core) completely eradicate the tumor without obvious reoccurrence. This work not only provides a novel strategy for efficiently combating HCC by developing MXene‐based composite nanoplatforms, but also paves a new way for extending the biomedical applications of MXenes by surface‐nanopore engineering.     

A Hypoxia‐Responsive Albumin‐Based Nanosystem for Deep Tumor Penetration and Excellent Therapeutic Efficacy

Uncontrolled cancer cell proliferation, insufficient blood flow, and inadequate endogenous oxygen lead to hypoxia in tumor tissues. Herein, a unique type of hypoxia‐responsive human serum albumin (HSA)‐based nanosystem (HCHOA) is reported, prepared by cross‐linking the hypoxia‐sensitive azobenzene group between photosensitizer chlorin e6 (Ce6)‐conjugated HSA (HC) and oxaliplatin prodrug‐conjugated HSA (HO). The HCHOA nanosystem is stable under normal oxygen partial pressure with a size of 100–150 nm. When exposed to the hypoxic tumor microenvironment, the nanosystem can quickly dissociate into ultrasmall HC and HO therapeutic nanoparticles with a diameter smaller than 10 nm, significantly enabling their enhanced intratumoral penetration. After the dissociation, the quenched fluorescence of Ce6 in the produced HC nanoparticles can be recovered for bioimaging. At the same time, the production of singlet oxygen is increased because of the enhancement in the photoactivity of the photosensitizer. On account of these improvements, combined photodynamic therapy and chemotherapy is realized to display superior antitumor efficacy in vivo. Based on this simple strategy, it is possible to achieve the dissociation of hypoxic‐responsive nanosystem to enhance the tumor penetration and therapeutic effect.     

A Time‐Programmed Release of Dual Drugs from an Implantable Trilayer Structured Fiber Device for Synergistic Treatment of Breast Cancer

Combination chemotherapy with time‐programmed administration of multiple drugs is a promising method for cancer treatment. However, realizing time‐programmed release of combined drugs from a single carrier is still a great challenge in enhanced cancer therapy. Here, an implantable trilayer structured fiber device is developed to achieve time‐programmed release of combined drugs for synergistic treatment of breast cancer. The fiber device is prepared by a modified microfluidic‐electrospinning technique. The glycerol solution containing chemotherapy agent doxorubicin (Dox) forms the internal periodic cavities of the fiber, and poly(l ‐lactic acid) and poly(ε‐caprolactone) containing the angiogenesis inhibitor apatinib (Apa) form the double walls of the fiber. Rapid release of Dox can be obtained by adjusting the wall thickness of the cavities, meanwhile sustained release of Apa is achieved through the slow degradation of the fiber matrix. After the fiber device is implanted subcutaneously near to the implanted solid tumor of mice, an excellent synergistic therapeutic effect is achieved through time‐programmed release of the combined dual drugs. The fiber device provides a platform to sequentially co‐deliver dual or multiple drugs for enhanced combined therapeutic efficacy.     

Photoactivated Trifunctional Platinum Nanobiotics for Precise Synergism of Multiple Antibacterial Modes

Integrating multiple strategies of antibacterial mechanisms into one has been proven to have tremendous promise for improving antimicrobial efficiency. Hence, dual‐valent platinum nanoparticles (dvPtNPs) with a zero‐valent platinum core (Pt⁰) and bi‐valent platinum shell (Pt²⁺ ions), combining photothermal and photodynamic therapy, together with “chemotherapy,” emerge as spatiotemporally light‐activatable platinum nano‐antibiotics. Under near‐infrared (NIR) exposure, the multiple antibacterial modes of dvPtNPs are triggered. The Pt⁰ core reveals significant hyperthermia via effective photothermal conversion while an immediate release of chemotherapeutic Pt²⁺ ions occurs through hyperthermia‐initiated destabilization of metallic interactions, together with reactive oxygen species (ROS) level increase, thereby resulting in synergistic antibacterial effects. The precise cooperative effects between photothermal, photodynamic, and Pt²⁺ antibacterial effects are achieved on both Gram‐negative Escherichia coli and Gram‐positive methicillin‐resistant Staphylococcus aureus, where bacterial viability and colony‐forming units are significantly reduced. Moreover, similar results are observed in mice subcutaneous abscess models. Significantly, after NIR treatment, dvPtNP exhibits a more robust bacteria‐killing efficiency than other PtNP groups, owing to its integration of dramatic damage to the bacterial membrane and DNA, and alteration to ATP and ROS metabolism. This study broadens the avenues for designing and synthesizing antibacterial materials with higher efficiency.     

pH‐Responsive PEG‐Shedding and Targeting Peptide‐Modified Nanoparticles for Dual‐Delivery of Irinotecan and microRNA to Enhance Tumor‐Specific Therapy

Irinotecan is one of the main chemotherapeutic agents for colorectal cancer (CRC). MicroRNA‐200 (miR‐200) has been reported to inhibit metastasis in cancer cells. Herein, pH‐sensitive and peptide‐modified liposomes and solid lipid nanoparticles (SLN) are designed for encapsulation of irinotecan and miR‐200, respectively. These peptides include one cell‐penetrating peptide, one ligand targeted to tumor neovasculature undergoing angiogenesis, and one mitochondria‐targeting peptide. The peptide‐modified nanoparticles are further coated with a pH‐sensitive PEG‐lipid derivative with an imine bond. These specially‐designed nanoparticles exhibit pH‐responsive release, internalization, and intracellular distribution in acidic pH of colon cancer HCT116 cells. These nanoparticles display low toxicity to blood and noncancerous intestinal cells. Delivery of miR‐200 by SLN further increases the cytotoxicity of irinotecan‐loaded liposomes against CRC cells by triggering apoptosis and suppressing RAS/β‐catenin/ZEB/multiple drug resistance (MDR) pathways. Using CRC‐bearing mice, the in vivo results further indicate that irinotecan and miR‐200 in pH‐responsive targeting nanoparticles exhibit positive therapeutic outcomes by inhibiting colorectal tumor growth and reducing systemic toxicity. Overall, successful delivery of miR and chemotherapy by multifunctional nanoparticles may modulate β‐catenin/MDR/apoptosis/metastasis signaling pathways and induce programmed cancer cell death. Thus, these pH‐responsive targeting nanoparticles may provide a potential regimen for effective treatment of colorectal cancer.     

A General Hypoxia-Responsive Molecular Container for Tumor-Targeted Therapy

Enhanced drug delivery can improve the therapeutic efficacy of drugs and help overcome side effects. However, many reported drug-delivery systems are too complex and irreproducible for practical use. In this work, the design of a hypoxia-responsive molecular container based on calixarene, called CAC4A, which presents a significant advance in practical, hypoxia-targeted drug-delivery, is reported. CAC4A enables a wide variety of clinical drugs to be quantitatively loaded to improve their solubility and stability, as well as enable the administration of reduced doses. Furthermore, as a result of its azo functional groups, which are sensitive to reduction within a hypoxic environment, it is possible to achieve tumor-targeted drug-release with reduced side effects. CAC4A fulfils all essential requirements for a drug-delivery system in addition to multiple advantages, including facile preparation, well-defined molecular weight, and structure, and universal applicability. Such features collectively enable supramolecular prodrugs to be formulated simply and reproducibly, with potential for bench-to-bedside translation. Moreover, CAC4A is amenable to other therapy modalities and can be facilely decorated with functional groups and hybridized with nanomaterials, providing ample possibilities for its role in future drug-delivery systems.     

Towards Light-Activated Ruthenium–Arene (RAPTA-Type) Prodrug Candidates

Cancer is currently one of the deadliest diseases worldwide. Based on the high incidence of this disease, the side effects associated with current chemotherapies and the appearance of drug resistance, considerable efforts have been directed towards the development of new anticancer drugs with new modes of action. Metal-based compounds are particularly attractive candidates due to their metabolic mechanisms, which differ substantially from those of organic drugs. Of special interest in this context are organometallic ruthenium(II) complexes of the type [Ru(η⁶-arene)(pta)Cl₂] (arene: p-cymene, toluene, benzene, etc.; pta: 1,3,5-triaza-7-phosphaadamantane), which are abbreviated to RAPTA. Complementary to chemotherapy, photoactivated chemotherapy is a technique that has received increasing attention towards the development of treatment for numerous kinds of cancer. With this in mind, a photoactive RAPTA-type complex bearing azide ligands has been designed. The diazide complex, [Ru(η⁶-p-cymene)pta-(N₃)₂], is inert in water, but slowly releases the azide ligand upon exposure to light. Consequently, the in vitro cytotoxicity of the complex in the dark and upon light exposure at λ=450 nm in human cervical carcinoma (HeLa) and noncancerous retinal pigment epithelium (RPE-1) cells was investigated. Although the cytotoxicity of the complex was found to be modest in the dark, an increase in toxicity upon light exposure was observed.     

Prebiotics: A Potential Treatment Strategy for the Chemotherapy-damaged Gut?

Mucositis, characterized by ulcerative lesions along the alimentary tract, is a common consequence of many chemotherapy regimens. Chemotherapy negatively disrupts the intestinal microbiota, resulting in increased numbers of potentially pathogenic bacteria, such as Clostridia and Enterobacteriaceae, and decreased numbers of “beneficial” bacteria, such as Lactobacilli and Bifidobacteria. Agents capable of restoring homeostasis in the bowel microbiota could, therefore, be applicable to mucositis. Prebiotics are indigestible compounds, commonly oligosaccharides, that seek to reverse chemotherapy-induced intestinal dysbiosis through selective colonization of the intestinal microbiota by probiotic bacteria. In addition, evidence is emerging that certain prebiotics contribute to nutrient digestibility and absorption, modulate intestinal barrier function through effects on mucin expression, and also modify mucosal immune responses, possibly via inflammasome-mediated processes. This review examines the known mechanisms of prebiotic action, and explores their potential for reducing the severity of chemotherapy-induced mucositis in the intestine.     

靶向药物曲妥珠单抗联合化疗对人类表皮生长因子受体2阳性局部晚期乳腺癌患者临床疗效研究

目的: 观察曲妥珠单抗联合化疗对人类表皮生长因子受体2(HER-2)阳性的局部晚期乳腺癌(LABC)临床治疗结果。方法: 将228例HER-2阳性手术无法切除的晚期乳腺癌病例随机分到曲妥珠单抗辅助疗法+化疗组或单纯化疗组。其中115例接受曲妥珠单抗+化疗,113例单纯接受化疗,经过10个疗程治疗后,观察两组患者中临床和病理的完全缓解人数及符合手术要求的人数。结果: 数据显示与单纯化疗相比,曲妥珠单抗+化疗组病例对治疗的临床完全缓解病例(cCR)(化疗+曲妥珠单抗组89%,单纯化疗组77%)、病理学完全缓解(pCR)病例(两组分别为43%和23%)以及乳房和腋下淋巴结完全缓解(tpCR)病例(分别为39%和20%)比例更高,同时可以使更多的患者获得手术和保留乳房的机会。结论: 曲妥珠单抗联合化疗药物治疗HER-2过度表达的局部晚期乳腺癌均有较好的临床疗效,是治疗晚期乳癌并延长生存时间的一种新方法。     

多种口服升白药物治疗化疗相关白细胞减少症的实验研究

目的: 通过小鼠实验研究评价5种常用口服升白细胞药物治疗化疗相关白细胞减少症的疗效。方法: 采用环磷酰胺腹腔注射法制备小鼠化疗相关白细胞减少症模型,以瑞白为阳性对照药物,分别将5种口服升白细胞药物(芪胶升白胶囊、维血宁、复方皂矾丸、升白安和利可君)灌胃,用全血细胞分析仪测定血细胞计数,解剖小鼠并将其重要脏器称重,计算脏器指数。结果: 各组小鼠死亡率无明显差别。按照升白细胞计数的功效,从高到低依次为瑞白、利可君、升白安、维血宁、芪胶升白胶囊、复方皂矾丸,其中芪胶升白胶囊、复方皂矾丸升白细胞作用不明显;除此之外,升白安、利可君还可以提高红细胞计数、血红蛋白浓度及血小板计数。心、脾、肺3个脏器的脏器指数受较多的药物影响,就单种药物而言,升白安对脏器的影响最小,而复方皂矾丸影响的脏器最多。结论: 瑞白提升白细胞效果最佳,其次是利可君,升白安对血三系提升均有一定的作用,且对脏器的影响最小。