Publications by authors named "Young Jik Kwon"

63 Publications

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

COVID-19: An unprecedented challenge and an opportunity for change.

Adv Drug Deliv Rev 2021 Jan 29;171:48-49. Epub 2021 Jan 29.

Department of Molecular Biology and Biochemistry, School of Biological Sciences, University of California, Irvine, USA; Division of Infectious Diseases, Department of Medicine, University of California, Irvine, USA.

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http://dx.doi.org/10.1016/j.addr.2021.01.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845530PMC
January 2021

COVID-19 vaccines: The status and perspectives in delivery points of view.

Adv Drug Deliv Rev 2021 03 24;170:1-25. Epub 2020 Dec 24.

Department of Pharmaceutical Sciences, University of California, Irvine, CA 92697, United States of America; Department of Chemical and Biomolecular Engineering, University of California, Irvine, CA 92697, United States of America; Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697, United States of America; Department of Biomedical Engineering, University of California, Irvine, CA 92697, United States of America. Electronic address:

Due to the high prevalence and long incubation periods often without symptoms, the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has infected millions of individuals globally, causing the coronavirus disease 2019 (COVID-19) pandemic. Even with the recent approval of the anti-viral drug, remdesivir, and Emergency Use Authorization of monoclonal antibodies against S protein, bamlanivimab and casirimab/imdevimab, efficient and safe COVID-19 vaccines are still desperately demanded not only to prevent its spread but also to restore social and economic activities via generating mass immunization. Recent Emergency Use Authorization of Pfizer and BioNTech's mRNA vaccine may provide a pathway forward, but monitoring of long-term immunity is still required, and diverse candidates are still under development. As the knowledge of SARS-CoV-2 pathogenesis and interactions with the immune system continues to evolve, a variety of drug candidates are under investigation and in clinical trials. Potential vaccines and therapeutics against COVID-19 include repurposed drugs, monoclonal antibodies, antiviral and antigenic proteins, peptides, and genetically engineered viruses. This paper reviews the virology and immunology of SARS-CoV-2, alternative therapies for COVID-19 to vaccination, principles and design considerations in COVID-19 vaccine development, and the promises and roles of vaccine carriers in addressing the unique immunopathological challenges presented by the disease.
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http://dx.doi.org/10.1016/j.addr.2020.12.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759095PMC
March 2021

Solvent-driven, self-assembled acid-responsive poly(ketalized serine)/siRNA complexes for RNA interference.

Biomater Sci 2020 Dec 28;8(23):6718-6729. Epub 2020 Oct 28.

Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University of California, Irvine, CA 92697, USA.

Advances in bionanotechnology aim to develop smart nucleic acid delivery carriers with stimuli-responsive features to overcome challenges such as non-biodegradability, rapid clearance, immune response, and reaching intracellular targets. Peptide-based nanomaterials have become widely used in the field of gene and drug delivery due to their structural versatility and biomimetic properties. Particularly, polypeptide gene vectors that respond to biological stimuli, such as acidic intracellular environments, have promising applications in mediating efficient endosomal escape and drug release. Unfortunately, synthesis strategies for efficient polymerization of acid-labile peptides have been limited due to conditions that fail to preserve acid-degradable functional groups. Stable urethane derivatives of the acid-labile amino acid ketalized serine (kSer) were synthesized and polymerized to a high molecular weight under permissive conditions independent of elevated temperature, restrictive solvents, or an inert atmosphere. A new formulation strategy utilizing solvent-driven self-assembly of poly(kSer) peptides with small interfering RNA (siRNA) was developed, and the resulting poly(kSer)/siRNA complexes were further cross-linked for reinforced stability under physiological conditions. The complexes were highly monodisperse and precisely spherical in morphology, which has significant clinical implications in definitive biodistribution, cellular internalization, and intracellular trafficking patterns. Self-assembled, cross-linked poly(kSer)/siRNA complexes demonstrated efficient nucleic acid encapsulation, internalization, endosomal escape, and acid-triggered cargo release, tackling multiple hurdles in siRNA delivery. The acid-responsive polypeptides and solvent-driven self-assembly strategies demonstrated in this study could be applicable to developing other efficient and safe delivery systems for gene and drug delivery.
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http://dx.doi.org/10.1039/d0bm01478hDOI Listing
December 2020

Synthetically Engineered Adeno-Associated Virus for Efficient, Safe, and Versatile Gene Therapy Applications.

ACS Nano 2020 11 19;14(11):14262-14283. Epub 2020 Oct 19.

Gene therapy directly targets mutations causing disease, allowing for a specific treatment at a molecular level. Adeno-associated virus (AAV) has been of increasing interest as a gene delivery vehicle, as AAV vectors are safe, effective, and capable of eliciting a relatively contained immune response. With the recent FDA approval of two AAV drugs for treating rare genetic diseases, AAV vectors are now on the market and are being further explored for other therapies. While showing promise in immune privileged tissue, the use of AAV for systemic delivery is still limited due to the high prevalence of neutralizing antibodies (nAbs). To avoid nAb-mediated inactivation, engineered AAV vectors with modified protein capsids, materials tethered to the capsid surface, or fully encapsulated in a second, larger carrier have been explored. Many of these engineered AAVs have added benefits, including avoided immune response, overcoming the genome size limit, targeted and stimuli-responsive delivery, and multimodal therapy of two or more therapeutic modalities in one platform. Native and engineered AAV vectors have been tested to treat a broad range of diseases, including spinal muscular atrophy, retinal diseases, cancers, and tissue damage. This review will cover the benefits of AAV as a promising gene vector by itself, the progress and advantages of engineered AAV vectors, particularly synthetically engineered ones, and the current state of their clinical translation in therapy.
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http://dx.doi.org/10.1021/acsnano.0c03850DOI Listing
November 2020

Extracellular vesicles (EVs): Comprehensive packages with promises and complications for clinical translation and commercialization.

Authors:
Young Jik Kwon

Methods 2020 05 4;177. Epub 2020 Mar 4.

Department of Pharmaceutical Sciences, University of California, Irvine, 132 Sprague Hall, Irvine, CA 92617, United States. Electronic address:

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http://dx.doi.org/10.1016/j.ymeth.2020.03.001DOI Listing
May 2020

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

Extracellular blebs: Artificially-induced extracellular vesicles for facile production and clinical translation.

Methods 2020 05 14;177:135-145. Epub 2019 Nov 14.

Department of Chemical and Biomolecular Engineering, University of California, Irvine, CA 92697, United States; Department of Pharmaceutical Sciences, University of California, Irvine, CA 92697, United States; Department of Biomedical Engineering, University of California, Irvine, CA 92697, United States; Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697, United States. Electronic address:

Extracellular vesicles (EVs) have emerged as promising biologic and comprehensive therapies for precision medicine. Despite their potential demonstrated at the benchtop, few EV formulations have made it to the clinic due to challenges in regulatory compliant scalable production; including purity, homogeneity, and reproducibility. For translation of this technology, there is a strong need for novel production methods that can meet clinical production criteria. Initial research aimed to address these challenges by taking advantage of natural pathways to increase EV yields. Such "conventional" approaches moderately increased yields but produced inhomogeneous EVs. Additionally, as there are currently no standard methods for isolation, characterization, or quantification, isolated EVs were often impure, contaminated with proteins and other biomacromolecules, and highly diverse in function. The use of shear stress and extrusion methods for EV-like vesicle production has also been investigated. While these processes can produce large EV-like vesicle yields nearly immediately, the harsh processes still result in inhomogeneous loading, and still suffer from poor purity. Chemically-induced membrane blebbing is a promising alternative production method that has the potential to overcome the previously insurmountable barriers of these current methods. This technique produces pure, and well defined EV-like vesicles, termed extracellular blebs (EBs), in clinically relevant scales over the course of minutes to hours. Furthermore, blebbing agents act on the cell in a way which locks the current surface properties and contents, preventing change, allowing for homogeneous EB production, and further preventing post-production changes. EBs may provide a promising pathway for clinical translation of EV technology.
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http://dx.doi.org/10.1016/j.ymeth.2019.11.007DOI Listing
May 2020

Engineered extracellular vesicles and their mimetics for clinical translation.

Methods 2020 05 15;177:80-94. Epub 2019 Oct 15.

Department of Chemical Engineering, University of Seoul, 163 Seoulsiripdaero, Dongdaemungu, Seoul 02504, Republic of Korea. Electronic address:

Cells secrete extracellular vesicles (EVs) to external environments to achieve cellular homeostasis and cell-to-cell communication. Their therapeutic potential has been constantly spotlighted since they mirror both cytoplasmic and membranous components of parental cells. Meanwhile, growing evidence suggests that EV engineering could further promote EVs with a maximized capacity. In this review, a range of engineering techniques as well as upscaling approaches to exploit EVs and their mimetics are introduced. By laying out the pros and cons of each technique from different perspectives, we sought to provide an overview potentially helpful for understanding the current state of the art EV engineering and a guideline for choosing a suitable technique for engineering EVs. Furthermore, we envision that the advances in each technique will give rise to the combinatorial engineering of EVs, taking us a step closer to a clinical translation of EV-based therapeutics.
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http://dx.doi.org/10.1016/j.ymeth.2019.10.005DOI Listing
May 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.
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http://dx.doi.org/10.1021/acsnano.8b05377DOI Listing
September 2018

Corrigendum to molecular genetics and emerging therapies for retinitis pigmentosa: Basic research and clinical perspective progress in retinal and eye research (2018) Vol 63,107-131.

Prog Retin Eye Res 2018 09 11;66:220-221. Epub 2018 Aug 11.

Department of Pharmaceutical Sciences, University of California, Irvine, CA, USA; Department of Chemical Engineering and Materials 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:

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http://dx.doi.org/10.1016/j.preteyeres.2018.08.001DOI 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.
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http://dx.doi.org/10.1021/acs.biomac.8b00170DOI Listing
May 2018

Stimuli-disassembling gold nanoclusters for diagnosis of early stage oral cancer by optical coherence tomography.

Nano Converg 2018 26;5(1). Epub 2018 Jan 26.

1Department of Chemical Engineering and Materials Science, University of California, Irvine, 916 Engineering Tower, Irvine, CA 92697-2575 USA.

A key design consideration in developing contrast agents is obtaining distinct, multiple signal changes in diseased tissue. Plasmonic gold nanoparticles (Au NPs) have been developed as contrast agents due to their strong surface plasmon resonance (SPR). This study aims to demonstrate that stimuli-responsive plasmonic Au nanoclusters (Au NCs) can be used as a contrast agent for optical coherence tomography (OCT) in detecting early-stage cancer. Au NPs were clustered via acid-cleavable linkers to synthesize Au NCs that disassemble under mildly acidic conditions into individual Au NPs, simultaneously diminishing SPR effect (quantified by scattering intensity) and increasing Brownian motion (quantified by Doppler variance). The acid-triggered morphological and accompanying optico-physical property changes of the acid-disassembling Au NCs were confirmed by TEM, DLS, UV/Vis, and OCT. Stimuli-responsive Au NCs were applied in a hamster check pouch model carrying early-stage squamous carcinoma tissue. The tissue was visualized by OCT imaging, which showed reduced scattering intensity and increased Doppler variance in the dysplastic tissue. This study demonstrates the promise of diagnosing early-stage cancer using molecularly programmable, inorganic nanomaterial-based contrast agents that are capable of generating multiple, stimuli-triggered diagnostic signals in early-stage cancer.
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http://dx.doi.org/10.1186/s40580-018-0134-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5785591PMC
January 2018

Molecular genetics and emerging therapies for retinitis pigmentosa: Basic research and clinical perspectives.

Prog Retin Eye Res 2018 03 31;63:107-131. Epub 2017 Oct 31.

Department of Pharmaceutical Sciences, University of California, Irvine, CA, USA; Department of Chemical Engineering and Materials 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:

Retinitis Pigmentosa (RP) is a hereditary retinopathy that affects about 2.5 million people worldwide. It is characterized with progressive loss of rods and cones and causes severe visual dysfunction and eventual blindness in bilateral eyes. In addition to more than 3000 genetic mutations from about 70 genes, a wide genetic overlap with other types of retinal dystrophies has been reported with RP. This diversity of genetic pathophysiology makes treatment extremely challenging. Although therapeutic attempts have been made using various pharmacologic agents (neurotrophic factors, antioxidants, and anti-apoptotic agents), most are not targeted to the fundamental cause of RP, and their clinical efficacy has not been clearly proven. Current therapies for RP in ongoing or completed clinical trials include gene therapy, cell therapy, and retinal prostheses. Gene therapy, a strategy to correct the genetic defects using viral or non-viral vectors, has the potential to achieve definitive treatment by replacing or silencing a causative gene. Among many clinical trials of gene therapy for hereditary retinal diseases, a phase 3 clinical trial of voretigene neparvovec (AAV2-hRPE65v2, Luxturna) recently showed significant efficacy for RPE65-mediated inherited retinal dystrophy including Leber congenital amaurosis and RP. It is about to be approved as the first ocular gene therapy biologic product. Despite current limitations such as limited target genes and indicated patients, modest efficacy, and the invasive administration method, development in gene editing technology and novel gene delivery carriers make gene therapy a promising therapeutic modality for RP and other hereditary retinal dystrophies in the future.
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http://dx.doi.org/10.1016/j.preteyeres.2017.10.004DOI Listing
March 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.
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http://dx.doi.org/10.1186/s40580-016-0085-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5271158PMC
October 2016

Good things come in small packages: Overcoming challenges to harness extracellular vesicles for therapeutic delivery.

J Control Release 2016 11 22;241:174-185. Epub 2016 Sep 22.

Department of Chemical Engineering and Materials Science, University of California, Irvine, CA 92697, United States; Department of Chemical and Biological Engineering, Korea University, Seoul, Republic of Korea; Department of Pharmaceutical Sciences, University of California, Irvine, CA 92697, United States; Department of Biomedical Engineering, University of California, Irvine, CA 92697, United States; Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697, United States. Electronic address:

Extracellular vesicles (EVs) hold great promise as potential therapeutic carriers. EVs are biologically active, intrinsically transporting cargo between cells. Moreover, they can be loaded with specific cargo for distribution and/or engineered to achieve enhanced uptake. Although studies have already demonstrated therapeutic delivery using EVs, various challenges must be overcome before EV technology is ready for the clinic. Since the properties of EVs are dependent upon their cell of origin and the conditions of their formation, establishing clear characterization practices is essential to ensuring reproducibility and safety. Identifying methods for mass production of EVs is crucial for achieving high EV yields necessary for clinical trials. This review introduces current theory behind EV formation and function, describes the latest methods for characterization and mass production, and discusses future opportunities for extracellular vesicles in therapeutic delivery.
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http://dx.doi.org/10.1016/j.jconrel.2016.09.016DOI Listing
November 2016

Gold nanocrystals with DNA-directed morphologies.

Nat Commun 2016 09 16;7:12873. Epub 2016 Sep 16.

Department of Chemical &Biological Engineering, Korea University, Seoul 136713, Republic of Korea.

Precise control over the structure of metal nanomaterials is important for developing advanced nanobiotechnology. Assembly methods of nanoparticles into structured blocks have been widely demonstrated recently. However, synthesis of nanocrystals with controlled, three-dimensional structures remains challenging. Here we show a directed crystallization of gold by a single DNA molecular regulator in a sequence-independent manner and its applications in three-dimensional topological controls of crystalline nanostructures. We anchor DNA onto gold nanoseed with various alignments to form gold nanocrystals with defined topologies. Some topologies are asymmetric including pushpin-, star- and biconcave disk-like structures, as well as more complex jellyfish- and flower-like structures. The approach of employing DNA enables the solution-based synthesis of nanocrystals with controlled, three-dimensional structures in a desired direction, and expands the current tools available for designing and synthesizing feature-rich nanomaterials for future translational biotechnology.
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http://dx.doi.org/10.1038/ncomms12873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5028415PMC
September 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.
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http://dx.doi.org/10.1021/acsnano.6b04155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5602606PMC
September 2016

Aptamers: The "evolution" of SELEX.

Methods 2016 08 19;106:21-8. Epub 2016 Apr 19.

Department of Pharmaceutical Sciences, University of California, Irvine, CA 92697, United States; Department of Chemical Engineering and Materials Science, University of California, Irvine, CA 92697, United States; Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697, United States; Department of Biomedical Engineering, University of California, Irvine, CA 92697, United States. Electronic address:

It has been more than two decades since the first aptamer molecule was discovered. Since then, aptamer molecules have gain much attention in the scientific field. This increasing traction can be attributed to their many desirable traits, such as 1) their potentials to bind a wide range of molecules, 2) their malleability, and 3) their low cost of production. These traits have made aptamer molecules an ideal platform to pursue in the realm of pharmaceuticals and bio-sensors. Despite the broad applications of aptamers, tedious procedure, high resource consumption, and limited nucleobase repertoire have hindered aptamer in application usage. To address these issues, new innovative methodologies, such as automation and single round SELEX, are being developed to improve the outcomes and rates in which aptamers are discovered.
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http://dx.doi.org/10.1016/j.ymeth.2016.04.020DOI Listing
August 2016

Killing two birds or more with one stone.

Adv Drug Deliv Rev 2016 Mar;98:1-2

Department of Pharmaceutical Sciences, University of California, Irvine, CA 92697, United States; Department of Chemical Engineering and Materials Science, University of California, Irvine, CA 92697, United States; Department of Biomedical Engineering, University of California, Irvine, CA 92697, United States; Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697, United States.

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http://dx.doi.org/10.1016/j.addr.2016.01.019DOI Listing
March 2016

"Combo" nanomedicine: Co-delivery of multi-modal therapeutics for efficient, targeted, and safe cancer therapy.

Adv Drug Deliv Rev 2016 Mar 4;98:3-18. Epub 2015 Nov 4.

Department of Pharmaceutical Sciences, University of California, Irvine, CA 92697, United States; Department of Chemical Engineering and Materials Science,University of California, Irvine, CA 92697, United States; Department of Biomedical Engineering,University of California, Irvine, CA 92697, United States; Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697, United States. Electronic address:

The dynamic and versatile nature of diseases such as cancer has been a pivotal challenge for developing efficient and safe therapies. Cancer treatments using a single therapeutic agent often result in limited clinical outcomes due to tumor heterogeneity and drug resistance. Combination therapies using multiple therapeutic modalities can synergistically elevate anti-cancer activity while lowering doses of each agent, hence, reducing side effects. Co-administration of multiple therapeutic agents requires a delivery platform that can normalize pharmacokinetics and pharmacodynamics of the agents, prolong circulation, selectively accumulate, specifically bind to the target, and enable controlled release in target site. Nanomaterials, such as polymeric nanoparticles, gold nanoparticles/cages/shells, and carbon nanomaterials, have the desired properties, and they can mediate therapeutic effects different from those generated by small molecule drugs (e.g., gene therapy, photothermal therapy, photodynamic therapy, and radiotherapy). This review aims to provide an overview of developing multi-modal therapies using nanomaterials ("combo" nanomedicine) along with the rationale, up-to-date progress, further considerations, and the crucial roles of interdisciplinary approaches.
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http://dx.doi.org/10.1016/j.addr.2015.10.019DOI Listing
March 2016

Photochemical internalization-mediated nonviral gene transfection: polyamine core-shell nanoparticles as gene carrier.

J Biomed Opt 2014 ;19(10):105009

University of California, Beckman Laser Institute, 1002 Health Sciences Road East, Irvine, California 92612, United StateseUniversity of Nevada, Department of Health Physics and Diagnostic Sciences, 4505 Maryland Parkway, Las Vegas, Nevada 89154, United S.

The overall objective of the research was to investigate the utility of photochemical internalization (PCI) for the enhanced nonviral transfection of genes into glioma cells. The PCI-mediated introduction of the tumor suppressor gene phosphatase and tensin homolog (PTEN) or the cytosine deaminase (CD) pro-drug activating gene into U87 or U251 glioma cell monolayers and multicell tumor spheroids were evaluated. In the study reported here, polyamine-DNA gene polyplexes were encapsulated in a nanoparticle (NP) with an acid degradable polyketal outer shell. These NP synthetically mimic the roles of viral capsid and envelope, which transport and release the gene, respectively. The effects of PCI-mediated suppressor and suicide genes transfection efficiency employing either “naked” polyplex cores alone or as NP-shelled cores were compared. PCI was performed with the photosensitizer AlPcS 2a and λ=670-nm laser irradiance. The results clearly demonstrated that the PCI can enhance the delivery of both the PTEN or CD genes in human glioma cell monolayers and multicell tumor spheroids. The transfection efficiency, as measured by cell survival and inhibition of spheroid growth, was found to be significantly greater at suboptimal light and DNA levels for shelled NPs compared with polyamine-DNA polyplexes alone.
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http://dx.doi.org/10.1117/1.JBO.19.10.105009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4206751PMC
March 2015

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

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

Synthetically designed peptide-based biomaterials with stimuli-responsive and membrane-active properties for biomedical applications.

J Mater Chem B 2014 Feb 9;2(6):595-615. Epub 2013 Dec 9.

Department of Pharmaceutical Sciences, University of California Irvine, 132 Sprague Hall, Irvine, CA 92697, USA.

Peptide-based biomaterials have been extensively investigated for biomedical applications due to their high structural and functional versatility. Particularly, peptides that can respond to different stimuli, such as pH, redox potential, temperature, light, and enzymes can offer controllable actions in target body locations. Therefore, smart, multifunctional peptide-based nanoparticle (NP) systems that respond to pathological stimuli with the ability to facilitate cellular internalization and enhance cytosolic release via disrupting membranes are of great interest in biomaterials research. This review predominantly focuses on synthetically designed stimuli-responsive peptides that serve different biomedical applications, with emphasis on drug and gene delivery, and touches upon recent advances in membrane-active peptide NPs for enhanced therapeutic activity. The review also provides an outlook on future directions on the maturing field of peptide-based therapeutics.
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http://dx.doi.org/10.1039/c3tb21344gDOI Listing
February 2014

Stimuli-responsive siRNA carriers for efficient gene silencing in tumors via systemic delivery.

Biomater Sci 2014 Jan 24;2(1):35-40. Epub 2013 Oct 24.

Division of Bioengineering, Incheon National University, Incheon 406-772, Republic of Korea.

Development of efficient carriers for small interfering RNA (siRNA) delivery and validation tools for assessing in vivo RNA interference (RNAi) efficiency is crucial to advance RNAi-based therapeutics to the clinic. Here, acid-degradable ketalized linear polyethylenimine (KL-PEI) designed for efficient, stimuli-responsive, and biocompatible siRNA delivery was used to complex with GFP-silencing siRNA (GFP siRNA) for in vivo RNAi. The in vivo gene silencing efficiency of GFP siRNA/KL-PEI polyplexes was evaluated at mRNA, protein, and histological levels using a mouse bearing a GFP-expressing tumor. Intravenously injected GFP siRNA/KL-PEI polyplexes significantly reduced GFP expression in tumors and whole blood of mice, depending on the dosage of GFP siRNA and the time course. Average GFP mRNA levels in the tumors of siRNA/KL-PEI polyplex-injected mice were also reduced. The described siRNA carriers and RNAi validation methodologies in this study may provide insightful clues for the development of RNAi-based therapeutics and preclinical trials.
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http://dx.doi.org/10.1039/c3bm60187kDOI Listing
January 2014

Acid-degradable core-shell nanoparticles for reversed tamoxifen-resistance in breast cancer by silencing manganese superoxide dismutase (MnSOD).

Biomaterials 2013 Dec 19;34(38):10228-37. Epub 2013 Sep 19.

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

Drug resistance acquired by cancer cells is a significant challenge in the clinic and requires impairing the responsible pathological pathway. Administering chemotherapeutics along with silencing resistance-basis activity using RNA interference (RNAi) is expected to restore the activity of the chemotherapeutic and generate synergistic cancer eradication. This study attempted to reverse tamoxifen (TAM)-resistance in breast cancer by silencing a mitochondrial enzyme, manganese superoxide dismutase (MnSOD), which dismutates TAM-induced reactive oxygen species (ROS) (i.e., superoxide) to less harmful hydrogen peroxide and hampers therapeutic effects. Breast cancer cells were co-treated with TAM and MnSOD siRNA-delivering nanoparticles (NPs) made of a siRNA/poly(amidoamine) (PAMAM) dendriplex core and an acid-degradable polyketal (PK) shell. The (siRNA/PAMAM)-PK NPs were designed for the PK shell to shield siRNA from nucleases, minimize detrimental aggregation in serum, and facilitate cytosolic release of siRNA from endosomal compartments. This method of forming the PK shell around the siRNA/PAMAM core via surface-initiated photo-polymerization enables ease of tuning NPs' size for readily controlled siRNA release kinetics. The resulting NPs were notably homogenous in size, resistant to aggregation in serum, and invulnerable to heparan sulfate-mediated disassembly, compared to siRNA/PAMAM dendriplexes. Gel electrophoresis and confocal microscopy confirmed efficient siRNA release from the (siRNA/PAMAM)-PK NPs upon stimuli-responsive hydrolysis of the PK shell. Sensitization of TAM-resistant MCF7-BK-TR breast cancer cells with (MnSOD siRNA/PAMAM)-PK NPs restored TAM-induced cellular apoptosis in vitro and significantly suppressed tumor growth in vivo, as confirmed by biochemical assays and histological observations. This study implies that combined gene silencing and chemotherapy is a promising strategy to overcoming a significant challenge in cancer therapy.
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http://dx.doi.org/10.1016/j.biomaterials.2013.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3989112PMC
December 2013

Imaging and quantifying Brownian motion of micro- and nanoparticles using phase-resolved Doppler variance optical coherence tomography.

J Biomed Opt 2013 Mar;18(3):030504

Different types and sizes of micro- and nanoparticles have been synthesized and developed for numerous applications. It is crucial to characterize the particle sizes. Traditional dynamic light scattering, a predominant method used to characterize particle size, is unable to provide depth resolved information or imaging functions. Doppler variance optical coherence tomography (OCT) measures the spectral bandwidth of the Doppler frequency shift due to the Brownian motion of the particles utilizing the phase-resolved approach and can provide quantitative information about particle size. Spectral bandwidths of Doppler frequency shifts for various sized particles were quantified and were demonstrated to be inversely proportional to the diameter of the particles. The study demonstrates the phase-resolved Doppler variance spectral domain OCT technique has the potential to be used to investigate the properties of particles in highly scattering media.
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http://dx.doi.org/10.1117/1.JBO.18.3.030504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3603150PMC
March 2013

Real-time, sensitive, and specific detection of promoter-polymerase interactions in gene transcription using a nanoplasmonic sensor.

Adv Mater 2013 Mar 20;25(9):1265-9. Epub 2012 Nov 20.

Department of Chemical Engineering, Sungkyunkwan University, Suwon 440-746, Korea.

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http://dx.doi.org/10.1002/adma.201203467DOI Listing
March 2013

Glioma cell growth inhibition following photochemical internalization enhanced non-viral PTEN gene transfection.

Lasers Surg Med 2012 Nov 27;44(9):746-54. Epub 2012 Sep 27.

Department of Neurosurgery, University of California, Irvine, California, USA.

Background And Objective: One of many limitations for cancer gene therapy is the inability of the therapeutic gene to transfect a sufficient number of tumor cells. Photochemical internalization (PCI) is a photodynamic therapy-based approach for improving the delivery of macromolecules and genes into the cell cytosol. The utility of PCI for the delivery of the GFP reporter gene on the same plasmid as a tumor suppressor gene (PTEN) was investigated in monolayers of U251 human glioma cells and muticell U87 glioma spheroids.

Materials And Methods: U251 monolayers or U87 spheroids were incubated in AlPcS(2a) and non-viral vector polyplexes for 18 hours. In all cases, light treatment was performed with a diode laser at a wavelength of 670 nm. The non-viral transfection agents, branched polyethylenimine (bPEI), or protamine sulfate (PS), were used with the plasmid constructs GFP/PTEN or GFP.

Results: PS/GFP polyplexes were much less toxic to the glioma cells compared to bPEI/GFP polyplexes but were highly inefficient at gene transfection if used alone. PCI resulted in a 5- to 10-fold increase in GFP protein expression compared to controls. PCI-bPEI/PTEN or PCI-PS/PTEN transfection of either U251 monolayers or U87 spheroids significantly inhibited their growth. but had no effect on MCF-7 cells containing a wild-type PTEN gene. In addition PCI-GFP transfection of gliomas cells had no effect on their growth pattern.

Conclusions: Collectively, the results suggest that AlPcS(2a) -mediated PCI can be used to enhance cell growth inhibition via transfection of tumor suppressor genes in glioma cells containing mutant PTEN genes.
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http://dx.doi.org/10.1002/lsm.22082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4141883PMC
November 2012