Catalytically Selective Chemotherapy from Tumor‐Metabolic Generated Lactic Acid

Lactic acid (LA) is a powerful molecule as the metabolic driver in tumor microenvironments (TMEs). Inspired by its high intratumoral level (5–20 µmol g^?1), a novel treatment paradigm via the cascade release of H₂O₂ and ·OH from the LA generated by tumor metabolism is developed for catalytic and pH‐dependent selective tumor chemotherapy. By utilizing the acidity and overexpression of LA within the TME, the constructed lactate oxidase (LOD)‐immobilized Ce‐benzenetricarboxylic acid (Ce‐BTC) metal organic framework enables the intratumoral generation of ·OH via a cascade reaction: 1) the in situ catalytic release of H₂O₂ from LA by LOD, and 2) the catalytic production of ·OH from H₂O₂ by Ce‐BTC with peroxidase‐like activity. Highly toxic ·OH effectively induces tumor apoptosis/death. A new strategy for selective tumor chemotherapy is provided herein.     

Doxorubicin- and cisplatin-loaded nanostructured lipid carriers for breast cancer combination chemotherapy

Context: Combination anticancer therapy is promising to generate synergistic anticancer effects, to maximize the treatment effect and to overcome multi-drug resistance. Nanostructured lipid carriers (NLCs), composed of solid and liquid lipids, and surfactants are potentially good colloidal drug carriers.

Objective: The aim of this study is to construct novel NLCs as nanocarriers for co-delivery of doxorubicin (DOX) and cisplatin (CDDP) to treat breast cancer.

Methods: DOX and CDDP loaded NLCs (D–C-NLCs) were prepared by the solvent diffusion method. The in vitro cytotoxicity and synergistic studies of different formulations were evaluated on human breast cancer cells (doxorubicin resistant) (MCF-7/ADR cells). In vivo anti-tumor effects were observed on the murine bearing MCF-7/ADR cells model.

Results: D–C-NLCs showed the highest cytotoxicity and synergistic effect of two drugs in tumor cells in vitro. The in vivo study revealed the greatest anti-tumor activity than the other formulations in the breast cancer model.

Conclusion: The constructed NLCs could be used as a novel carrier for co-delivery of DOX and CDDP for breast cancer therapy. D–C-NLCs could be a promising targeted and combinational therapy nanomedicine.     

Targeted hepatocellular carcinoma therapy: transferrin modified,self-assembled polymeric nanomedicine for co-delivery of cisplatin and doxorubicin

Background: Targeted hepatocellular carcinoma (HCC) therapy was carried out to improve the efficacy of liver cancers. The aim of this study was to develop transferrin (Tf) modified, self-assembled polymeric nanoparticles for co-delivery doxorubicin (DOX) and cisplatin (DDP), to achieve combination tumor therapy.

Methods: Tf modified polyethylene glycol (PEG) containing DOX prodrug (Tf-PEG-DOX) was synthesized. DDP containing poly(lactic-co-glycolic) acid (PLGA) materials (PLGA-DDP) were prepared. Tf modified DOX and DDP loaded PLGA nanoparticles (Tf-DOX/DDP NPs) were prepared by using nanoprecipitation method. The particles sizes, zeta potentials, drug loading effects were characterized. The cytotoxicity of the NPs was evaluated in human hepatoma carcinoma cell lines (HepG2 cells), and in vivo anti-tumor was observed in mice bearing human HepG2 cells model.

Results: Tf-DOX/DDP NPs displayed higher cytotoxicity and enhanced antitumor activity both in vitro and in vivo over their non-modified and single drug loaded counterparts.

Conclusion: Tf-DOX/DDP NPs can achieve outstanding anti-tumor activity due to the combination effect of two drugs and the active targeting ability of Tf ligands. The self-assembled polymeric nanomedicine could act as an efficient therapy method for HCC treatment.     

Tumor Microenvironment-Activatable Nanoenzymes for Mechanical Remodeling of Extracellular Matrix and Enhanced Tumor Chemotherapy

Increased tissue stiffness is a hallmark of cancer and promotes tumor progression. It is hypothesized that decreased tumorous stress may aid or sensitize chemotherapies. To overcome extracellular matrix (ECM) stiffening and fulfill sensitized chemotherapy in one nanosystem, a reactive oxygen species-activatable nanoenzyme (SP-NE) based on a dendritic polyglycerol scaffold, integrating collagenase and paclitaxel (PTX) prodrug, is constructed. The dense and tough ECM is highly remitted by SP-NE in the tumor microenvironment (TME) mimicking gelatin hydrogel models, which causes cell shrinkage, disorders cytoskeletal constructions, and subsequently enhances chemotherapeutic efficacy. ECM softening via SP-NE downregulates mechanotransduction signaling pathways of integrin-focal adhesion kinase (FAK)-Ras homolog family member A (RhoA) implicated in cytoskeletal assembly, and integrin-FAK-phosphorylated extracellular signal regulated kinase (pERK 1/2) mediating mitosis. Notably, this programmed nanosystem in human breast MCF-7 tumor-bearing mice models displays a significant relief of ECM stress from 4300 to 1200 Pa and results in 87.1% suppression of tumor growth at a low PTX dosage of 3 mg kg⁻¹. The attenuated expression of the key players RhoA and pERK 1/2 involved in cellular mechano-sensing is further verified in vivo. This study thus provides a new and potential nanoplatform to selectively decrease TME stiffness for enhanced chemotherapy.     

Fabrication of Glyco‐Metal‐Organic Frameworks for Targeted Interventional Photodynamic/Chemotherapy for Hepatocellular Carcinoma through Percutaneous Transperitoneal Puncture

Hepatocellular carcinoma (HCC) causes high morbidity and mortality due to a lack of adequate treatments. Cancer treatments have benefited from nanotechnology approaches that integrate multimodal synergistic therapies. A synergistic, minimally invasive strategy of interventional photodynamic therapy (IPDT) and chemotherapy for HCC treatment through percutaneous transperitoneal puncture is disclosed that is based on photosensitive porphyrinic galactose‐modified metal‐organic frameworks (PCN‐224) first used as hepatic targeting and encapsulated with anticancer drug doxorubicin (DOX@Gal‐PCN‐224). Real‐time imaging reveals the effective accumulation of the integrated nanosystem in the HCC cells and tumor tissues due to hepatic targeting. Evaluation of the anti‐tumor efficiency of this nanosystem on orthotopic transplantation tumors with the aid of minimally invasive intervention shows a tumor inhibition rate of 98%. The synergistic effects induce high‐level cell apoptosis and tissue necrosis in vitro and in vivo. This bimodal IPDT/chemotherapy strategy holds great potential in the clinical treatment for HCC.     

功能化硼纳米双载药复合物的制备及其体外药物释放

通过耦合热氧化蚀刻与液相剥离技术制备了硼纳米片(B NSs),随后用氨基化PEG(H2N-PEG-NH2)对B NSs进行改性制备了改性聚乙二醇化硼纳米片(B-PEG NSs),再以环精氨酸-甘氨酸-天冬氨酸(c RGD)三肽为单体,1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)与N-羟基琥珀酰亚胺(NHS)为引发剂制备了B-PEG-c RGD复合材料。最后,B-PEG-c RGD与阿霉素(DOX)和热休克蛋白90抑制剂17-丙烯胺基-17-去甲氧基格尔德霉素(17AAG)共混得到DOX-17AAG@B-PEG-cRGD纳米载药复合物。采用透射电子显微镜(TEM)、紫外分光光度计及动态光散射仪(DLS)对BNSs和载药复合物的形貌、结构进行了表征。结果表明,功能化硼载药复合物的流体动力学平均直径约为184nm,具有良好的稳定性。体外释药研究表明,DOX-17AAG@B-PEG-cRGD复合物具有近红外光(NIR)和pH双响应性以及良好的药物缓释效果。当体外微环境pH=5.0且存在NIR时,DOX和17AAG在72 h内的累计释放率最高达66.53%和73.01%。     

FLT3 Tyrosine Kinase Inhibitors for the Treatment of Fit and Unfit Patients with FLT3-Mutated AML: A Systematic Review

FLT3-mutated acute myeloid leukemia accounts for around 30% of acute myeloid leukemia (AML). The mutation carried a poor prognosis until the rise of tyrosine kinase inhibitors (TKIs). New potent and specific inhibitors have successfully altered the course of the disease, increasing the complete response rate and the survival of patients with FLT3-mutated AML. The aim of this article is to review all the current knowledge on these game-changing drugs as well as the unsolved issues raised by their use for fit and unfit FLT3-mutated AML patients. To this end, we analyzed the results of phase I, II, III clinical trials evaluating FLT3-TKI both in the first-line, relapse monotherapy or in combination referenced in the PubMed, the American Society of Hematology, the European Hematology Association, and the Clinicaltrials.gov databases, as well as basic science reports on TKI resistance from the same databases. The review follows a chronological presentation of the different trials that allowed the development of first- and second-generation TKI and ends with a review of the current lines of evidence on leukemic blasts resistance mechanisms that allow them to escape TKI.     

Pro- and Antiangiogenic Factors in Gliomas: Implications for Novel Therapeutic Possibilities

Angiogenesis, a complex, multistep process of forming new blood vessels, plays crucial role in normal development, embryogenesis, and wound healing. Malignant tumors characterized by increased proliferation also require new vasculature to provide an adequate supply of oxygen and nutrients for developing tumor. Gliomas are among the most frequent primary tumors of the central nervous system (CNS), characterized by increased new vessel formation. The processes of neoangiogenesis, necessary for glioma development, are mediated by numerous growth factors, cytokines, chemokines and other proteins. In contrast to other solid tumors, some biological conditions, such as the blood–brain barrier and the unique interplay between immune microenvironment and tumor, represent significant challenges in glioma therapy. Therefore, the objective of the study was to present the role of various proangiogenic factors in glioma angiogenesis as well as the differences between normal and tumoral angiogenesis. Another goal was to present novel therapeutic options in oncology approaches. We performed a thorough search via the PubMed database. In this paper we describe various proangiogenic factors in glioma vasculature development. The presented paper also reviews various antiangiogenic factors necessary in maintaining equilibrium between pro- and antiangiogenic processes. Furthermore, we present some novel possibilities of antiangiogenic therapy in this type of tumors.     

奥沙利铂联合氟尿嘧啶亚叶酸钙一线治疗转移性大肠癌2周方案与3周方案的对比研究

目的:比较奥沙利铂(L-OHP)联合5-氟尿嘧啶/亚叶酸钙(5-FU/CF)的2周方案与3周方案一线治疗转移性结直肠癌的临床疗效及不良反应。方法:66例转移性结直肠癌患者随机接受治疗。A 组, 予L-OHP 85 mg/m², 第1天, 静脉滴注2h, 同时或之后予CF 200 mg/m², 静脉滴注2h,续5-FU 400 mg/m², 静脉推注, 600 mg/m² 持续静脉滴注22h, 次日重复CF 与5-FU 。每2周重复1次, 每2次计为1周期。B 组, 予L-OHP130 mg/m², 第1天, 静脉滴注2h, CF 200 mg/m²,静脉滴注2h, 续5-FU 375～425 mg/m² 静脉滴注4～6h, 连用5d, 每3周重复1次, 每次计为1周期。结果:A 、B 两组疗效相近, RR 分别为42.9%和38.7%(P>0.05)。两组病例不良反应发生率相似, 主要表现为消化道反应、神经系统毒性和脱发。结论:L-OHP 联合5-FU/CF 的2周方案与3周方案均可作为晚期转移性大肠癌一线治疗的选择之一。     

国产重组人粒细胞集落刺激因子在妇科恶性肿瘤化疗中的应用

目的: 探讨不同剂量国产重组人粒细胞集落刺激因子（rhG-CSF)在妇科恶性肿瘤化疗中的疗效,并与进口 rhG-CSF比较。方法: 98例卵巢癌、宫体癌和宫颈癌患者随机分成3组,分别按75 μg·d^-1和150 μg·d^-1剂量皮下注射国产rhG-CSF和进口75 μg·d^-1 rhG-CSF,直到白细胞或中性粒细胞绝对数升至正常水平以上。结果: 不同剂量国产或进口rhG-CSF均能使3组患者血WBC和ANC水平在用药d4后升至正常水平以上;在初次化疗时,用不同剂量（75 μg 和 150 μg）国产和进口（75 μg) rhG-CSF升WBC至正常水平的天数无显著差异（P>0.05),但重复化疗期间150μg国产rhG-CSF升白细胞的疗效显著优于75μg国产或进口 rhG-CSF;同等剂量国产AG-CSF与进口 rhG-CSF升WBC效果一致。结论: 75μg小剂量国产rhG-CSF在妇科恶性肿瘤初期化疗中升WBC的疗效肯定,重复化疗时较大剂量(150μg）rhG-CSF升WBC的效果优于小剂量rhG-CSF。同等剂量国产rhG-CSF与进口 rhG-CSF的疗效无明显差异。