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Endosomes Cancer

Bo-Ya Liu, Xiao-Yan He, Ren-Xi Zhuo, Si-Xue Cheng
For effective regulation of cell behaviors and prevention of tumor development by genome editing, we constructed multi-functional self-assembled nanoparticles based on natural polymers to deliver CRISPR-Cas9 plasmid to tumorous cells. The CRISPR based gene editing plasmid to knockout CDK11 gene was complexed with protamine sulfate, and then the complex was decorated by a multi-functional outer layer composed of an endosomolytic peptide (KALA) and aptamer AS1411 incorporated carboxymethyl chitosan. The resultant multi-functional nanoparticles, which exhibit significantly enhanced delivery efficiency, can specifically deliver the plasmid into tumor cell nuclei owing to the favorable effects of KALA in cellular uptake and endosomal escape, together with the cancer cell and cell nucleus targeting capability of AS1411 ligands...
October 16, 2018: Journal of Controlled Release: Official Journal of the Controlled Release Society
Wangxiao He, Jin Yan, Fang Sui, Simeng Wang, Xi Su, Yiping Qu, Qingchen Yang, Hui Guo, Meiju Ji, Wuyuan Lu, Yongping Shao, Peng Hou
The peptide-derived self-assembly platform has attracted increasing attention for its great potential to develop into multitargeting nanomedicines as well as its inherent biocompatibility and biodegradability. However, their clinical application potentials are often compromised by low stability, weak membrane penetrating ability, and limited functions. Herein, inspired by a natural protein from the seeds of Luffa cylindrica, we engineered via epitope grafting and structure design a hybrid peptide-based nanoplatform, termed Lupbin, which is capable of self-assembling into a stable superstructure and concurrently targeting multiple protein-protein interactions (PPIs) located in cytoplasm and nuclei...
October 18, 2018: ACS Nano
Joseph Ryan Polli, Frank A Engler, Joseph P Balthasar
Engineered monoclonal antibodies (mAb) with pH-sensitive target release, or "catch-and-release" (CAR) binding, have shown promise in decreasing the extent of target-mediated mAb elimination, increasing mAb exposure, and increasing dose-potency. This study developed a mechanistic physiologically-based pharmacokinetic (PBPK) model to evaluate the effects of pH-sensitive CAR target binding on the disposition of anti-carcinoembryonic antigen (CEA) mAb in mouse models of colorectal cancer. The PBPK model was qualified by comparing model-predicted plasma concentration-time data to data observed in tumor-bearing mice following the administration of T84...
October 12, 2018: Journal of Pharmaceutical Sciences
Diptiman Chanda, Eva Otoupalova, Kenneth P Hough, Morgan L Locy, Karen Bernard, Jessy S Deshane, Ralph D Sanderson, James A Mobley, Victor J Thannickal
Extracellular vesicles (EVs) are endosome and plasma membrane-derived nanosized vesicles that participate in intercellular signaling. Although EV cargo may signal via multiple mechanisms, how signaling components on the surface of EVs mediate cellular signaling is less well understood. In this study, we show that fibroblast-derived EVs carry fibronectin on the vesicular surface, as evidenced by mass spectrometry-based proteomics (sequential windowed acquisition of all theoretical peptides; SWATH) and flow cytometric analyses...
October 15, 2018: American Journal of Respiratory Cell and Molecular Biology
Akram Assali, Omid Akhavan, Fatemeh Mottaghitalab, Mohsen Adeli, Rassoul Dinarvand, Shayan Razzazan, Ehsan Arefian, Masoud Soleimani, Fatemeh Atyabi
Introduction: MicroRNA-101 (miR-101) is an intense cancer suppressor with special algorithm to target a wide range of pathways and genes which indicates the ability to regulate apoptosis, cellular stress, metastasis, autophagy, and tumor growth. Silencing of some genes such as Stathmin1 with miR-101 can be interpreted as apoptotic accelerator and autophagy suppressor. It is hypothesized that hybrid microRNA (miRNA) delivery structures based on cationized graphene oxide (GO) could take superiority of targeting and photothermal therapy to suppress the cancer cells...
2018: International Journal of Nanomedicine
Zhenqiang Sun, Ke Shi, Shuaixi Yang, Jinbo Liu, Quanbo Zhou, Guixian Wang, Junmin Song, Zhen Li, Zhiyong Zhang, Weitang Yuan
Exosomes, extracellular vesicles with diameters ranging from 30 to 150 nm, are widely present in various body fluids. Recently, microRNAs (miRNAs) have been identified in exosomes, the biogenesis, release, and uptake of which may involve the endosomal sorting complex required for transport (ESCRT complex) and relevant proteins. After release, exosomes are taken up by neighboring or distant cells, and the miRNAs contained within modulate such processes as interfering with tumor immunity and the microenvironment, possibly facilitating tumor growth, invasion, metastasis, angiogenesis and drug resistance...
October 11, 2018: Molecular Cancer
Gary Eitzen, Cameron C Smithers, Allan Murray, Michael Overduin
FYVE domains are highly conserved protein modules that typically bind phosphatidylinositol 3-phosphate (PI3P) on the surface of early endosomes. Along with pleckstrin homology (PH) and phox homology (PX) domains, FYVE domains are the principal readers of the phosphoinositide (PI) code that mediate specific recognition of eukaryotic organelles. Of all the human FYVE domain-containing proteins, those within the Faciogenital dysplasia (Fgd) subfamily are particularly divergent, and couple with GTPases to exert unique cellular functions...
October 11, 2018: Biochemistry and Cell Biology, Biochimie et Biologie Cellulaire
Xin Jin, Jianping Zhou, Zhenhai Zhang, Huixia Lv
BACKGROUND: Combinations of natural products with low toxicities using tumor-targeting carriers may improve cancer treatment. The combined parthenolide and ginsenoside compound K (CK) within tLyp-1 liposomes, with the aim of improving the efficacy of lung cancer treatment. RESULTS: In vitro studies in A549 human pulmonary adenocarcinoma cells demonstrated that parthenolide/CK tLyp-1 liposomes increased reactive oxygen species levels and induced mitochondrial apoptosis...
October 11, 2018: Artificial Cells, Nanomedicine, and Biotechnology
Huanli Sun, Yangyang Dong, Jan Feijen, Zhiyuan Zhong
The advancement of tissue and cell-specific drug delivery systems is a key to precision cancer therapy. Peptides, with easy synthesis, low immunogenicity and biological functions closely mimicking or surpassing natural proteins, have been actively engineered and explored to provide nanomedicines with the ability to overcome various extracellular and intracellular delivery barriers ranging from phagocytic clearance in the circulation, low tumor penetration, poor cancer cell selectivity, inferior cell penetration, to endosomal entrapment as well as poor blood brain barrier permeation for brain cancer therapy...
October 2, 2018: Journal of Controlled Release: Official Journal of the Controlled Release Society
Peili Yao, Yifan Zhang, Hao Meng, Huanli Sun, Zhiyuan Zhong
Low cell selectivity and uptake coupled with endosomal entrapment pose critical hurdles for intracellular delivery and clinical translation of therapeutic proteins. Herein, we report that smart polymersomes dually functionalized with cRGD and fusogenic GALA peptides (cRGD/GALA-Ps) enable αν β3 -specific and high-efficiency cytosolic delivery of cytochrome C (CC), a model apoptotic protein, to A549 human lung cancer cells. cRGD/GALA-Ps was prepared with 20 mol % cRGD and varying GALA contents from 2 to 4 to 6 mol % via coassembly of PEG- b-poly(trimethylene carbonate- co-dithiolane trimethylene carbonate)-spermine (PEG- b-P(TMC- co-DTC)-spermine), cRGD-PEG- b-P(TMC- co-DTC), and maleimide-PEG- b-P(TMC- co-DTC) and postmodification using GALA-SH (sequence: CWEAALAEALAEALAEHLAEALAEALEALAA)...
October 18, 2018: Biomacromolecules
Zihnil Adha Islamy Mazrad, Pham Thi My Phuong, Cheong A Choi, Insik In, Kang Dae Lee, Sung Young Park
In the present study, pH/redox responsive cationic polymer dot (CD) was successfully prepared for a near-infrared (NIR)-mediated simultaneously controllable photothermal temperature guided imaging off/on system to monitor therapeutic delivery. The carbonized disulfide crosslinked branched-polyethyleneimine (bPEI) with a folic acid (FA) conjugation as the targeting moiety and a partially ionic complex between anionic indocyanine green (ICG) and bPEI-based CD (ICG-CD). This was responsive to mild reductive (GSH) and acidic tumor conditions, which enabled the simultaneous biodegradation of those hydrophobic and complex sites...
October 4, 2018: ChemMedChem
Yolanda Salinas, Carolin Hoerhager, Alba García-Fernández, Marina Resmini, Félix Sancenón, Ramón Matínez-Máñez, Oliver Brueggemann
Biocompatible ZnS-based nanocrystals capped with 4-mercaptophenylboronic acid (ZnS@B) have been size-designed as excellent pH-responsive gatekeepers on mesoporous silica nanoparticles (MSNs), which encapsulate fluorophore safranin O (S2-Saf) or anticancer drug epirubicin hydrochloride (S2-Epi) for delivery applications in cancer cells. In this novel hybrid system, the gate mechanism consists of reversible pH-sensitive boronate ester moieties linking the nanocrystals directly to the alcohol groups from silica surface scaffold, avoiding tedious intermediate functionalization steps...
October 10, 2018: ACS Applied Materials & Interfaces
Thomas Mbimba, Nazar J Hussein, Ayesha Najeed, Fayez F Safadi
Trafficking protein particle complex 9 (TRAPPC9) is a protein subunit of the transport protein particle II (TRAPPII), which has been reported to be important in the trafficking of cargo from the endoplasmic reticulum (ER) to the Golgi, and in intra‑Golgi and endosome‑to‑Golgi transport in yeast cells. In mammalian cells, TRAPPII has been shown to be important in Golgi vesicle tethering and intra‑Golgi transport. TRAPPC9 is considered to be a novel molecule capable of modulating the activation of nuclear factor‑κB (NF‑κB)...
September 21, 2018: International Journal of Molecular Medicine
Yun Xia, Yonghua Xie, Zhengsen Yu, Hongying Xiao, Guimei Jiang, Xiaoying Zhou, Yunyun Yang, Xin Li, Meng Zhao, Liping Li, Mingke Zheng, Shuai Han, Zhaoyun Zong, Xianbin Meng, Haiteng Deng, Huahu Ye, Yunzhi Fa, Haitao Wu, Eric Oldfield, Xiaoyu Hu, Wanli Liu, Yan Shi, Yonghui Zhang
Motivated by the clinical observation that interruption of the mevalonate pathway stimulates immune responses, we hypothesized that this pathway may function as a druggable target for vaccine adjuvant discovery. We found that lipophilic statin drugs and rationally designed bisphosphonates that target three distinct enzymes in the mevalonate pathway have potent adjuvant activities in mice and cynomolgus monkeys. These inhibitors function independently of conventional "danger sensing." Instead, they inhibit the geranylgeranylation of small GTPases, including Rab5 in antigen-presenting cells, resulting in arrested endosomal maturation, prolonged antigen retention, enhanced antigen presentation, and T cell activation...
September 20, 2018: Cell
Lu Zhang, Zhenzhen Wang, Yan Zhang, Fangfang Cao, Kai Dong, Jinsong Ren, Xiaogang Qu
Shutting down glucose supply by glucose oxidase (GOx) to starve tumors has been considered to be an attractive strategy in cancerous starvation therapy. Nevertheless, the in vivo applications of GOx-based starvation therapy are severely restricted by the poor GOx delivery efficiency and the self-limiting therapeutic effect. Herein, a biomimetic nanoreactor has been fabricated for starvation-activated cancer therapy by encapsulating GOx and prodrug tirapazamine (TPZ) in an erythrocyte membrane cloaked metal-organic framework (MOF) nanoparticle (TGZ@eM)...
October 3, 2018: ACS Nano
Lyndsay Murrow, Jayanta Debnath
We recently identified an interaction between Atg12-Atg3, a complex between 2 core autophagy regulators, and the ESCRT-associated protein Pdcd6ip (programmed cell death 6 interacting protein, commonly known as Alix), which coordinately regulates basal autophagy, late endosome-to-lysosome trafficking, and exosome release. Because these processes all serve fundamental roles in cancer progression and therapy, Atg12-Atg3 may be an attractive anticancer target.
2018: Molecular & Cellular Oncology
Huishan Guo, Remy Sadoul, Derrick Gibbings
Autophagy-related-5 (Atg5) and Autophagy-related-16-Like-1 (Atg16L1) canonically participate in autophagy. Recent research demonstrates that apart from this, they also control production of extracellular vesicles called exosomes by regulating acidification of late endosomes. Atg5-mediated exosome production increased migration and metastasis of breast cancer cells suggesting exosomes may perform some functions ascribed to autophagy.
2018: Molecular & Cellular Oncology
Fabrice Lucien, Roxane R Lavoie, Claire M Dubois
Altered pH homeostasis in cancer cells has been linked with essentially all classical hallmarks of cancer, including chemoresistance. We recently identified a conceptually novel mechanism for how dysregulated pH in hypoxic cells causes chemoresistance which is based on the aberrant cellular distribution of the endosomal pH regulator, the sodium/hydrogen exchanger 6 (NHE6).
2018: Molecular & Cellular Oncology
Remah Ali, Wells Brown, Stephen Connor Purdy, V Jo Davisson, Michael K Wendt
Inhibition of epidermal growth factor receptor (EGFR) signaling by small molecule kinase inhibitors and monoclonal antibodies has proven effective in the treatment of multiple cancers. In contrast, metastatic breast cancers (BC) derived from EGFR-expressing mammary tumors are inherently resistant to EGFR-targeted therapies. Mechanisms that contribute to this inherent resistance remain poorly defined. Here, we show that in contrast to primary tumors, ligand-mediated activation of EGFR in metastatic BC is dominated by STAT1 signaling...
September 24, 2018: Cell Death & Disease
Kun Yang, Chuanfeng Zhang, Lei Sun, Dong Li, Xin Hong
Aim of Study: Recent studies have suggested neprilysin (NEP) play a key role in cigarette smoke-induced nonsmall-cell lung carcinoma; however, the detailed mechanism was still unclear. Here, we employed in vitro human bronchial epithelial BEAS-2B cells to investigate whether and how NEP involved in cigarette smoke condensate (CSC)-induced cancer occurrence. Materials and Methods: In vitro MTT and transwell assay was applied. Live cell imaging and staining were also employed...
September 2018: Journal of Cancer Research and Therapeutics
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