Publications by authors named "Vincent M Rotello"

438 Publications

Polymeric Nanoparticles Active against Dual-Species Bacterial Biofilms.

Molecules 2021 Aug 16;26(16). Epub 2021 Aug 16.

Department of Chemistry, University of Massachusetts Amherst, Amherst, MA 01003, USA.

Biofilm infections are a global public health threat, necessitating new treatment strategies. Biofilm formation also contributes to the development and spread of multidrug-resistant (MDR) bacterial strains. Biofilm-associated chronic infections typically involve colonization by more than one bacterial species. The co-existence of multiple species of bacteria in biofilms exacerbates therapeutic challenges and can render traditional antibiotics ineffective. Polymeric nanoparticles offer alternative antimicrobial approaches to antibiotics, owing to their tunable physico-chemical properties. Here, we report the efficacy of poly(oxanorborneneimide) (PONI)-based antimicrobial polymeric nanoparticles (PNPs) against multi-species bacterial biofilms. PNPs showed good dual-species biofilm penetration profiles as confirmed by confocal laser scanning microscopy. Broad-spectrum antimicrobial activity was observed, with reduction in both bacterial viability and overall biofilm mass. Further, PNPs displayed minimal fibroblast toxicity and high antimicrobial activity in an in vitro co-culture model comprising fibroblast cells and dual-species biofilms of and . This study highlights a potential clinical application of the presented polymeric platform.
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http://dx.doi.org/10.3390/molecules26164958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8399783PMC
August 2021

Biodegradable Poly(lactic acid) Stabilized Nanoemulsions for the Treatment of Multidrug-Resistant Bacterial Biofilms.

ACS Appl Mater Interfaces 2021 Sep 20;13(34):40325-40331. Epub 2021 Aug 20.

Department of Chemistry, University of Massachusetts Amherst, 710 North Pleasant Street, Amherst, Massachusetts 01003, United States.

Biofilm infections caused by multidrug-resistant (MDR) bacteria are an urgent global health threat. Incorporation of natural essential oils into biodegradable oil-in-water cross-linked polymeric nanoemulsions (X-NEs) provides effective eradication of MDR bacterial biofilms. The X-NE platform combines the degradability of functionalized poly(lactic acid) polymers with the antimicrobial activity of carvacrol (from oregano oil). These X-NEs exhibited effective penetration and killing of biofilms formed by pathogenic bacteria. Biofilm-fibroblast coculture models demonstrate that X-NEs selectively eliminate bacteria without harming mammalian cells, making them promising candidates for antibiofilm therapeutics.
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http://dx.doi.org/10.1021/acsami.1c11265DOI Listing
September 2021

In situ activation of therapeutics through bioorthogonal catalysis.

Adv Drug Deliv Rev 2021 09 29;176:113893. Epub 2021 Jul 29.

Department of Chemistry, University of Massachusetts Amherst, 710 N. Pleasant St., Amherst, MA 01003, USA. Electronic address:

Bioorthogonal chemistry refers to any chemical reactions that can occur inside of living systems without interfering with native biochemical processes, which has become a promising strategy for modulating biological processes. The development of synthetic metal-based catalysts to perform bioorthogonal reactions has significantly expanded the toolkit of bioorthogonal chemistry for medicinal chemistry and synthetic biology. A wide range of homogeneous and heterogeneous transition metal catalysts (TMCs) have been reported, mediating different transformations such as cycloaddition reactions, as well as bond forming and cleaving reactions. However, the direct application of 'naked' TMCs in complex biological media poses numerous challenges, including poor water solubility, toxicity and catalyst deactivation. Incorporating TMCs into nanomaterials to create bioorthogonal nanocatalysts can solubilize and stabilize catalyst molecules, with the decoration of the nanocatalysts used to provide spatiotemporal control of catalysis. This review presents an overview of the advances in the creation of bioorthogonal nanocatalysts, highlighting different choice of nano-scaffolds, and the therapeutic and diagnostic applications.
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http://dx.doi.org/10.1016/j.addr.2021.113893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8440397PMC
September 2021

Nanodelivery vehicles induce remote biochemical changes in vivo.

Nanoscale 2021 Aug 15;13(29):12623-12633. Epub 2021 Jul 15.

Department of Chemistry, University of Massachusetts Amherst, 240 Thatcher Way, Life Sciences Laboratory, Amherst, MA 01003, USA.

Nanomaterial-based platforms are promising vehicles for the controlled delivery of therapeutics. For these systems to be both efficacious and safe, it is essential to understand where the carriers accumulate and to reveal the site-specific biochemical effects they produce in vivo. Here, a dual-mode mass spectrometry imaging (MSI) method is used to evaluate the distributions and biochemical effects of anti-TNF-α nanoparticle stabilized capsules (NPSCs) in mice. It is found that most of the anticipated biochemical changes occur in sub-organ regions that are separate from where the nanomaterials accumulate. In particular, TNF-α-specific lipid biomarker levels change in immune cell-rich regions of organs, while the NPSCs accumulate in spatially isolated filtration regions. Biochemical changes that are associated with the nanomaterials themselves are also observed, demonstrating the power of matrix-assisted laser desorption/ionization (MALDI) MSI to reveal markers indicating possible off-target effects of the delivery agent. This comprehensive assessment using MSI provides spatial context of nanomaterial distributions and efficacy that cannot be easily achieved with other imaging methods, demonstrating the power of MSI to evaluate both expected and unexpected outcomes associated with complex therapeutic delivery systems.
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http://dx.doi.org/10.1039/d1nr02563eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380036PMC
August 2021

High-content and high-throughput identification of macrophage polarization phenotypes.

Chem Sci 2020 Jul 22;11(31):8231-8239. Epub 2020 Jul 22.

Molecular and Cellular Biology Program, University of Massachusetts Amherst 710 N. Pleasant St. Amherst MA 01003 USA

Macrophages are plastic cells of the innate immune system that perform a wide range of immune- and homeostasis-related functions. Due to their plasticity, macrophages can polarize into a spectrum of activated phenotypes. Rapid identification of macrophage polarization states provides valuable information for drug discovery, toxicological screening, and immunotherapy evaluation. The complexity associated with macrophage activation limits the ability of current biomarker-based methods to rapidly identify unique activation states. In this study, we demonstrate the ability of a 2-element sensor array that provides an information-rich 5-channel output to successfully determine macrophage polarization phenotypes in a matter of minutes. The simple and robust sensor generates a high dimensional data array which enables accurate macrophage evaluations in standard cell lines and primary cells after cytokine treatment, as well as following exposure to a model disease environment.
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http://dx.doi.org/10.1039/d0sc02792hDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163325PMC
July 2020

Antimicrobial Peptide-Loaded Pectolite Nanorods for Enhancing Wound-Healing and Biocidal Activity of Titanium.

ACS Appl Mater Interfaces 2021 Jun 10;13(24):28764-28773. Epub 2021 Jun 10.

Department of Chemistry, University of Massachusetts Amherst, Amherst, Massachusetts 01003, United States.

Titanium is widely utilized for manufacturing medical implants due to its inherent mechanical strength and biocompatibility. Recent studies have focused on developing coatings to impart unique properties to Ti implants, such as antimicrobial behavior, enhanced cell adhesion, and osteointegration. Ca- and Si-based ceramic (CS) coatings can enhance bone integration through the release of Ca and Si ions. However, high degradation rates of CS ceramics create a basic environment that reduces cell viability. Polymeric or protein-based coatings may be employed to modulate CS degradation. However, it is challenging to ensure coating stability over extended periods of time without compromising biocompatibility. In this study, we employed a fluorous-cured collagen shell as a drug-loadable scaffold around CS nanorod coatings on Ti implants. Fluorous-cured collagen coatings have enhanced mechanical and enzymatic stability and are able to regulate the release of Ca and Si ions. Furthermore, the collagen scaffold was loaded with antimicrobial peptides to impart antimicrobial activity while promoting cell adhesion. These multifunctional collagen coatings simultaneously regulate the degradation of CS ceramics and enhance antimicrobial activity, while maintaining biocompatibility.
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http://dx.doi.org/10.1021/acsami.1c04895DOI Listing
June 2021

Activity of Biodegradable Polymeric Nanosponges against Dual-Species Bacterial Biofilms.

ACS Biomater Sci Eng 2021 05 1;7(5):1780-1786. Epub 2020 Dec 1.

Department of Chemistry, University of Massachusetts Amherst, 710 North Pleasant Street, Amherst, Massachusetts 01003, United States.

Infections caused by multidrug-resistant (MDR) bacteria present an emerging global health crisis, and the threat is intensified by the involvement of biofilms. Some biofilm infections involve more than one species; this can further challenge treatment using traditional antibiotics. Nanomaterials are being developed as alternative therapeutics to traditional antibiotics; here we report biodegradable polymer-stabilized oil-in-water nanosponges (BNS) and show their activity against dual-species bacterial biofilms. The described engineered nanosponges demonstrated broad-spectrum antimicrobial activity through prevention of dual-species biofilm formation as well as eradication of preformed biofilms. The BNS showed no toxicity against mammalian cells. Together, these data highlight the therapeutic potential of this platform.
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http://dx.doi.org/10.1021/acsbiomaterials.0c01433DOI Listing
May 2021

Engineering the Interface between Inorganic Nanoparticles and Biological Systems through Ligand Design.

Nanomaterials (Basel) 2021 Apr 13;11(4). Epub 2021 Apr 13.

Department of Chemistry, University of Massachusetts Amherst, 710 N. Pleasant St., Amherst, MA 01003, USA.

Nanoparticles (NPs) provide multipurpose platforms for a wide range of biological applications. These applications are enabled through molecular design of surface coverages, modulating NP interactions with biosystems. In this review, we highlight approaches to functionalize nanoparticles with "small" organic ligands (Mw < 1000), providing insight into how organic synthesis can be used to engineer NPs for nanobiology and nanomedicine.
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http://dx.doi.org/10.3390/nano11041001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069843PMC
April 2021

Efficient in vivo wound healing using noble metal nanoclusters.

Nanoscale 2021 Apr 25;13(13):6531-6537. Epub 2021 Mar 25.

Department of Orthopedics, The First Affiliated Hospital of Jinzhou Medical University, 40 Songpo Road, Jinzhou, China 121001, China.

The wound healing process involves multiple steps including hemostasis, inflammation, proliferation, and tissue remodeling. Nanomaterials have been employed externally for healing wounds. However, their use as systemic therapeutics has not been extensively explored. We report the use of ultra-small noble metal nanoclusters (NCs) for the treatment of skin wounds. Both in vitro and in vivo studies indicate NCs have comprehensive therapeutic effects for wound healing, promoting cell proliferation and migration while decreasing inflammation.
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http://dx.doi.org/10.1039/d0nr07176eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084111PMC
April 2021

Protein Delivery: If Your GFP (or Other Small Protein) Is in the Cytosol, It Will Also Be in the Nucleus.

Bioconjug Chem 2021 05 19;32(5):891-896. Epub 2021 Apr 19.

Department of Chemistry, University of Massachusetts, 710 North Pleasant Street, Amherst, Massachusetts 01003, United States.

Intracellular protein delivery is a transformative tool for biologics research and medicine. Delivery into the cytosol allows proteins to diffuse throughout the cell and access subcellular organelles. Inefficient delivery caused by endosomal entrapment is often misidentified as cytosolic delivery. This inaccuracy muddles what should be a key checkpoint in assessing delivery efficiency. Green fluorescent protein (GFP) is a robust cargo small enough to passively diffuse from the cytosol into the nucleus. Fluorescence of GFP in the nucleus is a direct readout for cytosolic access and effective delivery. Here, we highlight recent examples from the literature for the accurate assessment of cytosolic protein delivery using GFP fluorescence in the cytosol and nucleus.
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http://dx.doi.org/10.1021/acs.bioconjchem.1c00103DOI Listing
May 2021

Strategies for Fabricating Protein Films for Biomaterials Applications.

Adv Sustain Syst 2021 Jan 11;5(1). Epub 2020 Oct 11.

Department of Chemistry, University of Massachusetts, Amherst, 710 N Pleasant St., Amherst, MA, 01002.

Proteins are naturally occurring functional building blocks that are useful for the fabrication of materials. Naturally-occurring proteins are biodegradable and most are biocompatible and non-toxic, making them attractive for the fabrication of biomaterials. Moreover, the fabrication of protein-based materials can be conducted in a green and sustainable manner due to their high aqueous solubility. Consequently, the applicability of protein-based materials is limited by their aqueous and mechanical instability. This review summarizes strategies for the stabilization of protein films, highlighting their salient features and potential limitations. Applications of protein films ranging from food packaging materials, tissue engineering scaffolds, antimicrobial coatings etc. are also discussed. Finally, the need for robust and efficient fabrication strategies for translation to commercial applications as well as potential applications of protein films in the field of sensing, diagnostics and controlled release systems are discussed.
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http://dx.doi.org/10.1002/adsu.202000167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7942017PMC
January 2021

Generation of Antibiotics using Bioorthogonal "Nanofactories".

Microbiol Insights 2021 24;14:1178636121997121. Epub 2021 Feb 24.

Department of Chemistry, University of Massachusetts Amherst, Amherst, MA, USA.

Prodrug strategies use chemical modifications to improve the pharmacokinetic properties and therefore therapeutic effects of parent drugs. Traditional prodrug approaches use endogenous enzymes for activation. Bioorthogonal catalysis uses processes that endogenous enzymes cannot access, providing a complementary strategy for prodrug uncaging. Site-selective activation of prodrugs to drugs (uncaging) using synthetic catalysts is a promising strategy for localized drug activation. We discuss here recent studies that incorporate metal catalysts into polymers and nanoparticle scaffolds to provide biocompatible "enzyme-like" catalysts that can penetrate bacterial biofilms and activate prodrug antibiotics , affording a new strategy to treat bacterial biofilm infections with the potential for reduced off-target effects.
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http://dx.doi.org/10.1177/1178636121997121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907933PMC
February 2021

Regulation of Proteins to the Cytosol Using Delivery Systems with Engineered Polymer Architecture.

J Am Chem Soc 2021 03 11;143(12):4758-4765. Epub 2021 Mar 11.

Department of Chemistry, University of Massachusetts Amherst, 710 N. Pleasant St., Amherst, Massachusetts 01003, United States.

Intracellular protein delivery enables selective regulation of cellular metabolism, signaling, and development through introduction of defined protein quantities into the cell. Most applications require that the delivered protein has access to the cytosol, either for protein activity or as a gateway to other organelles such as the nucleus. The vast majority of delivery vehicles employ an endosomal pathway however, and efficient release of entrapped protein cargo from the endosome remains a challenge. Recent research has made significant advances toward efficient cytosolic delivery of proteins using polymers, but the influence of polymer architecture on protein delivery is yet to be investigated. Here, we developed a family of dendronized polymers that enable systematic alterations of charge density and structure. We demonstrate that while modulation of surface functionality has a significant effect on overall delivery efficiency, the endosomal release rate can be highly regulated by manipulating polymer architecture. Notably, we show that large, multivalent structures cause slower sustained release, while rigid spherical structures result in rapid burst release.
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http://dx.doi.org/10.1021/jacs.1c00258DOI Listing
March 2021

Hypersound-Assisted Size Sorting of Microparticles on Inkjet-Patterned Protein Films.

Langmuir 2021 03 12;37(8):2826-2832. Epub 2021 Feb 12.

Department of Chemistry, University of Massachusetts, Amherst, Amherst, Massachusetts 01002, USA.

Hydrodynamic approaches are important for biomedical diagnostics, chemical analysis, and a broad range of industrial applications. Size-based separation and sorting is an important tool for these applications. We report the integration of hypersound technology with patterned protein films to provide efficient sorting of microparticles based on particle charge and size. We employed a hypersonic resonator for the acoustic streaming of the fluidic system to generate microvortices that exert drag forces on the objects on the surface that are dictated by their radius of curvature. We demonstrate a size-based sorting of anionic silica particles using protein patterns and gradients fabricated using attractive cationic and repulsive anionic proteins.
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http://dx.doi.org/10.1021/acs.langmuir.0c03598DOI Listing
March 2021

Intracellular Activation of Anticancer Therapeutics Using Polymeric Bioorthogonal Nanocatalysts.

Adv Healthc Mater 2021 03 13;10(5):e2001627. Epub 2020 Dec 13.

Department of Chemistry, University of Massachusetts Amherst, 710 North Pleasant Street, Amherst, MA, 01003, USA.

Bioorthogonal catalysis provides a promising strategy for imaging and therapeutic applications, providing controlled in situ activation of pro-dyes and prodrugs. In this work, the use of a polymeric scaffold to encapsulate transition metal catalysts (TMCs), generating bioorthogonal "polyzymes," is presented. These polyzymes enhance the stability of TMCs, protecting the catalytic centers from deactivation in biological media. The therapeutic potential of these polyzymes is demonstrated by the transformation of a nontoxic prodrug to an anticancer drug (mitoxantrone), leading to the cancer cell death in vitro.
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http://dx.doi.org/10.1002/adhm.202001627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933084PMC
March 2021

Differentiation of Cancer Stem Cells through Nanoparticle Surface Engineering.

ACS Nano 2020 11 9;14(11):15276-15285. Epub 2020 Nov 9.

Molecular and Cellular Biology Program, University of Massachusetts, Amherst, Massachusetts 01003, United States.

Cancer stem cells (CSCs) are a crucial therapeutic target because of their role in resistance to chemo- and radiation therapy, metastasis, and tumor recurrence. Differentiation therapy presents a potential strategy for "defanging" CSCs. To date, only a limited number of small-molecule and nanomaterial-based differentiating agents have been identified. We report here the integrated use of nanoparticle engineering and hypothesis-free sensing to identify nanoparticles capable of efficient differentiation of CSCs into non-CSC phenotypes. Using this strategy, we identified a nanoparticle that induces CSC differentiation by increasing intracellular reactive oxygen species levels. Importantly, this unreported phenotype is more susceptible to drug treatment than either CSCs or non-CSCs, demonstrating a potentially powerful strategy for anticancer therapeutics.
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http://dx.doi.org/10.1021/acsnano.0c05589DOI Listing
November 2020

Anionic nanoparticle-induced perturbation to phospholipid membranes affects ion channel function.

Proc Natl Acad Sci U S A 2020 11 26;117(45):27854-27861. Epub 2020 Oct 26.

Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706;

Understanding the mechanisms of nanoparticle interaction with cell membranes is essential for designing materials for applications such as bioimaging and drug delivery, as well as for assessing engineered nanomaterial safety. Much attention has focused on nanoparticles that bind strongly to biological membranes or induce membrane damage, leading to adverse impacts on cells. More subtle effects on membrane function mediated via changes in biophysical properties of the phospholipid bilayer have received little study. Here, we combine electrophysiology measurements, infrared spectroscopy, and molecular dynamics simulations to obtain insight into a mode of nanoparticle-mediated modulation of membrane protein function that was previously only hinted at in prior work. Electrophysiology measurements on gramicidin A (gA) ion channels embedded in planar suspended lipid bilayers demonstrate that anionic gold nanoparticles (AuNPs) reduce channel activity and extend channel lifetimes without disrupting membrane integrity, in a manner consistent with changes in membrane mechanical properties. Vibrational spectroscopy indicates that AuNP interaction with the bilayer does not perturb the conformation of membrane-embedded gA. Molecular dynamics simulations reinforce the experimental findings, showing that anionic AuNPs do not directly interact with embedded gA channels but perturb the local properties of lipid bilayers. Our results are most consistent with a mechanism in which anionic AuNPs disrupt ion channel function in an indirect manner by altering the mechanical properties of the surrounding bilayer. Alteration of membrane mechanical properties represents a potentially important mechanism by which nanoparticles induce biological effects, as the function of many embedded membrane proteins depends on phospholipid bilayer biophysical properties.
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http://dx.doi.org/10.1073/pnas.2004736117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668003PMC
November 2020

Development of coinage metal nanoclusters as antimicrobials to combat bacterial infections.

J Mater Chem B 2020 10;8(41):9466-9480

Department of Chemistry, University of Massachusetts Amherst, 710 North Pleasant Street, Amherst, Massachusetts 01003, USA.

Infections from antibiotic-resistant bacteria have caused huge economic loss and numerous deaths over the past decades. Researchers are exploring multiple strategies to combat these bacterial infections. Metal nanomaterials have been explored as therapeutics against these infections owing to their relatively low toxicity, broad-spectrum activity, and low bacterial resistance development. Some coinage metal nanoclusters, such as gold, silver, and copper nanoclusters, can be readily synthesized. These nanoclusters can feature multiple useful properties, including ultra-small size, high catalytic activity, unique photoluminescent properties, and photothermal effect. Coinage metal nanoclusters have been investigated as antimicrobials, but more research is required to tap their full potential. In this review, we discuss multiple advantages and the prospect of using gold/silver/copper nanoclusters as antimicrobials.
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http://dx.doi.org/10.1039/d0tb00549eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606613PMC
October 2020

Accessing Intracellular Targets through Nanocarrier-Mediated Cytosolic Protein Delivery.

Trends Pharmacol Sci 2020 10 2;41(10):743-754. Epub 2020 Sep 2.

Department of Chemistry, University of Massachusetts, Amherst, MA 01003, USA. Electronic address:

Protein-based therapeutics have unique therapeutic potential due to their specificity, potency, and low toxicity. The vast majority of intracellular applications of proteins require access to the cytosol. Direct entry to the cytosol is challenging due to the impermeability of the cell membrane to proteins. As a result, multiple strategies have focused on endocytic uptake of proteins. Endosomally entrapped cargo, however, can have very low escape efficiency, with protein degradation occurring in acidic endolysosomal compartments. In this review, we briefly discuss endosomal escape strategies and review the strategy of cell membrane fusion, a recent strategy for direct delivery of proteins into the cell cytoplasm.
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http://dx.doi.org/10.1016/j.tips.2020.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502523PMC
October 2020

Nanomaterial-based therapeutics for antibiotic-resistant bacterial infections.

Nat Rev Microbiol 2021 01 19;19(1):23-36. Epub 2020 Aug 19.

Department of Chemistry, University of Massachusetts Amherst, Amherst, MA, USA.

Antibiotic-resistant bacterial infections arising from acquired resistance and/or through biofilm formation necessitate the development of innovative 'outside of the box' therapeutics. Nanomaterial-based therapies are promising tools to combat bacterial infections that are difficult to treat, featuring the capacity to evade existing mechanisms associated with acquired drug resistance. In addition, the unique size and physical properties of nanomaterials give them the capability to target biofilms, overcoming recalcitrant infections. In this Review, we highlight the general mechanisms by which nanomaterials can be used to target bacterial infections associated with acquired antibiotic resistance and biofilms. We emphasize design elements and properties of nanomaterials that can be engineered to enhance potency. Lastly, we present recent progress and remaining challenges for widespread clinical implementation of nanomaterials as antimicrobial therapeutics.
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http://dx.doi.org/10.1038/s41579-020-0420-1DOI Listing
January 2021

Delivery of drugs, proteins, and nucleic acids using inorganic nanoparticles.

Adv Drug Deliv Rev 2020 29;156:188-213. Epub 2020 Jun 29.

Department of Chemistry, University of Massachusetts Amherst, 710 N. Pleasant St., Amherst, MA 01003, USA. Electronic address:

Inorganic nanoparticles provide multipurpose platforms for a broad range of delivery applications. Intrinsic nanoscopic properties provide access to unique magnetic and optical properties. Equally importantly, the structural and functional diversity of gold, silica, iron oxide, and lanthanide-based nanocarriers provide unrivalled control of nanostructural properties for effective transport of therapeutic cargos, overcoming biobarriers on the cellular and organismal level. Taken together, inorganic nanoparticles provide a key addition to the arsenal of delivery vectors for fighting disease and improving human health.
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http://dx.doi.org/10.1016/j.addr.2020.06.020DOI Listing
September 2021

Polymer-Based Bioorthogonal Nanocatalysts for the Treatment of Bacterial Biofilms.

J Am Chem Soc 2020 06 8;142(24):10723-10729. Epub 2020 Jun 8.

Department of Chemistry, University of Massachusetts Amherst, 710 North Pleasant Street, Amherst, Massachusetts 01003, United States.

Bioorthogonal catalysis offers a unique strategy to modulate biological processes through the in situ generation of therapeutic agents. However, the direct application of bioorthogonal transition metal catalysts (TMCs) in complex media poses numerous challenges due to issues of limited biocompatibility, poor water solubility, and catalyst deactivation in biological environments. We report here the creation of catalytic "polyzymes", comprised of self-assembled polymer nanoparticles engineered to encapsulate lipophilic TMCs. The incorporation of catalysts into these nanoparticle scaffolds creates water-soluble constructs that provide a protective environment for the catalyst. The potential therapeutic utility of these nanozymes was demonstrated through antimicrobial studies in which a cationic nanozyme was able to penetrate into biofilms and eradicate embedded bacteria through the bioorthogonal activation of a pro-antibiotic.
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http://dx.doi.org/10.1021/jacs.0c01758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7339739PMC
June 2020

A modified and simplified method for purification of gold nanoparticles.

MethodsX 2020 21;7:100896. Epub 2020 Apr 21.

Department of Chemistry, University of Massachusetts, 710 North Pleasant Street, Amherst, MA, 01003, United States.

2 nm gold nanoparticles (AuNPs) have promising applications within drug and protein delivery, bioimaging, and biosensing. By performing ligand place-exchange reactions, AuNPs protected with alkanethiolate ligands can be functionalized to regulate their behaviors. In this reaction, a new ligand is incorporated by mixing a thiol with the AuNPs. To remove the excess new ligand as well as the displaced thiolate, dialysis has previously been the most widely used method. However, this purification method is time-consuming and fails to remove unwanted thiols completely. In this study, we describe a fast and efficient procedure to purify AuNP aqueous solution through liquid-liquid extraction using dichloromethane.•We demonstrate a facile way to purify AuNPs after ligand place-exchange reactions through liquid-liquid extraction.•Liquid-liquid extraction is a simple, inexpensive and efficient method for AuNP purification.•This protocol enables us to completely purify AuNPs in a few hours and can be used as a much quicker and more scaleable valid alternative to dialysis.
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http://dx.doi.org/10.1016/j.mex.2020.100896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210451PMC
April 2020

Protection and Isolation of Bioorthogonal Metal Catalysts by Using Monolayer-Coated Nanozymes.

Chembiochem 2020 10 22;21(19):2759-2763. Epub 2020 Jun 22.

Department of Chemistry, University of Massachusetts Amherst, 710 North Pleasant Street, Amherst, Massachusetts, 01003, USA.

We demonstrate here the protection of biorthogonal transition metal catalysts (TMCs) in biological environments by using self-assembled monolayers on gold nanoparticles (AuNPs). Encapsulation of TMCs in this hydrophobic environment preserves catalytic activity in presence of pH conditions and complex biological media that would deactivate free catalyst. Significantly, the protection affords by these nanozymes extends to isolation of the catalyst active site, as demonstrated by the independence of rate over a wide pH range, in strong contrast to the behavior of the free catalyst.
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http://dx.doi.org/10.1002/cbic.202000207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541601PMC
October 2020

Nano Assessing Nano: Nanosensor-Enabled Detection of Cell Phenotypic Changes Identifies Nanoparticle Toxicological Effects at Ultra-Low Exposure Levels.

Small 2020 09 29;16(36):e2002084. Epub 2020 Apr 29.

Department of Chemistry, University of Massachusetts Amherst, Amherst, MA, 01002, USA.

Industrial use of nanomaterials is rapidly increasing, making the effects of these materials on the environment and human health of critical concern. Standard nanotoxicity evaluation methods rely on detecting cell death or major dysfunction and will miss early signs of toxicity. In this work, the use of rapid and sensitive nanosensors that can efficiently detect subtle phenotypic changes on the cell surface following nanomaterial exposure is reported. Importantly, the method reveals significant phenotypic changes at dosages where other conventional methods show normal cellular activity. This approach holds promise in toxicological and pharmacological evaluations to ensure safer and better use of nanomaterials.
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http://dx.doi.org/10.1002/smll.202002084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486238PMC
September 2020

Triple-Negative Breast Cancer: A Review of Conventional and Advanced Therapeutic Strategies.

Int J Environ Res Public Health 2020 03 20;17(6). Epub 2020 Mar 20.

Department of Genetics and Molecular Biology, CINVESTAV, Zacatenco, Avenida Instituto Politécnico Nacional 2508, Mexico City 07360, Mexico.

Triple-negative breast cancer (TNBC) cells are deficient in estrogen, progesterone and ERBB2 receptor expression, presenting a particularly challenging therapeutic target due to their highly invasive nature and relatively low response to therapeutics. There is an absence of specific treatment strategies for this tumor subgroup, and hence TNBC is managed with conventional therapeutics, often leading to systemic relapse. In terms of histology and transcription profile these cancers have similarities to BRCA-1-linked breast cancers, and it is hypothesized that BRCA1 pathway is non-functional in this type of breast cancer. In this review article, we discuss the different receptors expressed by TNBC as well as the diversity of different signaling pathways targeted by TNBC therapeutics, for example, Notch, Hedgehog, Wnt/b-Catenin as well as TGF-beta signaling pathways. Additionally, many epidermal growth factor receptor (EGFR), poly (ADP-ribose) polymerase (PARP) and mammalian target of rapamycin (mTOR) inhibitors effectively inhibit the TNBCs, but they face challenges of either resistance to drugs or relapse. The resistance of TNBC to conventional therapeutic agents has helped in the advancement of advanced TNBC therapeutic approaches including hyperthermia, photodynamic therapy, as well as nanomedicine-based targeted therapeutics of drugs, miRNA, siRNA, and aptamers, which will also be discussed. Artificial intelligence is another tool that is presented to enhance the diagnosis of TNBC.
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http://dx.doi.org/10.3390/ijerph17062078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7143295PMC
March 2020

Intracellular Activation of Bioorthogonal Nanozymes through Endosomal Proteolysis of the Protein Corona.

ACS Nano 2020 04 7;14(4):4767-4773. Epub 2020 Apr 7.

Department of Chemistry, Hazara University, Mansehra 21300, Pakistan.

Bioorthogonal activation of prodrugs provides a strategy for on-demand on-site production of therapeutics. Intracellular activation provides a strategy to localize therapeutics, potentially minimizing off-target effects. To this end, nanoparticles embedded with transition metal catalysts (nanozymes) were engineered to generate either "hard" irreversible or "soft" reversible coronas in serum. The hard corona induced nanozyme aggregation, effectively inhibiting nanozyme activity, whereas only modest loss of activity was observed with the nonaggregating soft corona nanozymes. In both cases complete activity was restored by treatment with proteases. Intracellular activity mirrored this reactivation: endogenous proteases in the endosome provided intracellular activation of both nanozymes. The role of intracellular proteases in nanozyme reactivation was verified through treatment of the cells with protease inhibitors, which prevented reactivation. This study demonstrates the use of intracellular proteolysis as a strategy for localization of therapeutic generation to within cells.
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http://dx.doi.org/10.1021/acsnano.0c00629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8297610PMC
April 2020
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