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Dive into the research topics where Christopher J. Cheng is active.

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Featured researches published by Christopher J. Cheng.


Nature | 2015

MicroRNA silencing for cancer therapy targeted to the tumour microenvironment

Christopher J. Cheng; Raman Bahal; Imran Babar; Zachary Pincus; Francisco N. Barrera; Connie Liu; Alexander A. Svoronos; Demetrios T. Braddock; Peter M. Glazer; Donald M. Engelman; W. Mark Saltzman; Frank J. Slack

MicroRNAs are short non-coding RNAs expressed in different tissue and cell types that suppress the expression of target genes. As such, microRNAs are critical cogs in numerous biological processes, and dysregulated microRNA expression is correlated with many human diseases. Certain microRNAs, called oncomiRs, play a causal role in the onset and maintenance of cancer when overexpressed. Tumours that depend on these microRNAs are said to display oncomiR addiction. Some of the most effective anticancer therapies target oncogenes such as EGFR and HER2; similarly, inhibition of oncomiRs using antisense oligomers (that is, antimiRs) is an evolving therapeutic strategy. However, the in vivo efficacy of current antimiR technologies is hindered by physiological and cellular barriers to delivery into targeted cells. Here we introduce a novel antimiR delivery platform that targets the acidic tumour microenvironment, evades systemic clearance by the liver, and facilitates cell entry via a non-endocytic pathway. We find that the attachment of peptide nucleic acid antimiRs to a peptide with a low pH-induced transmembrane structure (pHLIP) produces a novel construct that could target the tumour microenvironment, transport antimiRs across plasma membranes under acidic conditions such as those found in solid tumours (pH approximately 6), and effectively inhibit the miR-155 oncomiR in a mouse model of lymphoma. This study introduces a new model for using antimiRs as anti-cancer drugs, which can have broad impacts on the field of targeted drug delivery.


Nature Materials | 2012

Biodegradable poly(amine-co-ester) terpolymers for targeted gene delivery

Jiangbing Zhou; Jie Liu; Christopher J. Cheng; Toral R. Patel; Caroline E. Weller; Joseph M. Piepmeier; Zhaozhong Jiang; W. Mark Saltzman

Many synthetic polycationic vectors for non-viral gene delivery show high efficiency in vitro, but their usually excessive charge density makes them toxic for in vivo applications. Here we describe the synthesis of a series of high molecular weight terpolymers with low charge density, and show that they exhibit efficient gene delivery, some surpassing the efficiency of the commercial transfection reagents Polyethylenimine and Lipofectamine 2000. The terpolymers were synthesized via enzyme-catalyzed copolymerization of lactone with dialkyl diester and amino diol, and their hydrophobicity adjusted by varying the lactone content and by selecting a lactone comonomer of specific ring size. Targeted delivery of the pro-apoptotic TRAIL gene to tumour xenografts by one of the terpolymers results in significant inhibition of tumour growth, with minimal toxicity both in vitro and in vivo. Our findings suggest that the gene delivery ability of the terpolymers stems from their high molecular weight and increased hydrophobicity, which compensates for their low charge density.


Nature Reviews Drug Discovery | 2015

A holistic approach to targeting disease with polymeric nanoparticles.

Christopher J. Cheng; Gregory T. Tietjen; Jennifer K. Saucier-Sawyer; W. Mark Saltzman

The primary goal of nanomedicine is to improve clinical outcomes. To this end, targeted nanoparticles are engineered to reduce non-productive distribution while improving diagnostic and therapeutic efficacy. Paradoxically, as this field has matured, the notion of targeting has been minimized to the concept of increasing the affinity of a nanoparticle for its target. This Opinion article outlines a holistic view of nanoparticle targeting, in which the route of administration, molecular characteristics and temporal control of the nanoparticles are potential design variables that must be considered simultaneously. This comprehensive vision for nanoparticle targeting will facilitate the integration of nanomedicines into clinical practice.


Biomaterials | 2011

Enhanced siRNA delivery into cells by exploiting the synergy between targeting ligands and cell-penetrating peptides.

Christopher J. Cheng; W. Mark Saltzman

We have developed a polymer nanoparticle-based siRNA delivery system that exploits a cell surface binding synergism between targeting ligands and cell-penetrating peptides. Nanoparticles were coated with folate and penetratin via a PEGylated phospholipid linker (DSPE-PEG): the combination of both of these ligands represents a strategy for enhancing intracellular delivery of attached polymer nanoparticles. Nanoparticles were characterized for size, morphology, density of surface modification, and ligand association and retention. The surface coverage achieved on DSPE-PEG-coated nanoparticles is as high as (or higher than) obtained with other ligand-modified nano-scale particulate systems (∼0.5-5 pmol ligand/cm²). Additionally, these nanoparticles were loaded with a high density of siRNA (∼130-140 pmol siRNA/mg nanoparticles), which is slowly released upon incubation in water. Synergies between the activity of surface binding and cell internalizing ligands on these siRNA-loaded nanoparticles impart delivery enhancements that improve their gene silencing efficacy both in culture and in tumor models. Traditionally, targeting ligands function by binding to cell surface receptors, while cell-penetrating peptides function by nonspecifically transporting across cell membranes. Interestingly, we have observed that improved delivery of these dual-functionalized nanoparticles was in part, a result of increased cell surface avidity afforded by both ligands. This siRNA delivery system presents an approach to surface modification of nanovehicles, in which multiple ligands function in parallel to enhance cell binding and uptake.


Molecular Pharmaceutics | 2012

Polymer nanoparticle-mediated delivery of microRNA inhibition and alternative splicing

Christopher J. Cheng; W. Mark Saltzman

The crux of current RNA-based therapeutics relies on association of synthetic nucleic acids with cellular RNA targets. Antisense oligonucleotide binding to mature microRNA and splicing junctions on pre-mRNA represent methods of gene therapy that respectively inhibit microRNA-mediated gene regulation and induce alternative splicing. We have developed biodegradable polymer nanoparticles, which are coated with cell-penetrating peptides, that can effectively deliver chemically modified oligonucleotide analogues to achieve these forms of gene regulation. We found that this nanoparticle system could block the activity of the oncogenic microRNA, miR-155, as well as modulate splicing to attenuate the expression of the proto-oncogene, Mcl-1. Regulation of these genes in human cancer cells reduced cell viability and produced pro-apoptotic effects. These findings establish polymer nanoparticles as delivery vectors for nonconventional forms of gene therapy activated by cellular delivery of RNA-targeted molecules, which have strong therapeutic implications.


Journal of Controlled Release | 2012

Surface modified poly(β amino ester)-containing nanoparticles for plasmid DNA delivery.

Rachel J. Fields; Christopher J. Cheng; Elias Quijano; Caroline E. Weller; Nina Kristofik; Nha Duong; Christopher J. Hoimes; Marie E. Egan; W. Mark Saltzman

The use of biodegradable polymers provides a potentially safe and effective alternative to viral and liposomal vectors for the delivery of plasmid DNA to cells for gene therapy applications. In this work we describe the formulation of a novel nanoparticle (NP) system containing a blend of poly(lactic-co-glycolic acid) and a representative poly(beta-amino) ester (PLGA and PBAE respectively) for use as gene delivery vehicles. Particles of different weight/weight (wt/wt) ratios of the two polymers were characterized for size, morphology, plasmid DNA (pDNA) loading and surface charge. NPs containing PBAE were more effective at cellular internalization and transfection (COS-7 and CFBE41o-) than NPs lacking the PBAE polymer. However, along with these delivery benefits, PBAE exhibited cytotoxic effects that presented an engineering challenge. Surface coating of these blended particles with the cell-penetrating peptides (CPPs) mTAT, bPrPp and MPG via a PEGylated phospholipid linker (DSPE-PEG2000) resulted in NPs that reduced surface charge and cellular toxicity to levels comparable with NPs formulated with only PLGA. Additionally, these coated nanoparticles showed an improvement in pDNA loading, intracellular uptake and transfection efficiency, when compared to NPs lacking the surface coating. Although all particles with a CPP coating outperformed unmodified NPs, respectively, bPrPp and MPG coating resulted in 3 and 4.5× more pDNA loading than unmodified particles and approximately an order of magnitude improvement on transfection efficiency in CFBE41o- cells. These results demonstrate that surface-modified PBAE containing NPs are a highly effective and minimally toxic platform for pDNA delivery.


Cancer Research | 2016

miR-34a Silences c-SRC to Attenuate Tumor Growth in Triple-Negative Breast Cancer.

Brian D. Adams; Vikram B. Wali; Christopher J. Cheng; Sachi Inukai; Carmen J. Booth; Seema Agarwal; David L. Rimm; Balázs Győrffy; Libero Santarpia; Lajos Pusztai; W. Mark Saltzman; Frank J. Slack

Triple-negative breast cancer (TNBC) is an aggressive subtype with no clinically proven biologically targeted treatment options. The molecular heterogeneity of TNBC and lack of high frequency driver mutations other than TP53 have hindered the development of new and effective therapies that significantly improve patient outcomes. miRNAs, global regulators of survival and proliferation pathways important in tumor development and maintenance, are becoming promising therapeutic agents. We performed miRNA-profiling studies in different TNBC subtypes to identify miRNAs that significantly contribute to disease progression. We found that miR-34a was lost in TNBC, specifically within mesenchymal and mesenchymal stem cell-like subtypes, whereas expression of miR-34a targets was significantly enriched. Furthermore, restoration of miR-34a in cell lines representing these subtypes inhibited proliferation and invasion, activated senescence, and promoted sensitivity to dasatinib by targeting the proto-oncogene c-SRC. Notably, SRC depletion in TNBC cell lines phenocopied the effects of miR-34a reintroduction, whereas SRC overexpression rescued the antitumorigenic properties mediated by miR-34a. miR-34a levels also increased when cells were treated with c-SRC inhibitors, suggesting a negative feedback exists between miR-34a and c-SRC. Moreover, miR-34a administration significantly delayed tumor growth of subcutaneously and orthotopically implanted tumors in nude mice, and was accompanied by c-SRC downregulation. Finally, we found that miR-34a and SRC levels were inversely correlated in human tumor specimens. Together, our results demonstrate that miR-34a exerts potent antitumorigenic effects in vitro and in vivo and suggests that miR-34a replacement therapy, which is currently being tested in human clinical trials, represents a promising therapeutic strategy for TNBC.


The FASEB Journal | 2014

Sustained delivery of proangiogenic microRNA-132 by nanoparticle transfection improves endothelial cell transplantation

Julie Devallière; William G. Chang; Jillian W. Andrejecsk; Parwiz Abrahimi; Christopher J. Cheng; Dan Jane-wit; W. Mark Saltzman; Jordan S. Pober

Transplantation of endothelial cells (ECs) for therapeutic vascularization or tissue engineering is a promising method for increasing tissue perfusion. Here, we report on a new approach for enhanced EC transplantation using targeted nanoparticle transfection to deliver proangiogenic microRNA‐132 (miR‐132) to cultured ECs before their transplantation, thereby sensitizing cells to the effects of endogenous growth factors. We synthesized biodegradable PLGA polymer nanoparticles (NPs) that were loaded with miR‐132 and coated with cyclic RGD (cRGD) peptides that target integrin αvβ3 expressed on cultured human umbilical vein ECs (HUVECs), increasing NP uptake through clathrin‐coated pits. Unlike previously reported NPs for miR delivery, these NPs slowly release RNA for several weeks. The endocytosed NPs remain in clathrin‐coated vesicles from which they mediate intracellular delivery of siRNA or miRNA. Transfection of HUVECs with miR‐132 enhances growth factor‐induced proliferation and migration in 2D culture, producing a 1.8‐ and 5‐fold increase, respectively. However, while the effects of conventional transfection were short‐lived, NP transfection produced protein knockdown and biological effects that were significantly longer in duration (≥6 d). Transfection of HUVECs with miR‐132 NP resulted in a 2‐fold increase in the number of microvessels per square millimeter compared to lipid after transplantation into immunodeficient mice and led to a higher number of mural cell‐invested vessels than control transfection. These data suggest that sustained delivery of miR‐132 encapsulated in a targeted biodegradable polymer NP is a safe and efficient strategy to improve EC transplantation and vascularization.—Devalliere, J., Chang, W. G., Andrejecsk, J. W., Abrahimi, P., Cheng, C. J., Jane‐wit, D., Saltzman, W. M., Pober, J. S. Sustained delivery of proangiogenic microRNA‐132 by nanoparticle transfection improves endothelial cell transplantation. FASEB J. 28, 908–922 (2014). www.fasebj.org


The Journal of Neuroscience | 2015

miR-155 Is Essential for Inflammation-Induced Hippocampal Neurogenic Dysfunction.

Maya E. Woodbury; Robert W. Freilich; Christopher J. Cheng; Hirohide Asai; Seiko Ikezu; Jonathan D. Boucher; Frank J. Slack; Tsuneya Ikezu

Peripheral and CNS inflammation leads to aberrations in developmental and postnatal neurogenesis, yet little is known about the mechanism linking inflammation to neurogenic abnormalities. Specific miRs regulate peripheral and CNS inflammatory responses. miR-155 is the most significantly upregulated miR in primary murine microglia stimulated with lipopolysaccharide (LPS), a proinflammatory Toll-Like Receptor 4 ligand. Here, we demonstrate that miR-155 is essential for robust IL6 gene induction in microglia under LPS stimulation in vitro. LPS-stimulated microglia enhance astrogliogenesis of cocultured neural stem cells (NSCs), whereas blockade of IL6 or genetic ablation of microglial miR-155 restores neural differentiation. miR-155 knock-out mice show reversal of LPS-induced neurogenic deficits and microglial activation in vivo. Moreover, mice with transgenic elevated expression of miR-155 in nestin-positive neural and hematopoietic stem cells, including microglia, show increased cell proliferation and ectopically localized doublecortin-positive immature neurons and radial glia-like cells in the hippocampal dentate gyrus (DG) granular cell layer. Microglia have proliferative and neurogenic effects on NSCs, which are significantly altered by microglial miR-155 overexpression. In addition, miR-155 elevation leads to increased microglial numbers and amoeboid morphology in the DG. Our study demonstrates that miR-155 is essential for inflammation-induced neurogenic deficits via microglial activation and induction of IL6 and is sufficient for disrupting normal hippocampal development.


Cancer Journal | 2012

The Duality of OncomiR Addiction in the Maintenance and Treatment of Cancer

Christopher J. Cheng; Frank J. Slack

AbstractIt has long been established that cancers can become addicted to particular oncogenes. Despite the genetic complexity that governs tumorigenesis, certain cancers can exhibit a critical dependency on the expression of a single oncogene, which when removed leads to death of the cancer cell. Recent observations on the relationships between regulatory RNAs and cancer have revealed that this concept of oncogene addiction extends to microRNAs (miRNAs) as well. Certain cancers exhibit a dependency on the expression of a single oncogenic miRNA, or oncomiR. The field of miRNA biology and its involvement in diseases such as cancer have seen tremendous advances over the past decade. However, little is known about the phenomenon of oncomiR addiction. In this review, we introduce the concept of proto-oncomiRs, or miRNAs that gain oncogenic activity after an initiating event. Furthermore, by highlighting the role of proto-oncomiRs in generating malignant phenotypes, we glean possible insights into the mechanisms that guide oncomiR addiction. In addition, toward the realization of genetically driven personalized medicine, some of the most clinically successful anticancer strategies have involved targeting addictive oncogenes such as HER2, BCR/ABL, EGFR, and VEGF. Elucidating how addictive miRNAs can perpetuate cancer may reveal additional critical molecular targets to exploit for therapeutic purposes. Therefore, in this review, we also summarize the field of anti-miRNA therapeutics, in which antisense and nanoscale delivery technologies are the driving force. Addictive oncomiRs are a double-edged sword; addicted cancers are dependent on oncomiRs that are highly potent therapeutic targets. Dissection of this phenomenon may reveal the mechanisms through which lynchpin miRNAs can perpetuate cancer and present a new paradigm for miRNA-based cancer therapy.

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Frank J. Slack

Beth Israel Deaconess Medical Center

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Christopher J. Hoimes

Case Western Reserve University

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