Oxygen‐Generating MnO2 Nanodots‐Anchored Versatile Nanoplatform for Combined Chemo‐Photodynamic Therapy in Hypoxic Cancer

Local hypoxia in tumors results in undesirable impediments for the efficiencies of oxygen‐dependent chemical and photodynamic therapy (PDT). Herein, a versatile oxygen‐generating and pH‐responsive nanoplatform is developed by loading MnO₂ nanodots onto the nanosystem that encapsulates g‐C₃N₄ and doxorubicin hydrochloride to overcome the hypoxia‐caused resistance in cancer therapy. The loaded MnO₂ nanodots can react with endogenous acidic H₂O₂ to elevate the dissolved oxygen concentration, leading to considerably enhanced cancer therapy efficacy. As such, the as‐prepared nanoplatform with excellent dispersibility and satisfactory biocompatibility can sustainably increase the oxygen concentration and rapidly release the encapsulated drugs in acid H₂O₂ environment. In vitro cytotoxicity experiments show a higher therapy effect by the designed nanoplatform, when compared to therapy without MnO₂ nanodots under hypoxia condition, or chemical and photodynamic therapy alone with the presence of MnO₂ nanodots. In vivo experiments also demonstrate that 4T1 tumors can be very efficiently eliminated by the designed nanoplatform under light irradiation. These results highlight that the MnO₂ nanodots‐based nanoplatform is promising for elevating the oxygen level in tumor microenvironments to overcome hypoxia limitations for high‐performance cancer therapy.     

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.     

Thiolated chitosan-modified PLA-PCL-TPGS nanoparticles for oral chemotherapy of lung cancer

Oral chemotherapy is a key step towards ‘chemotherapy at home’, a dream of cancer patients, which will radically change the clinical practice of chemotherapy and greatly improve the quality of life of the patients. In this research, three types of nanoparticle formulation from commercial PCL and self-synthesized d-α-tocopheryl polyethylene glycol 1000 succinate (PLA-PCL-TPGS) random copolymer were prepared in this research for oral delivery of antitumor agents, including thiolated chitosan-modified PCL nanoparticles, unmodified PLA-PCL-TPGS nanoparticles, and thiolated chitosan-modified PLA-PCL-TPGS nanoparticles. Firstly, the PLA-PCL-TPGS random copolymer was synthesized and characterized. Thiolated chitosan greatly increases its mucoadhesiveness and permeation properties, thus increasing the chances of nanoparticle uptake by the gastrointestinal mucosa and improving drug absorption. The PLA-PCL-TPGS nanoparticles were found by FESEM that they are of spherical shape and around 200 nm in diameter. The surface charge of PLA-PCL-TPGS nanoparticles was reversed from anionic to cationic after thiolated chitosan modification. The thiolated chitosan-modified PLA-PCL-TPGS nanoparticles have significantly higher level of the cell uptake than that of thiolated chitosan-modified PLGA nanoparticles and unmodified PLA-PCL-TPGS nanoparticles. In vitro cell viability studies showed advantages of the thiolated chitosan-modified PLA-PCL-TPGS nanoparticles over Taxol® in terms of cytotoxicity against A549 cells. It seems that the mucoadhesive nanoparticles can increase paclitaxel transport by opening tight junctions and bypassing the efflux pump of P-glycoprotein. In conclusion, PLA-PCL-TPGS nanoparticles modified by thiolated chitosan could enhance the cellular uptake and cytotoxicity, which revealed a potential application for oral chemotherapy of lung cancer.     

巴布亚新几内亚头颈部恶性淋巴瘤90例回顾性研究

目的：研究10年期间（1996至2005）,年龄18岁以上,90例成人巴布亚新几内亚头颈部恶性淋巴瘤的临床发病率及治疗资料。方法临床资料的获得是从莫尔比滋港总院的医学记录,相关的治疗方法和随访资料是从巴布亚新几内亚国家癌症中心,及Angau Memorial Hospital , Lae获得。结果：10年期间总的300例成人恶性淋巴瘤中,头颈部区域90例,非霍奇金氏淋巴瘤72例,其中包括8例成人 Burkitts - like lymphoma ,18例霍奇金氏淋巴瘤。结论在巴布亚新几内亚,恶性淋巴瘤原发在头颈区域的占总的淋巴瘤的30％。占头颈部所有恶性肿瘤的2．8％。这些淋巴瘤在这些区域表现更强的侵袭性,确切的组织病理学诊断和联合放化疗是治疗的关键因素。     

紫杉醇卡铂化疗联合放射治疗局部晚期非小细胞肺癌临床观察

目的 :观察紫杉醇卡铂化疗联合放射治疗局部晚期非小细胞肺癌 (NSCL C)的近期疗效及毒副反应。方法 :3 2例局部晚期NSCLC患者 ,采用紫杉醇加卡铂联合化疗 (紫杉醇 13 5 mg/m2 ,静滴 ,第 1天 ;卡铂 3 0 0 mg/m2 ,静滴 ,第 2天 ,每 2 1天为 1周期 ,共 2～ 3周期 ) ,并与放射治疗 (常规分割 ,DT62～ 68Gy/3 1～ 3 4次 )交替进行 (夹心疗法 )。结果 :全组 CR2例 ,PR16例 ,总有效率 (CR PR) 5 6.3 % ,无严重毒副反应。平均生存期 14 .5月。结论 :紫杉醇卡铂化疗联合放射治疗局部晚期 NSCLC能提高近期疗效 ,远处转移有降低趋势 ,且毒副作用可耐受 ,值得临床进一步观察研究     

Targets,Structures, and Recent Approaches in Malignant Melanoma Chemotherapy

Malignant metastatic melanoma is one of the oncologic diseases with the worst clinical prognosis, due primarily to resistance phenomena against chemotherapeutic agents in current use. However, over the last few years, characterization of the molecular mechanisms involved in the development and progression of the disease has contributed to elucidation of the main pathways by which tissue invasion and metastasis can occur. More importantly, the identification of abnormalities in signaling cascades in melanoma cells has facilitated new therapeutic approaches against malignant melanoma through the design of highly potent and selective drugs with low associated toxicity. Ultimately, recognition of the restricted applicability of new chemotherapies in certain genetic contexts has led to significant improvements in the results of clinical trials, anticipating the existing need for investment in personalized therapies, and taking into account the molecular alterations observed in tumors. Although significant advances have been made in terms of extending the median overall survival rate and improving the quality of life for patients, the mechanisms that compromise in vivo drug efficacy remain poorly understood, particularly those concerning therapeutic resistance phenomena. This review summarizes recently validated targets from the perspective of the medicinal chemistry carried out in the design of the most promising structures.     

Targeting Cancer Stem Cells with Small Molecules

Cancers arise as a result of physiological imbalances and subsequent uncontrolled cell division. Cancer initiation requires a set of biochemical alterations, including some occurring at the genetic and epigenetic levels. Thus, tumors are heterogeneous in nature making it challenging to selectively target different cancer cells by means of small molecule intervention. The paradigm of cancer stem cells (CSCs) describes subpopulations of cells with high self-renewal and tumor-seeding capacity. These cells, typically refractory to conventional therapies, can give rise to relapse after treatment. Combinatorial strategies, including drugs that selectively target this population of cells, have emerged in recent years. Here, we review how discovery-based – unbiased – screening approaches 1 have helped identify small molecules that specifically target CSCs. We also highlight biological pathways characteristic of CSCs that can potentially be selectively targeted in a hypothesis-driven manner by small molecules. We describe molecules that effectively target CSCs and emphasize what is known about their biological modes of action. The diversity and complexity of biochemical processes that CSCs may be addicted to, raises the question of how selective targeting of these pathways can be achieved. This challenge may be addressed by the continuing production of structurally complex and diverse small molecules using target and diversity-oriented synthesis approaches. 2     

Cytotoxic Autophagy in Cancer Therapy

Autophagy is a process of cellular self-digestion, whereby the cell degrades subcellular materials in order to generate energy and metabolic precursors in order to prolong survival, classically under conditions of nutrient deprivation. Autophagy can also involve the degradation of damaged or aged organelles, and misfolded or damaged proteins to eliminate these components that might otherwise be deleterious to cellular survival. Consequently, autophagy has generally been considered a prosurvival response. Many, if not most chemotherapeutic drugs and radiation also promote autophagy, which is generally considered a cytoprotective response, in that its inhibition frequently promotes apoptotic cells death. Furthermore, it has been shown that conventional chemotherapeutic drugs and radiation alone rarely induce a form of autophagy that leads to cell death. However, there are multiple examples in the literature where newer chemotherapeutic agents, drug combinations or drugs in combination with radiation promote autophagic cell death. This review will describe autophagic cell death induced in breast tumor cells, lung cancer cells as well as glioblastoma, demonstrating that it cannot be concluded that stress induced autophagy is, of necessity, cytoprotective in function.     

Optimal robust control of drug delivery in cancer chemotherapy: A comparison between three control approaches

During the drug delivery process in chemotherapy, both of the cancer cells and normal healthy cells may be killed. In this paper, three mathematical cell-kill models including log-kill hypothesis, Norton–Simon hypothesis and E_max hypothesis are considered. Three control approaches including optimal linear regulation, nonlinear optimal control based on variation of extremals and H_∞-robust control based on μ-synthesis are developed. An appropriate cost function is defined such that the amount of required drug is minimized while the tumor volume is reduced. For the first time, performance of the system is investigated and compared for three control strategies; applied on three nonlinear models of the process. In additions, their efficiency is compared in the presence of model parametric uncertainties. It is observed that in the presence of model uncertainties, controller designed based on variation of extremals is more efficient than the linear regulation controller. However, H_∞-robust control is more efficient in improving robust performance of the uncertain models with faster tumor reduction and minimum drug usage.