A Potent,Selective CBX2 Chromodomain Ligand and Its Cellular Activity During Prostate Cancer Neuroendocrine Differentiation

Polycomb group (PcG) proteins are epigenetic regulators that facilitate both embryonic development and cancer progression. PcG proteins form Polycomb repressive complexes 1 and 2 (PRC1 and PRC2). PRC2 trimethylates histone H3 lysine 27 (H3K27me3), a histone mark recognized by the N-terminal chromodomain (ChD) of the CBX subunit of canonical PRC1. There are five PcG CBX paralogs in humans. CBX2 in particular is upregulated in a variety of cancers, particularly in advanced prostate cancers. Using CBX2 inhibitors to understand and target CBX2 in prostate cancer is highly desirable; however, high structural similarity among the CBX ChDs has been challenging for developing selective CBX ChD inhibitors. Here, we utilize selections of focused DNA encoded libraries (DELs) for the discovery of a selective CBX2 chromodomain probe, SW2_152F. SW2_152F binds to CBX2 ChD with a K_d of 80 nM and displays 24-1000-fold selectivity for CBX2 ChD over other CBX paralogs in vitro. SW2_152F is cell permeable, selectively inhibits CBX2 chromatin binding in cells, and blocks neuroendocrine differentiation of prostate cancer cell lines in response to androgen deprivation.     

Temperature- and pH-sensitive core–shell nanogels as efficient carriers of doxorubicin with potential application in lung cancer treatment

Temperature- and pH-sensitive core–shell nanogels were prepared by one-pot soapless emulsion polymerization of N-isopropylacrylamide and 2-methacryloyloxy benzoic acid with the aid of a crosslinker (core) using poly(ethylene glycol) methyl ether methacrylate as stabilizer (shell). The size of nanogels depended on the crosslinker used, being considerable smaller (around 100?nm) with the use of the acid-labile crosslinker 9-divinyl-2,4,8,10-tetraoxaspiro[5.5]-undecane (DVA). Doxorubicine (DOX) was loaded in nanogels with good efficiency. The empty nanogels were biocompatible for a lung cancer cell line (NCI-H1437), while the DOX-loaded, DVA-crosslinked nanogels resulted with efficient cytotoxicity for that cell line.     

Synthesis and characterization of NaYF_4:Yb~(3+),Er~(3+)@silica-N=folic acid nanocomplex for bioimaginable detecting MCF-7 breast cancer cells

Upconversion nanophosphors are new promising nanomaterials to be used as biolabels for detection and imaging of cancer cells.These nanophosphors absorb long-wavelength excitation radiation in the infrared or near infrared region and emit shorter wavelength,higher energy radiation from ultraviolet to infrared.In this paper,we studied the hydrothermal method and optical properties of the functionalized NaYF_4:Yb~(3+),Er~(3+)for biomedical application.After synthesis,these NaYF_4:Yb~(3+),Er~(3+)nanophosphors were functionalized with aminosilanes and folic acid.Folic acid binds to the folate receptor on the surface of MCF-7 breast cancer cells and this binding promotes internalization of the nanophosphors via endocytosis.The sizes of the functionalized NaYF_4:Yb~(3+),Er~(3+)@silica-N=FA(folic acid) nanophosphors can be controlled with length of the rod about 300-800 nm and diameter of the rod about 100-200 nm.Phase structure of NaYF_4:Yb~(3+),Er~(3+)is in hexagonal crystal system.The photo luminescence(PL) spectra of the functionalized NaYF_4:Yb~(3+),Er~(3+)@silica-N=FA nanophosphors were measured.These nanophosphors emit in red color with the strongest band at 650 nm under 980 nm excitation.This result can provide NaYF_4:Er~(3+),Yb~(3+)@silica-N=FA complex for developing fluorescence label and image tool in cancer biology and medicine.     

Nanotherapeutics approaches to improve the efficacy of CAR-T cells in solid tumors

Adoptive cell therapy and Immune Checkpoint Blockade Inhibitors have recently revolutionized the field of oncology. However, these types of immunotherapeutic approaches have limited success in treating solid tumors. In particular, chimeric antigen receptor (CAR)-T cells efficacy is hampered by immunosuppressive signals in the tumor microenvironment (TME) and by a limited infiltration of re-infused T cells to the tumor site. The field of nanobiotechnology applied to oncology is also rapidly expanding. Nanoparticles-based delivery systems can be employed to modulate the activity of immune cells present in the TME enhancing the efficacy of CAR-T cells. Interestingly, nano-backpacks can be attached to CAR-T cells prior to re-infusion to support their homing to the tumor site and to slowly release immunopotentiators directly in the TME. Furthermore, nanovaccines can also be employed to support the in vivo expansion of CAR-T cells with consequent enhancement of their therapeutic potential. In this viewpoint, recent advancement in the field of nanobiotechnology to support CAR-T cell therapy will be discussed. The development of novel therapeutic CAR-T cells protocols together with nanotherapies is warranted in order to take full advantage of the high therapeutic potential of CAR-T cell therapy.     

Functions of ULK1 in autophagy and non-autophagy pathways and its implications in human physiology and disease

ULK1 (unc-51 like autophagy activating kinase 1), a mammalian serine/threonine kinase, is a key component of autophagy initiation complex and helps to induce all types of autophagy. Canonical autophagy is a process in which, through the interactions of a series of autophagy-related proteins, damaged organelles or misfolded proteins are engulfed by autophagosomes and then merged with lysosomes to be degraded. Thus, canonical autophagy is an important constituent part of the cellular “quality control.” Besides, accumulating evidence indicates that ULK1 exerts autophagy-independent effects in a cell-specific manner. For example, ULK1 facilitates neurite elongation through the regulation of endoplasmic reticulum (ER)–Golgi trafficking in neurons, stimulates phosphopentose pathway to help NADPH (nicotinamide adenine dinucleotide phosphate hydrogen) production, and acts as a duplex regulator in type I IFN (type I interferon) induced innate immune response. Considering the importance and diversity of ULK1 in various biological processes, this review aims to present a comprehensive overview of autophagy and non-autophagy related functions of ULK1 in a variety of human physiological, pathological, and disease processes.     

Development of docetaxel nanocapsules for improving in vitro cytotoxicity and cellular uptake in MCF-7 cells

The aim of this study was to fabricate docetaxel loaded nanocapsules (DTX-NCs) with a high payload using Layer-by-Layer (LbL) technique by successive coating with alternate layers of oppositely charged polyelectrolytes. Developed nanocapsules (NCs) were characterized in terms of morphology, particle size distribution, zeta potential (ζ-potential), entrapment efficiency and in vitro release. The morphological characteristics of the NCs were assessed using transmission electron microscopy (TEM) that revealed coating of polyelectrolytes around the surface of particles. The developed NCs successfully attained a submicron particle size while the ζ-potential of optimized NCs alternated between (+) 34.64?±?1.5 mV to (?) 33.25?±?2.1 mV with each coating step. The non-hemolytic potential of the NCs indicated the suitability of the developed formulation for intravenous administration. A comparative study indicated that the cytotoxicity of positively charged NCs (F4) was significant higher (p?in vitro on MCF-7 cells. Furthermore, cell uptake studies evidenced a higher uptake of positive NCs (≥1.2 fold) in comparison to negative NCs. In conclusion, formulated NCs are an ideal vehicle for passive targeting of drugs to tumor cells that may result in improved efficacy and reduced toxicity of encapsulated drug moiety.     

Exosomes: Key tools for cancer liquid biopsy

Precision medicine is based on the identification of biomarkers of tumor development and progression. Liquid biopsy is at the forefront of the ability to gather diagnostic and prognostic information on tumors, as it can be noninvasively performed prior or during treatment. Liquid biopsy mostly utilizes circulating tumor cells, or free DNA, but also exosomes. The latter are nanovesicles secreted by most cell types, found in any body fluid that deliver proteins, nucleic acids and lipids to nearby and distant cells with a unique homing ability. Exosomes function in signalling between the tumor microenvironment and the rest of the body, promoting metastasis, immune remodelling and drug resistance. Exosomes are emerging as a key tool in precision medicine for cancer liquid biopsy, as they efficiently preserve their biomarker cargo. Moreover, exosomes strongly resemble the parental cell, which can help in assessing the oxidative and metabolic state of the donor cell. In this respect, exosomes represent one of the most promising new tools to fight cancer. This review will discuss the clinical applications of profiling exosomal proteins and lipids by high-throughput proteomics and metabolomics, and nucleic acids by next generation sequencing, as well as how this may allow cancer diagnosis, therapy response monitoring and recurrence detection.     

MicroRNA-181a is elevated by 10-hydroxycamptothecin and represses lung carcinoma progression by downregulating FOXP1

Tumor progression is usually characterized by proliferation, migration, and angiogenesis, which is essential for supplying both nutrients and oxygen to the tumor cells. Therefore, targeting angiogenesis has been considered a promising therapeutic strategy for cancer prevention and treatment. In the present study, we demonstrated that in addition to suppressing lung cancer cell proliferation and migration in vitro, 10-hydroxycamptothecin (10-HCPT) is also capable of inhibiting angiogenesis in vivo with a miR-181a-dependent manner. Mechanistically, by upregulating miR-181a, which in turn downregulating FOXP1, 10-HCPT can inhibit the PI3K/Akt/ERK signaling pathwaymediated angiogenesis. Furthermore, reduced levels of miR-181a have been found in both lung cancer cell lines and xenograft with concurrently elevated levels of FOXP1, VEGF, bFGF, and HDGF. Consistent with the findings from the in vitro experiments, miR-181a impairs neovascularization in our xenograft model. In summary, our findings have not only established the anti-oncogenic role of miR-181a in lung cancer angiogenesis but also suggest that 10-HCPT could be a potential therapeutic reagent for lung cancer treatment.     

Gold-Nanoparticle-Decorated Metal-Organic Frameworks for Anticancer Therapy

Confinement of Au nanoparticles (NPs) within the porous materials with few nanometers (2-3 nm) has been a well established research area in the past decades in heterogeneous catalysis mainly due to the unique behaviour of Au NPs than its bulk counterpart. In this aspect, Au NPs encapsulated within the pore volumes of metal−organic frameworks (MOFs) have been intensively explored as heterogeneous solid catalysts for wide range of reactions. In recent years, Au NPs confined within the porous MOFs along with the photosensitizer or drug have been effectively used for the treatment of tumor cells through the generation of reactive oxygen species via cascade reactions. This work highlights the benefits of MOFs pores in the preparation of nanomedicine with high efficiency by assembling Au NPs, photosensitizer/drug with the combination of laser either for imaging or treatment of tumor cells. Further, the existing literature is grouped based on the nature of porous materials employed in the preparation of nanomedicine. The final section comments on our view on future developments in the field.     

Curcumin based nanomedicines as efficient nanoplatform for treatment of cancer: New developments in reversing cancer drug resistance,rapid internalization,and improved anticancer efficacy

BackgroundCancer is a group of diseases involving an abnormal growth of cells which tend to proliferate in an uncontrolled fashion and in some cases metastasize to the surrounding tissues (malignancy). Resistance to chemotherapy is typically intrinsic (heterogeneity); however, acquired resistance has also become prevelant due to multiple factors including expression of energy-dependent transporters causing expulsion of internalized drug contents extracellular, insensitivity of tumor cells to drug-induced apoptosis, and induction of drug-detoxifying mechanisms. Curcumin (CUR) has gained widespread recognition due to remarkable anticancer, anti-mutagenic, and anti-metastasizing potentials via downregulation of proliferation of cancer cells and induction of apoptosis. Nevertheless, pharmaceutical significance and therapeutic feasibility of CUR is restricted due to intrinsic physicochemical characteristics including poor aqueous solubility, inadequate biological stability, low bioavailability, and short half-life.Scope and approachOwing to these pharmaceutical limitations of CUR, nanodelivery systems have attained remarkable fascination in the recent years. Therefore, this review was aimed to overview and critically ponders recent developments in improving anticancer viability of CUR.Key findings and conclusionCritical analysis of the literature revealed that nanodelivery systems showed promising efficiency in achieving tumor specific targetability, maximizing internalization of drugs into cancer cells, mitigating tumor metastasis, as well as improving anticancer efficacy of CUR. Moreover, nanocarrier-mediated improved pharmacokinetics, drug accumulation, induced promising cytotoxicity, and enhanced anticancer efficacy by suppressing Egr-1 induction, Mitogen-activated protein kinase (MAPK) pathway, and protein tyrosine kinase (PTK) cascades while mitigating the progression of tumor, have also been discussed.