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Article ; Online: Omics approaches for the assessment of biological responses to nanoparticles.

Abdelkader, Yasmin / Perez-Davalos, Luis / LeDuc, Richard / Zahedi, Rene P / Labouta, Hagar I

2023 Volume 200, Page(s) 114992

Abstract: Nanotechnology has enabled the development of innovative therapeutics, diagnostics, and drug delivery systems. Nanoparticles (NPs) can influence gene expression, protein synthesis, cell cycle, metabolism, and other subcellular processes. While ... ...

Abstract	Nanotechnology has enabled the development of innovative therapeutics, diagnostics, and drug delivery systems. Nanoparticles (NPs) can influence gene expression, protein synthesis, cell cycle, metabolism, and other subcellular processes. While conventional methods have limitations in characterizing responses to NPs, omics approaches can analyze complete sets of molecular entities that change upon exposure to NPs. This review discusses key omics approaches, namely transcriptomics, proteomics, metabolomics, lipidomics and multi-omics, applied to the assessment of biological responses to NPs. Fundamental concepts and analytical methods used for each approach are presented, as well as good practices for omics experiments. Bioinformatics tools are essential to analyze, interpret and visualize large omics data, and to correlate observations in different molecular layers. The authors envision that conducting interdisciplinary multi-omics analyses in future nanomedicine studies will reveal integrated cell responses to NPs at different omics levels, and the incorporation of omics into the evaluation of targeted delivery, efficacy, and safety will improve the development of nanomedicine therapies.
MeSH term(s)	Humans ; Genomics/methods ; Proteomics/methods ; Computational Biology/methods ; Metabolomics/methods ; Nanoparticles
Language	English
Publishing date	2023-07-05
Publishing country	Netherlands
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	639113-8
ISSN	1872-8294 ; 0169-409X
ISSN (online)	1872-8294
ISSN	0169-409X
DOI	10.1016/j.addr.2023.114992
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Article ; Online: Microfluidics for Development of Lipid Nanoparticles: Paving the Way for Nucleic Acids to the Clinic.

Ali, Moustafa S / Hooshmand, Nasrin / El-Sayed, Mostafa / Labouta, Hagar I

ACS applied bio materials

2021 Volume 6, Issue 9, Page(s) 3566–3576

Abstract: Nucleic acid therapeutics hold an unprecedented promise toward treating many challenging diseases; however, their use is hampered by delivery issues. Microfluidics, dealing with fluids in the microscale dimensions, have provided a robust means to ... ...

Abstract	Nucleic acid therapeutics hold an unprecedented promise toward treating many challenging diseases; however, their use is hampered by delivery issues. Microfluidics, dealing with fluids in the microscale dimensions, have provided a robust means to screening raw materials for development of nano delivery vectors, in addition to controlling their size and minimizing their polydispersity. In this mini-review, we are briefly highlighting the different types of nucleic acid therapies with emphasis on the delivery requirement for each type. We provide a thorough review of available methods for the development of nanoparticles, especially lipid nanoparticles (LNPs) that resulted in FDA approval of the first ever nucleic acid nanomedicine. We then focus on recent research attempts for how microfluidic synthesis of lipid nanoparticles and discuss the various parameters required for successful formulation of LPNs including chip design, flow regimes, and lipid composition. We then identify key areas of research in microfluidics and related fields that require attention for future success in clinical translation of nucleic acid nanomedicines.
MeSH term(s)	Microfluidics/methods ; Lipids ; Nanoparticles ; Nanomedicine
Chemical Substances	Lipid Nanoparticles ; Lipids
Language	English
Publishing date	2021-09-08
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ISSN	2576-6422
ISSN (online)	2576-6422
DOI	10.1021/acsabm.1c00732
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Article ; Online: Critical design parameters to develop biomimetic organ-on-a-chip models for the evaluation of the safety and efficacy of nanoparticles.

Abdelkarim, Mahmoud / Perez-Davalos, Luis / Abdelkader, Yasmin / Abostait, Amr / Labouta, Hagar I

Expert opinion on drug delivery

2022 Volume 20, Issue 1, Page(s) 13–30

Abstract: Introduction: Organ-on-a-chip (OOC) models are based on microfluidics and can recapitulate the healthy and diseased microstructure of organs: Areas covered: The different design parameters of the microfluidic chip and the mechanical forces generated ... ...

Abstract	Introduction: Organ-on-a-chip (OOC) models are based on microfluidics and can recapitulate the healthy and diseased microstructure of organs Areas covered: The different design parameters of the microfluidic chip and the mechanical forces generated by fluid flow play a pivotal role in simulating the human environment. This review discusses the role of different key parameters on the performance of OOC models. These include the flow pattern, flow rate, shear stress (magnitude, rate, and distribution), viscosity of the media, and the microchannel dimensions and shape. We also discuss how the shear stress and other mechanical forces affect the transport of NPs across biological barriers, cell uptake, and their biocompatibility. Expert opinion: We describe several good practices and design parameters to consider for future OOC research. We submit that following these recommendations will help realize the full potential of the OOC models in the preclinical evaluation of novel therapies, including NPs.
MeSH term(s)	Humans ; Lab-On-A-Chip Devices ; Microphysiological Systems ; Biomimetics ; Microfluidics/methods ; Nanoparticles
Language	English
Publishing date	2022-12-05
Publishing country	England
Document type	Review ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2167286-6
ISSN	1744-7593 ; 1742-5247
ISSN (online)	1744-7593
ISSN	1742-5247
DOI	10.1080/17425247.2023.2152000
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Article: Localized Plasmonic Photothermal Therapy as a Life-saving Treatment Paradigm for Hospitalized COVID-19 Patients.

Labouta, Hagar I / Hooshmand, Nasrin / Upreti, Tushar / El-Sayed, Mostafa A

Plasmonics (Norwell, Mass.)

2021 Volume 16, Issue 4, Page(s) 1029–1033

Abstract: Lung failure is the main reason for mortality in COVID-19 patients, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To date, no drug has been clinically approved for treatment of COVID-19. Nanotechnology has a great potential ... ...

Abstract	Lung failure is the main reason for mortality in COVID-19 patients, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To date, no drug has been clinically approved for treatment of COVID-19. Nanotechnology has a great potential in contributing significantly to the fight against COVID-19 by developing effective therapies that can selectively eradicate the respiratory virus load. We propose a novel COVID-19 management approach that is efficient in eliminating the virus load from the airways and protecting the lungs from the fatal effects of the virus. This approach relies on targeting the virus using ACE-2-functionalized gold nanorods (AuNRs) followed by irradiation with near-infrared (NIR) light for the selective eradication of SARS-CoV-2 without off-target effects, i.e., targeted plasmonic photothermal therapy. Using discrete dipole approximation (DDA), we quantitatively determined the efficiency of AuNRs (31 nm × 8 nm) in absorbing NIR when present at different orientations relative to one another on the surface of the virus. The safety and the local administration of AuNRs using a well-tolerated flexible bronchoscopy technique, commonly used for hospitalized COVID-19 patients, ensure feasibility and clinical translation. While requiring further research, we anticipate this approach to result in a first-line treatment for hospitalized COVID-19 patients that are experiencing severe respiratory conditions or belong to a high-risk population, e.g., seniors and diabetic patients.
Language	English
Publishing date	2021-01-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	2237548-X
ISSN	1557-1963 ; 1557-1955
ISSN (online)	1557-1963
ISSN	1557-1955
DOI	10.1007/s11468-020-01353-x
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Article ; Online: Collagen - a newly discovered major player in protein corona formation on nanoparticles.

Upreti, Tushar / Wolfe, Kathryn M / Van Bavel, Nicolas / Anikovskiy, Max / Labouta, Hagar I

Physical chemistry chemical physics : PCCP

2022 Volume 24, Issue 9, Page(s) 5610–5617

Abstract: Tracking protein corona (PC) formation on the surface of nanoparticles (NPs) is a prerequisite for successful design of next generation nanocarriers with predictable fate and behavior. However, PC formation has mostly been investigated for plasma ... ...

Abstract	Tracking protein corona (PC) formation on the surface of nanoparticles (NPs) is a prerequisite for successful design of next generation nanocarriers with predictable fate and behavior. However, PC formation has mostly been investigated for plasma proteins without considering potential competition with the extravascular proteins either when the NPs exit the blood circulation or when they are injected extravascularly. This study investigates the deposition of collagen, an extravascular protein that is the most abundant in the body, and albumin, the most abundant vascular protein, on the surface of gold (Au) NPs using UV-Vis and fluorescence spectroscopy with the support of mathematical modeling. Moreover, a novel spectroscopic approach to determining the protein-NP binding constants and surface occupancy is presented. We show that albumin and collagen have drastically different affinities for Au NPs. Our data demonstrates that the surface bound albumin can be exchanged with collagen confirming the dynamic nature of PC in the extravascular milieu. We propose that future PC investigations in the framework of drug delivery should rely on understanding of the NP transit in the body, and include competition experiments with relevant vascular and extravascular proteins. Furthermore, our results that reveal very strong binding of collagen to AuNPs may lay the foundation for designing long circulating collagen-coated NPs with minimal surface adsorption of plasma proteins and, thus, reduced immune recognition.
MeSH term(s)	Collagen ; Gold/chemistry ; Metal Nanoparticles/chemistry ; Nanoparticles/chemistry ; Protein Corona/chemistry ; Spectrometry, Fluorescence
Chemical Substances	Protein Corona ; Gold (7440-57-5) ; Collagen (9007-34-5)
Language	English
Publishing date	2022-03-02
Publishing country	England
Document type	Journal Article
ZDB-ID	1476244-4
ISSN	1463-9084 ; 1463-9076
ISSN (online)	1463-9084
ISSN	1463-9076
DOI	10.1039/d1cp03968g
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Article ; Online: The maternal-fetal transfer of passive immunity as a mechanism of transplacental nanoparticle drug delivery for prenatal therapies.

Tse, Wai Hei / Higgins, Sean / Patel, Daywin / Xing, Malcolm / West, Adrian R / Labouta, Hagar I / Keijzer, Richard

Biomaterials science

2022 Volume 10, Issue 18, Page(s) 5243–5253

Abstract: Nanoparticles administered into the maternal circulation and across the placenta are a potential clinical therapy to treat congenital diseases. The mechanism by which nanoparticles can safely cross the placenta for targeted drug delivery to the fetus ... ...

Abstract	Nanoparticles administered into the maternal circulation and across the placenta are a potential clinical therapy to treat congenital diseases. The mechanism by which nanoparticles can safely cross the placenta for targeted drug delivery to the fetus remains poorly understood. We demonstrate that the maternal-fetal transfer of passive immunity through the neonatal Fc Receptor (FcRn) can induce the transplacental transfer of chitosan nanoparticles modifed with IgG antibodies (414 ± 27 nm). The transfer of FITC-tagged IgG-modified chitosan nanoparticles was 2.8 times higher (
MeSH term(s)	Chitosan/metabolism ; Female ; Fetus ; Humans ; Immunoglobulin G ; Infant, Newborn ; Nanoparticles ; Placenta ; Pregnancy
Chemical Substances	Immunoglobulin G ; Chitosan (9012-76-4)
Language	English
Publishing date	2022-09-13
Publishing country	England
Document type	Journal Article
ZDB-ID	2693928-9
ISSN	2047-4849 ; 2047-4830
ISSN (online)	2047-4849
ISSN	2047-4830
DOI	10.1039/d2bm00293k
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Article ; Online: Role of drug delivery technologies in the success of COVID-19 vaccines: a perspective.

Labouta, Hagar I / Langer, Robert / Cullis, Pieter R / Merkel, Olivia M / Prausnitz, Mark R / Gomaa, Yasmine / Nogueira, Sara S / Kumeria, Tushar

Drug delivery and translational research

2022 Volume 12, Issue 11, Page(s) 2581–2588

Abstract: The triumphant success of mRNA vaccines is a testimony to the important role drug delivery technologies have played in protecting billions of people against SARS-CoV-2 (or the Corona Virus Disease 2019; COVID-19). Several lipid nanoparticle (LNP) mRNA ... ...

Abstract	The triumphant success of mRNA vaccines is a testimony to the important role drug delivery technologies have played in protecting billions of people against SARS-CoV-2 (or the Corona Virus Disease 2019; COVID-19). Several lipid nanoparticle (LNP) mRNA vaccines were developed and have been instrumental in preventing the disease by boosting the immune system against the pathogen, SARS-CoV-2. These vaccines have been built on decades of scientific research in drug delivery of mRNA, vaccines, and other biologicals. In this manuscript, several leading and emerging scientists in the field of drug delivery share their perspective on the role of drug delivery technologies in developing safe and efficacious vaccines, in a roundtable discussion. The authors also discussed their viewpoint on the current challenges, and the key research questions that should drive this important area of research.
MeSH term(s)	COVID-19/prevention & control ; COVID-19 Vaccines ; Humans ; Liposomes ; Nanoparticles ; RNA, Messenger ; SARS-CoV-2 ; Viral Vaccines
Chemical Substances	COVID-19 Vaccines ; Lipid Nanoparticles ; Liposomes ; RNA, Messenger ; Viral Vaccines
Language	English
Publishing date	2022-03-15
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2590155-2
ISSN	2190-3948 ; 2190-393X
ISSN (online)	2190-3948
ISSN	2190-393X
DOI	10.1007/s13346-022-01146-1
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Article ; Online: Placental Nanoparticle Uptake-On-a-Chip: The Impact of Trophoblast Syncytialization and Shear Stress.

Abostait, Amr / Tyrrell, Jack / Abdelkarim, Mahmoud / Shojaei, Shahla / Tse, Wai Hei / El-Sherbiny, Ibrahim M / Keijzer, Richard / Labouta, Hagar I

Molecular pharmaceutics

2022 Volume 19, Issue 11, Page(s) 3757–3769

Abstract: The placenta is a dynamic and complex organ that plays an essential role in the health and development of the fetus. Placental disorders can affect the health of both the mother and the fetus. There is currently an unmet clinical need to develop ... ...

Abstract	The placenta is a dynamic and complex organ that plays an essential role in the health and development of the fetus. Placental disorders can affect the health of both the mother and the fetus. There is currently an unmet clinical need to develop nanoparticle-based therapies to target and treat placental disorders. However, little is known about the interaction of nanoparticles (NPs) with the human placenta under biomimetic conditions. Specifically, the impact of shear stress exerted on the trophoblasts (placental epithelial cells) by the maternal blood flow, the gradual fusion of the trophoblasts along the gestation period (syncytialization), and the impact of microvilli formation on the cell uptake of NPs is not known. To this end, we designed dynamic placenta-on-a-chip models using BeWo cells to recapitulate the micro-physiological environment, and we induced different degrees of syncytialization via chemical induction with forskolin. We characterized the degree of syncytialization quantitatively by measuring beta human chorionic gonadotropin (β-hCG) secretion, as well as qualitatively by immunostaining the tight junction protein, ZO-1, and counter nuclear staining. We also characterized microvilli formation under static and dynamic conditions via F-actin staining. We used these models to measure the cell uptake of chondroitin sulfate a binding protein (CSA) conjugated and control liposomes using confocal microscopy, followed by image analysis. Interestingly, exposure of the cells to a dynamic flow of media intrinsically induced syncytialization and microvilli formation compared to static controls. Under dynamic conditions, BeWo cells produced more β-hCG in conditions that increased the cell exposure time to forskolin (
MeSH term(s)	Female ; Pregnancy ; Humans ; Trophoblasts/metabolism ; Placenta/metabolism ; Colforsin/pharmacology ; Colforsin/metabolism ; Liposomes/metabolism ; Lab-On-A-Chip Devices ; Carrier Proteins/metabolism ; Nanoparticles
Chemical Substances	Colforsin (1F7A44V6OU) ; Liposomes ; Carrier Proteins
Language	English
Publishing date	2022-09-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2138405-8
ISSN	1543-8392 ; 1543-8384
ISSN (online)	1543-8392
ISSN	1543-8384
DOI	10.1021/acs.molpharmaceut.2c00216
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Article: Characterizing Extracellular Vesicles and Particles Derived from Skeletal Muscle Myoblasts and Myotubes and the Effect of Acute Contractile Activity.

Bydak, Benjamin / Pierdoná, Taiana M / Seif, Samira / Sidhom, Karim / Obi, Patience O / Labouta, Hagar I / Gordon, Joseph W / Saleem, Ayesha

Membranes

2022 Volume 12, Issue 5

Abstract: Extracellular vesicles (EVs), released from all cells, are essential to cellular communication and contain biomolecular cargo that can affect recipient cell function. Studies on the effects of contractile activity (exercise) on EVs usually rely on plasma/ ...

Abstract	Extracellular vesicles (EVs), released from all cells, are essential to cellular communication and contain biomolecular cargo that can affect recipient cell function. Studies on the effects of contractile activity (exercise) on EVs usually rely on plasma/serum-based assessments, which contain EVs from many different cells. To specifically characterize skeletal muscle−derived vesicles and the effect of acute contractile activity, we used an in vitro model where C2C12 mouse myoblasts were differentiated to form myotubes. EVs were isolated from conditioned media from muscle cells at pre-differentiation (myoblasts) and post-differentiation (myotubes) and also from acutely stimulated myotubes (1 h @ 14 V, C-Pace EM, IonOptix, Westwood, MA, USA) using total exosome isolation reagent (TEI, ThermoFisher (Waltham, MA, USA), referred to as extracellular particles [EPs]) and differential ultracentrifugation (dUC; EVs). Myotube-EPs (~98 nm) were 41% smaller than myoblast-EPs (~167 nm, p < 0.001, n = 8−10). Two-way ANOVA showed a significant main effect for the size distribution of myotube vs. myoblast-EPs (p < 0.01, n = 10−13). In comparison, myoblast-EPs displayed a bimodal size distribution profile with peaks at <200 nm and 400−600, whereas myotube-Eps were largely 50−300 nm in size. Total protein yield from myotube-EPs was nearly 15-fold higher than from the myoblast-EPs, (p < 0.001 n = 6−9). Similar biophysical characteristics were observed when EVs were isolated using dUC: myotube-EVs (~195 nm) remained 41% smaller in average size than myoblast-EVs (~330 nm, p = 0.07, n = 4−6) and had comparable size distribution profiles to EPs isolated via TEI. Myotube-EVs also had 4.7-fold higher protein yield vs. myoblast EVs (p < 0.05, n = 4−6). Myotube-EPs exhibited significantly decreased expression of exosomal marker proteins TSG101, CD63, ALIX and CD81 compared with myoblast-EPs (p < 0.05, n = 7−12). Conversely, microvesicle marker ARF6 and lipoprotein marker APO-A1 were only found in the myotube-EPs (p < 0.05, n = 4−12). There was no effect of acute stimulation on myotube-EP biophysical characteristics (n = 7) or on the expression of TSG101, ARF6 or CD81 (n = 5−6). Myoblasts treated with control or acute stimulation−derived EPs (13 µg/well) for 48 h and 72 h showed no changes in mitochondrial mass (MitoTracker Red, ThermoFisher, Waltham, MA, USA), cell viability or cell count (n = 3−4). Myoblasts treated with EP-depleted media (72 h) exhibited ~90% lower cell counts (p < 0.01, n = 3). Our data show that EVs differed in size, distribution, protein yield and expression of subtype markers pre vs. post skeletal muscle−differentiation into myotubes. There was no effect of acute stimulation on biophysical profile or protein markers in EPs. Acute stimulation−derived EPs did not alter mitochondrial mass or cell count/viability. Further investigation into the effects of chronic contractile activity on the biophysical characteristics and cargo of skeletal muscle−specific EVs are warranted.
Language	English
Publishing date	2022-04-26
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2614641-1
ISSN	2077-0375
ISSN	2077-0375
DOI	10.3390/membranes12050464
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Article ; Online: Meta-Analysis of Nanoparticle Cytotoxicity via Data-Mining the Literature.

Labouta, Hagar I / Asgarian, Nasimeh / Rinker, Kristina / Cramb, David T

ACS nano

2019 Volume 13, Issue 2, Page(s) 1583–1594

Abstract: Developing predictive modeling frameworks of potential cytotoxicity of engineered nanoparticles is critical for environmental and health risk analysis. The complexity and the heterogeneity of available data on potential risks of nanoparticles, in ... ...

Abstract	Developing predictive modeling frameworks of potential cytotoxicity of engineered nanoparticles is critical for environmental and health risk analysis. The complexity and the heterogeneity of available data on potential risks of nanoparticles, in addition to interdependency of relevant influential attributes, makes it challenging to develop a generalization of nanoparticle toxicity behavior. Lack of systematic approaches to investigate these risks further adds uncertainties and variability to the body of literature and limits generalizability of existing studies. Here, we developed a rigorous approach for assembling published evidence on cytotoxicity of several organic and inorganic nanoparticles and unraveled hidden relationships that were not targeted in the original publications. We used a machine learning approach that employs decision trees together with feature selection algorithms ( e.g., Gain ratio) to analyze a set of published nanoparticle cytotoxicity sample data (2896 samples). The specific studies were selected because they specified nanoparticle-, cell-, and screening method-related attributes. The resultant decision-tree classifiers are sufficiently simple, accurate, and with high prediction power and should be widely applicable to a spectrum of nanoparticle cytotoxicity settings. Among several influential attributes, we show that the cytotoxicity of nanoparticles is primarily predicted from the nanoparticle material chemistry, followed by nanoparticle concentration and size, cell type, and cytotoxicity screening indicator. Overall, our study indicates that following rigorous and transparent methodological experimental approaches, in parallel to continuous addition to this data set developed using our approach, will offer higher predictive power and accuracy and uncover hidden relationships. Results obtained in this study help focus future studies to develop nanoparticles that are safe by design.
MeSH term(s)	Animals ; Cell Survival/physiology ; Data Mining ; Humans ; Machine Learning ; Nanoparticles/chemistry
Language	English
Publishing date	2019-01-31
Publishing country	United States
Document type	Journal Article ; Meta-Analysis ; Research Support, Non-U.S. Gov't
ISSN	1936-086X
ISSN (online)	1936-086X
DOI	10.1021/acsnano.8b07562
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