Chemotherapy-Induced Cognitive Impairment and Hippocampal Neurogenesis: A Review of Physiological Mechanisms and Interventions

A wide range of cognitive deficits, including memory loss associated with hippocampal dysfunction, have been widely reported in cancer survivors who received chemotherapy. Changes in both white matter and gray matter volume have been observed following chemotherapy treatment, with reduced volume in the medial temporal lobe thought to be due in part to reductions in hippocampal neurogenesis. Pre-clinical rodent models confirm that common chemotherapeutic agents used to treat various forms of non-CNS cancers reduce rates of hippocampal neurogenesis and impair performance on hippocampally-mediated learning and memory tasks. We review the pre-clinical rodent literature to identify how various chemotherapeutic drugs affect hippocampal neurogenesis and induce cognitive impairment. We also review factors such as physical exercise and environmental stimulation that may protect against chemotherapy-induced neurogenic suppression and hippocampal neurotoxicity. Finally, we review pharmacological interventions that target the hippocampus and are designed to prevent or reduce the cognitive and neurotoxic side effects of chemotherapy.     

XELOX方案对比卡培他滨单药方案在老年结直肠癌患者术后辅助化疗中的疗效及安全性探讨

目的：探讨XELOX方案（卡培他滨联合奥沙利铂）对比卡培他滨单药方案在老年结直肠癌患者术后辅助化疗中的疗效及安全性。方法：本研究纳入从2010年1月到2017年12月在郑州人民医院进行R0手术切除结直肠癌老年患者（60～82岁）195例,术后接受卡培他滨单药或XELOX方案的辅助化疗（根据患者美国东部肿瘤协作组（ECOG）评分、体能状态、医生评估、患者耐受能力及意愿选择辅助化疗方案）。通过医院的病历系统统计入组患者基线临床资料并按照试验方案进行患者随访。两种辅助化疗方案患者的无疾病生存期（DFS）和总生存期（OS）用Kaplan-Meier生存分析方法进行分析。建立Cox风险比例模型,评估在风险因素相同的情况下,两种辅助治疗方案的疗效。依据CTCAE 4.0的标准,记录2级以上不良反应发生情况并进行安全性分析。结果：该研究中位随访5.75年（随访时间范围：0.30～7.50年）。纳入研究的195例患者均可评价疗效,整体患者人群中位无疾病生存期（mDFS）为5.0年,其中XELOX方案组的mDFS为5.5年,显著高于卡培他滨单药方案组的mDFS 3.6年（P=0.047,95% CI：2.06-5.14）。患者整体中位总生存期（mOS）为7.1年,其中XELOX方案组mOS为7.1年,显著高于卡培他滨单药方案组的mOS 4.5年（P=0.021,95% CI：3.30-5.70）。在风险因素相同的情况下,当患者年龄<70岁,无论是DFS（HR=0.74,P=0.036）还是OS（HR=0.78,P=0.041）患者均能够从XELOX方案中获益;当患者年龄≥70岁时,患者仅DFS（HR=0.77,P=0.035）可以从XELOX方案中获益。无论患者合并症状如何,患者的DFS和OS均能从XELOX方案中获益。但是仅当淋巴结送检的枚数≤12枚、患者接受辅助化疗周期数≥6的时候,患者DFS和OS才能从XELOX方案中获益。不良反应方面,中性粒细胞减少（61.54% vs. 39.74%,P=0.003）及神经毒性发生率（65.81% vs. 0%）,XELOX方案组显著高于卡培他滨单药方案组;其他的不良反应,如腹泻、口腔炎、血小板减少、手足综合征、贫血、恶心呕吐、AST/ALT升高、脱发的发生率,两用药方案之间均无统计学差异（P>0.05）。结论：XELOX方案不会明显增加老年患者的不良反应,且老年患者（年龄<70岁时）在卡培他滨单药的基础上联合奥沙利铂DFS和OS都可以显著获益,当患者年龄≥70岁时候,仅有DFS获益,而OS则无法获益。     

The Utilization of the Immune System in Lung Cancer Treatment: Beyond Chemotherapy

Lung cancer is ranked first worldwide as one of the main cancers in terms of prevalence and mortality rate. The development of effective treatment strategies against lung cancer is therefore of paramount importance. Traditionally, chemotherapy was employed in the treatment of various cancers. However, the non-specific nature of the actions of chemotherapeutic drugs and the potential for tumors to develop resistance to these drugs may render chemotherapy a less favorable option for cancer treatment. Immunotherapy provides an alternative strategy for this purpose. It involves the utilization of the immune system and the immune effector cells to elicit an immune response to the tumors, thereby eliminating them. Strategies include the administration of pro-inflammatory cytokines for immune stimulation, the removal of immunological checkpoints using monoclonal antibodies, and the use of cancer vaccines to enhance immunity against tumors. This article summarizes the above strategies, highlights the reasons why immunotherapy is superior to chemotherapy for the purpose of tumor removal, and reviews the recent clinical studies comparing the clinical outcomes of patients undergoing immunotherapy and chemotherapy. The article also describes advances in immunotherapeutic strategies for the treatment of lung cancer.     

Gold‐Coated Fe3O4 Nanoroses with Five Unique Functions for Cancer Cell Targeting,Imaging, and Therapy

The development of nanomaterials that combine diagnostic and therapeutic functions within a single nanoplatform is extremely important for molecular medicine. Molecular imaging with simultaneous diagnosis and therapy will provide the multimodality needed for accurate diagnosis and targeted therapy. Here, gold‐coated iron oxide (Fe₃O₄@Au) nanoroses with five distinct functions are demonstrated, integrating aptamer‐based targeting, magnetic resonance imaging (MRI), optical imaging, photothermal therapy. and chemotherapy into one single probe. The inner Fe₃O₄ core functions as an MRI agent, while the photothermal effect is achieved through near‐infrared absorption by the gold shell, causing a rapid rise in temperature and also resulting in a facilitated release of the anticancer drug doxorubicin carried by the nanoroses. Where the doxorubicin is released, it is monitored by its fluorescence. Aptamers immobilized on the surfaces of the nanoroses enable efficient and selective drug delivery, imaging, and photothermal effect with high specificity. The five‐function‐embedded nanoroses show great advantages in multimodality.     

Design of Mitoxantrone-Loaded Biomimetic Nanocarrier with Sequential Photothermal/Photodynamic/Chemotherapy Effect for Synergized Immunotherapy

Metastatic triple-negative breast cancer (TNBC) has a poor prognosis and high mortality with no effective treatment options, and immunotherapy is highly anticipated as a potential treatment but is limited by the lack of tumor-infiltrating T lymphocytes in TNBC. Herein, red blood cell (RBC) membrane-camouflaged polyphosphoester (PPE) nanoparticles (RBC@PPE_MTO/PFA) are prepared as the nanocarriers of mitoxantrone (MTO) and perfluoroalkane (PFA) for synergized immunotherapy. The encapsulated MTO can generate heat and reactive oxygen species (ROS) to achieve photothermal and photodynamic therapy; moreover, ROS further triggers the self-accelerating release of MTO from the ROS-sensitive PPE core to enable chemotherapy. The RBC@PPE_MTO/PFA-mediated sequential photothermal/photodynamic/chemotherapy efficiently promotes the infiltration of CD8⁺ T cells into TNBC tumor tissue and synergizes the therapeutic activity of an immune checkpoint blockade antibody for metastatic TNBC treatment in distant and lung metastasis models. This biomimetic nanomedicine of MTO provides a convenient and available strategy to sensitize TNBC to immune checkpoint blockade antibody.     

Enhancing Chemotherapy of p53‐Mutated Cancer through Ubiquitination‐Dependent Proteasomal Degradation of Mutant p53 Proteins by Engineered ZnFe‐4 Nanoparticles

A significant percentage of human cancers harbor missense mutations in the TP53 gene and express highly stabilized mutant p53 protein (mutp53) with tumor‐promoting gain‐of‐function (GOF) properties. Inducing mutp53 degradation is a viable precision anti‐tumor therapeutic strategy. Based on the previously reported finding that a zinc‐curcumin compound induced mutp53 degradation, a series of ZnFe nanoparticles (ZnFe NPs) are synthesized and it is found that ZnFe‐4, with an Zn:Fe ratio of 1:2, exhibits outstanding mutp53‐degrading capability. ZnFe‐4 induced ubiquitination‐mediated proteasomal degradation of several different mutp53 species, but not the wild‐type p53 protein. Cellular internalization, intracellular Zn++ elevation and increased ROS are all necessary for ZnFe‐4‐induced mutp53 degradation. Degradation of mutp53 by ZnFe‐4, abrogated mutp53‐manifested GOF, leading to increased p21 expression, cell cycle arrest, reduced cell proliferation and cell migration, and cell demise. ZnFe‐4 also sensitized to cisplatin‐elicited killing in p53 S241F ES‐2 ovarian cancer cells, and dramatically improved the therapeutic efficacy of cisplatin in a subcutaneous ES‐2 tumor model. The potential clinical utility of ZnFe‐4 is further demonstrated in an orthotopically‐implanted p53 Y220C patient‐derived xenograft (PDX) breast cancer model. ZnFe‐4 is the first reported mutp53‐degrading nanomaterial, and further materials engineering may lead to the development of zinc‐based nanoparticles with minimal toxicity and maximized mutp53‐degrading capability.     

Cancer Modeling‐on‐a‐Chip with Future Artificial Intelligence Integration

Cancer is one of the leading causes of death worldwide, despite the large efforts to improve the understanding of cancer biology and development of treatments. The attempts to improve cancer treatment are limited by the complexity of the local milieu in which cancer cells exist. The tumor microenvironment (TME) consists of a diverse population of tumor cells and stromal cells with immune constituents, microvasculature, extracellular matrix components, and gradients of oxygen, nutrients, and growth factors. The TME is not recapitulated in traditional models used in cancer investigation, limiting the translation of preliminary findings to clinical practice. Advances in 3D cell culture, tissue engineering, and microfluidics have led to the development of “cancer‐on‐a‐chip” platforms that expand the ability to model the TME in vitro and allow for high‐throughput analysis. The advances in the development of cancer‐on‐a‐chip platforms, implications for drug development, challenges to leveraging this technology for improved cancer treatment, and future integration with artificial intelligence for improved predictive drug screening models are discussed.     

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.     

Polyhedral Oligomeric Silsesquioxane-Based Nanoparticles for Efficient Chemotherapy of Glioblastoma

Glioblastoma (GBM) is the most common lethal brain tumor with dismal treatment outcomes and poor response to chemotherapy. As the regulatory center of cytogenetics and metabolism, most tumor chemotherapeutic molecules exert therapeutic effects in the nucleus. Nanodrugs showing the nuclear aggregation effect are expected to eliminate and fundamentally suppress tumor cells. In this study, a nanodrug delivery system based on polyhedral oligomeric silsesquioxane (POSS) is introduced to deliver drugs into the nuclei of GBM cells, effectively enhancing the therapeutic efficacy of chemotherapy. The nanoparticles are modified with folic acid and iRGD peptides molecules to improve their tumor cell targeting and uptake via receptor-mediated endocytosis. Nuclear aggregation allows for the direct delivery of chemotherapeutic drug temozolomide (TMZ) to the tumor cell nuclei, resulting in more significant DNA damage and inhibition of tumor cell proliferation. Herein, TMZ-loaded POSS nanoparticles can significantly improve the survival of GBM-bearing mice. Therefore, the modified POSS nanoparticles may serve as a promising drug-loaded delivery platform to improve chemotherapy outcomes in GBM patients.