Publications by authors named "Julius A Edson"

7 Publications

  • Page 1 of 1

Eradication of Intracellular Salmonella Typhimurium by Polyplexes of Acid-Transforming Chitosan and Fragment DNA.

Macromol Biosci 2021 Apr 18:e2000408. Epub 2021 Apr 18.

132 Sprague Hall, Irvine, CA, 92697, USA.

Antibiotics are highly successful against microbial infections. However, current challenges include rising antibiotic resistance rates and limited efficacy against intracellular pathogens. A novel form of a nanomaterial-based antimicrobial agent is investigated for efficient treatment of an intracellular Salmonella enterica sv Typhimurium infection. A known antimicrobial polysaccharide, chitosan, is engineered to be readily soluble under neutral aqueous conditions for systemic administration. The modified biologic, named acid-transforming chitosan (ATC), transforms into an insoluble, antimicrobial compound in the mildly acidic intracellular compartment. In cell culture experiments, ATC is confirmed to have antimicrobial activity against intracellular S. Typhimurium in a concentration- and pH-dependent manner, without affecting the host cells, RAW264.7 macrophages. For improved cellular uptake and pharmacokinetic/pharmacodynamic properties, ATC is further complexed with fragment DNA (fDNA), to form nano-sized spherical polyplexes. The resulting ATC/fDNA polyplexes efficiently eradicated S. Typhimurium from RAW264.7 macrophages. ATC/fDNA polyplexes may bind with microbial wall and membrane components. Consistent with this expectation, transposon insertion sequencing of a complex random mutant S. Typhimurium library incubated with ATC does not reveal specific genomic target regions of the antimicrobial. This study demonstrates the utility of a molecularly engineered nanomaterial as an efficient and safe antimicrobial agent, particularly against an intracellular pathogen.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mabi.202000408DOI Listing
April 2021

Biocompatible Chemotherapy for Leukemia by Acid-Cleavable, PEGylated FTY720.

Bioconjug Chem 2020 03 27;31(3):673-684. Epub 2020 Jan 27.

Zymo Research Corporation, Irvine, California 92604, United States.

Targeting the inability of cancerous cells to adapt to metabolic stress is a promising alternative to conventional cancer chemotherapy. FTY720 (Gilenya), an FDA-approved drug for the treatment of multiple sclerosis, has recently been shown to inhibit cancer progression through the down-regulation of essential nutrient transport proteins, selectively starving cancer cells to death. However, the clinical use of FTY720 for cancer therapy is prohibited because of its capability of inducing immunosuppression (lymphopenia) and bradycardia when phosphorylated upon administration. A prodrug to specifically prevent phosphorylation during circulation, hence avoiding bradycardia and lymphopenia, was synthesized by capping its hydroxyl groups with polyethylene glycol (PEG) via an acid-cleavable ketal linkage. Improved aqueous solubility was also accomplished by PEGylation. The prodrug reduces to fully potent FTY720 upon cellular uptake and induces metabolic stress in cancer cells. Enhanced release of FTY720 at a mildly acidic endosomal pH and the ability to substantially down-regulate cell-surface nutrient transporter proteins in leukemia cells only by an acid-cleaved drug were confirmed. Importantly, the prodrug demonstrated nearly identical efficacy to FTY720 in an animal model of BCR-Abl-driven leukemia without inducing bradycardia or lymphopenia in vivo, highlighting its potential clinical value. The prodrug formulation of FTY720 demonstrates the utility of precisely engineering a drug to avoid undesirable effects by tackling specific molecular mechanisms as well as a financially favorable alternative to new drug development. A multitude of existing cancer therapeutics may be explored for prodrug formulation to avoid specific side effects and preserve or enhance therapeutic efficacy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.bioconjchem.9b00822DOI Listing
March 2020

Cancer Cell-Derived, Drug-Loaded Nanovesicles Induced by Sulfhydryl-Blocking for Effective and Safe Cancer Therapy.

ACS Nano 2018 09 24;12(9):9568-9577. Epub 2018 Aug 24.

Department of Chemical Engineering and Materials Science , University of California , Irvine , California 92697 , United States.

Extracellular vesicles (EVs) pose great promise as therapeutic carriers due to their ideal size range and intrinsic biocompatibility. Limited scalability, poor quality control during production, and cumbersome isolation and purification processes have caused major setbacks in the progression of EV therapeutics to the clinic. Here, we overcome these setbacks by preparing cell-derived nanovesicles induced by sulfhydryl-blocking (NIbS), in the desirable size range for therapeutic delivery, that can be further loaded with the chemotherapeutic drug, doxorubicin (DOX), resulting in NIbS/DOX. Applicable to most cell types, this chemical blebbing approach enables efficient, quick, and simple harvest and purification as well as easily scalable production. Cellular uptake and intracellular release of DOX was improved using NIbS/DOX compared to a liposomal formulation. We also confirmed that in tumor-challenged C57BL/6 mice NIbS/DOX significantly slowed tumor growth and led to improved survival compared to treatment with free drug or liposomal drug. NIbS are a promising therapeutic carrier for improving cancer treatment outcomes since they are easy to prepare at a large scale, good candidates for drug loading, and capable of efficient administration of therapeutic agents with avoided nonspecific major distribution in vital organs. In addition, the utility of NIbS can be easily expanded to immunotherapy, gene therapy, and cell therapy when they are derived from applicable cell types.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsnano.8b05377DOI Listing
September 2018

Aqueous-Soluble, Acid-Transforming Chitosan for Efficient and Stimuli-Responsive Gene Silencing.

Biomacromolecules 2018 05 30;19(5):1508-1516. Epub 2018 Mar 30.

Despite its promises for biomedical applications, the lack of solubility in a physiological solution, the limited molecular interactions with nucleic acids due to the rigid backbone, and the inefficient intracellular release limit the use of chitosan, a natural cationic polysaccharide, for gene delivery. In this study, a flexible, aqueous-soluble aminoethoxy branch was conjugated to the primary hydroxyl group of chitosan via an acid-cleavable ketal linkage, resulting in acid-transforming chitosan (ATC) with greatly increased aqueous solubility, improved siRNA complexation, and degradability in response to an acidic pH. Acid-hydrolysis of ketal linkages, which triggers the loss of the flexible, cationic aminoethoxy branch, transforms ATC to the native form of chitosan with low water solubility, reduces molecular interaction with siRNA, and cooperatively facilitates the cytosolic release of siRNA. The siRNA complexation by ATC resulted in stable polyplexes under a neutral physiological condition, rapid cytosolic siRNA release from the mildly acidic endosome/lysosome, and substantial silencing of GFP expression in cells, notably with minimal cytotoxicity. This study demonstrates a molecularly engineered natural polymer for a biomedical application.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.biomac.8b00170DOI Listing
May 2018

Design, challenge, and promise of stimuli-responsive nanoantibiotics.

Nano Converg 2016 15;3(1):26. Epub 2016 Oct 15.

Department of Chemical Engineering and Material Science, University of California, Irvine, Irvine, CA USA ; Department of Pharmaceutical Sciences, University of California, Irvine, Irvine, CA USA ; Department of Biomedical Engineering, University of California, Irvine, Irvine, CA USA ; Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA USA ; 132 Sprague Hall, Irvine, CA USA.

Over the past few years, there have been calls for novel antimicrobials to combat the rise of drug-resistant bacteria. While some promising new discoveries have met this call, it is not nearly enough. The major problem is that although these new promising antimicrobials serve as a short-term solution, they lack the potential to provide a long-term solution. The conventional method of creating new antibiotics relies heavily on the discovery of an antimicrobial compound from another microbe. This paradigm of development is flawed due to the fact that microbes can easily transfer a resistant mechanism if faced with an environmental pressure. Furthermore, there has been some evidence to indicate that the environment of the microbe can provide a hint as to their virulence. Because of this, the use of materials with antimicrobial properties has been garnering interest. Nanoantibiotics, (nAbts), provide a new way to circumvent the current paradigm of antimicrobial discovery and presents a novel mechanism of attack not found in microbes yet; which may lead to a longer-term solution against drug-resistance formation. This allows for environment-specific activation and efficacy of the nAbts but may also open up and create new design methods for various applications. These nAbts provide promise, but there is still ample work to be done in their development. This review looks at possible ways of improving and optimizing nAbts by making them stimuli-responsive, then consider the challenges ahead, and industrial applications.Graphical abstractA graphic detailing how the current paradigm of antibiotic discovery can be circumvented by the use of nanoantibiotics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40580-016-0085-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5271158PMC
October 2016

Viral/Nonviral Chimeric Nanoparticles To Synergistically Suppress Leukemia Proliferation via Simultaneous Gene Transduction and Silencing.

ACS Nano 2016 09 5;10(9):8705-14. Epub 2016 Aug 5.

Department of Pharmaceutical Sciences, ‡Department of Chemical Engineering and Materials Science, §Department of Biological Sciences, ∥Division of Hematology/Oncology, ⊥Department of Molecular Biology and Biochemistry, and #Department of Biomedical Engineering, University of California , Irvine, California 92697, United States.

Single modal cancer therapy that targets one pathological pathway often turns out to be inefficient. For example, relapse of chronic myelogenous leukemia (CML) after inhibiting BCR-ABL fusion protein using tyrosine kinase inhibitors (TKI) (e.g., Imatinib) is of significant clinical concern. This study developed a dual modal gene therapy that simultaneously tackles two key BCR-ABL-linked pathways using viral/nonviral chimeric nanoparticles (ChNPs). Consisting of an adeno-associated virus (AAV) core and an acid-degradable polymeric shell, the ChNPs were designed to simultaneously induce pro-apoptotic BIM expression by the AAV core and silence pro-survival MCL-1 by the small interfering RNA (siRNA) encapsulated in the shell. The resulting BIM/MCL-1 ChNPs were able to efficiently suppress the proliferation of BCR-ABL+ K562 and FL5.12/p190 cells in vitro and in vivo via simultaneously expressing BIM and silencing MCL-1. Interestingly, the synergistic antileukemic effects generated by BIM/MCL-1 ChNPs were specific to BCR-ABL+ cells and independent of a proliferative cytokine, IL-3. The AAV core of ChNPs was efficiently shielded from inactivation by anti-AAV serum and avoided the generation of anti-AAV serum, without acute toxicity. This study demonstrates the development of a synergistically efficient, specific, and safe therapy for leukemia using gene carriers that simultaneously manipulate multiple and interlinked pathological pathways.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsnano.6b04155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5602606PMC
September 2016

RNAi for silencing drug resistance in microbes toward development of nanoantibiotics.

J Control Release 2014 Sep 2;189:150-7. Epub 2014 Jul 2.

Department of Chemical Engineering and Material Science, University of California, Irvine, CA, USA; Department of Pharmaceutical Sciences, University of California, Irvine, CA, USA; Department of Biomedical Engineering, University of California, Irvine, CA, USA; Department of Molecular Biology and Biochemistry, University of California, Irvine, CA, USA. Electronic address:

Multidrug-resistant microorganisms (MDRMOs) are progressively becoming an unavoidable challenge to worldwide health. Conventional antibiotics pressure resulted in increased bacterial efflux pumps lessening drug concentrations, up-regulated enzymes modifying/inactivating antibiotic compounds, or elevated mutations in the drug target site reducing antibiotic potency. Therefore, effective therapy for combating the emerging rate of MDRMOs requires innovative, combinatory strategies of generating conventional antimicrobial effects and simultaneously silencing drug-resistance processes in microbes. RNA interference (RNAi) is a revolutionary technology with high potential for obtaining synergistic therapies by knocking down antagonistic pathways with genomic specificity at a translational level. However, employing RNAi in antimicrobial therapy, particularly treating drug-resistant infections, has not received a great deal of attention. This paper briefly reviews key drug-resistance mechanisms in microbes, discusses the possibility of sensitizing MDRMOs to conventional antimicrobial therapy by combining it with RNAi, and introduces novel nano-scale formulation for efficient administration of such therapy (nanoantibiotics). The combined, synergistic antimicrobial therapy using antibiotics and RNAi may shed light when the current pipeline for new antibiotics is outrun by emergence of MDRMOs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jconrel.2014.06.054DOI Listing
September 2014