Anthony Tabet

Massachusetts Institute of Technology

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Polina Anikeeva

Massachusetts Institute of Technology

Oren A. Scherman

University of Cambridge

Atharva Sahasrabudhe

Massachusetts Institute of Technology

Vijay Kumar Rana

B.P. Koirala Institute of Health Sciences

Harry Bulstrode

Addenbrooke's Hospital

Florian Koehler

Massachusetts Institute of Technology

David H. Rowitch

University of Cambridge

Chun Wang

University of Minnesota

Dekel Rosenfeld

Tel Aviv University

Marc‐Joseph Antonini

Massachusetts Institute of Technology

Cooperative Institutions

Massachusetts Institute of Technology

McGovern Institute for Brain Research

University of Cambridge

University of Minnesota

Harvard University

Allen Institute

Koch Institute for Integrative Cancer Research At MIT

IIT@MIT

Addenbrooke's Hospital

Harvard–MIT Division of Health Sciences and Technology

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Customizing Multifunctional Neural Interfaces through Thermal Drawing Process

bioRxiv (Cold Spring Harbor Laboratory) (2021)

Marc‐Joseph Antonini Atharva Sahasrabudhe Anthony Tabet Miriam Schwalm Dekel Rosenfeld

Abstract Fiber drawing enables scalable fabrication of multifunctional flexible fibers that integrate electrical, optical and microfluidic modalities to record and modulate neural activity. Constraints on thermomechanical properties of materials, however, have prevented integrated drawing of metal electrodes with low-loss polymer waveguides for concurrent electrical recording and optical neuromodulation. Here we introduce two fabrication approaches: (1) an iterative thermal drawing with a soft, low melting temperature (T m ) metal indium, and (2) a metal convergence drawing with traditionally non-drawable high T m metal tungsten. Both approaches deliver multifunctional flexible neural interfaces with low-impedance metallic electrodes and low-loss waveguides, capable of recording optically-evoked and spontaneous neural activity in mice over several weeks. We couple these fibers with a light-weight mechanical microdrive (1g) that enables depth-specific interrogation of neural circuits in mice following chronic implantation. Finally, we demonstrate the compatibility of these fibers with magnetic resonance imaging (MRI) and apply them to visualize the delivery of chemical payloads through the integrated channels in real time. Together, these advances expand the domains of application of the fiber-based neural probes in neuroscience and neuroengineering.

10.1101/2021.05.17.444577

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Scientists have a responsibility to the public

Anthony Tabet

The training of most scientists in the United States is largely supported by significant public funds. The public expects a return on that investment. Scientists therefore have an obligation to engage with and inform the public on how emerging technologies and challenges will affect our communities. In founding the MIT Science Policy Review, we seek to provide a platform to fulfill such a public obligation.

Obligation

Affect

Investment

10.38105/spr.jwqjndux4i

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Reprogramming brain immunosurveillance with engineered cytokines

bioRxiv (Cold Spring Harbor Laboratory) (2022)

Anthony Tabet Yash Agarwal Jordan A. Stinson Caroline Apra Veronica Will

Abstract Immune surveillance of the brain is regulated by resident non-neuronal cells and the blood-brain barrier. 1 Dys-regulation of immunosurveillance is a hallmark feature of several diseases 2–5 including brain tumors 6 that interact with and rely heavily on immune cells, 7 suggesting that disrupting the neuroimmunology of tumors could slow their progression. Yet few tools are available to control brain immunology in vivo with local precision, and fewer yet are used for therapeutic intervention. 2 Here, we propose engineered cytokines as a neuroimmune-modulation platform. We demonstrate that the residence time of cytokines in the brain can be tuned by binding them to the extracellular matrix or synthetic scaffolds. We then show that the aluminum hydroxide adjuvant (alum) is retained in the brain >2 weeks. Tethering of inflammatory cytokines such as interleukins (IL) 2 and 12 to alum yields extended neuroinflammation and brain immunosurveillance after intracranial administration, while avoiding systemic toxicity. In mouse models of both immunologically hot and cold brain tumors, the intracranial deposition of alum-tethered cytokines causes significant delay in tumor progression. RNA profiling reveals that engineered cytokines engage both innate and adaptive immunity in the brain. These findings suggest that engineered cytokines can reprogram brain immunosurveillance, informing the development of future therapies for neuroimmune diseases.

Immunosurveillance

Proinflammatory cytokine

Neuroimmunology

10.1101/2022.06.21.497082

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Region-specific targeting of microglia in vivo using direct delivery of tamoxifen metabolites via microfluidic polymer fibers

Brain Behavior and Immunity (2023)

Alexis M. Stranahan Anthony Tabet Polina Anikeeva

Gliosis

10.1016/j.bbi.2023.09.021

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Maximizing response to intratumoral immunotherapy in mice by tuning local retention

Nature Communications (2022)

Noor Momin Joseph R. Palmeri Emi A. Lutz Noor Jailkhani Howard H. Mak

Abstract Direct injection of therapies into tumors has emerged as an administration route capable of achieving high local drug exposure and strong anti-tumor response. A diverse array of immune agonists ranging in size and target are under development as local immunotherapies. However, due to the relatively recent adoption of intratumoral administration, the pharmacokinetics of locally-injected biologics remains poorly defined, limiting rational design of tumor-localized immunotherapies. Here we define a pharmacokinetic framework for biologics injected intratumorally that can predict tumor exposure and effectiveness. We find empirically and computationally that extending the tumor exposure of locally-injected interleukin-2 by increasing molecular size and/or improving matrix-targeting affinity improves therapeutic efficacy in mice. By tracking the distribution of intratumorally-injected proteins using positron emission tomography, we observe size-dependent enhancement in tumor exposure occurs by slowing the rate of diffusive escape from the tumor and by increasing partitioning to an apparent viscous region of the tumor. In elucidating how molecular weight and matrix binding interplay to determine tumor exposure, our model can aid in the design of intratumoral therapies to exert maximal therapeutic effect.

10.1038/s41467-021-27390-6

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Applying support-vector machine learning algorithms toward predicting host-guest interactions with cucurbit[7]uril

Anthony Tabet Cole Baker Polina Anikeeva

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Polymer-Based Dual-Responsive Self-Emulsifying Nanodroplets as Potential Carriers for Poorly Soluble Drugs

ACS Applied Bio Materials (2021)

Li Zhang Zhiming Zhang Wenshou Wang Anthony Tabet Samuel Hanson

A biodegradable amphiphilic liquid polymer was designed to form self-emulsifying nanodroplets in water for delivering poorly soluble drugs. The polymer was composed of multiple short blocks of poly(ethylene glycol) (PEG) and poly(caprolactone) (PCL) connected through acid-labile acetal linkages. With an overall average molecular weight of over 18 kDa, the polymer remained as a viscous liquid under room and physiological temperatures. Dispersing the polymer in an aqueous buffer gave rise to highly stable micelle-like nanodroplets with an average size of approximately 15-20 nm. The nanodroplet dispersions underwent reversible temperature-sensitive aggregation with cloud points ranging from 45 to 50 °C, depending on polymer concentration. Nuclear magnetic resonance (NMR) and dynamic light scattering analyses revealed that while the nanodroplets were stable at pH 7.4 for several days, hydrolysis of the acetal linkages in the polymer backbone was much accelerated under mildly acidic pH 5.0, resulting in the formation of large microdroplets. Nile red (NR), a poorly water-soluble fluorophore, can be solubilized in the nanodroplets, and efficient intracellular delivery of NR was achieved. The hydrophobic indocyanine green (ICG) was also encapsulated in the nanodroplets. Near-infrared (NIR) fluorescence imaging and in vivo biocompatibility of the ICG-loaded nanodroplets were demonstrated in mice. In summary, the self-emulsifying nanodroplets of amphiphilic liquid polymer would be a promising material system for poorly soluble drug delivery and imaging in vivo.

Nile red

Biocompatibility

10.1021/acsabm.1c00194

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Designing Next‐Generation Local Drug Delivery Vehicles for Glioblastoma Adjuvant Chemotherapy: Lessons from the Clinic

Advanced Healthcare Materials (2019)

Anthony Tabet Melanie P. Jensen Christopher C. Parkins Parag G. Patil Colin Watts

Abstract To date, the clinical outcomes and survival rates for patients with glioblastoma (GB) remain poor. A promising approach to disease‐modification involves local delivery of adjuvant chemotherapy into the resection cavity, thus circumventing the restrictions imposed by the blood–brain barrier. The clinical performance of the only FDA‐approved local therapy for GB [carmustine (BCNU)‐loaded polyanhydride wafers], however, has been disappointing. There is an unmet medical need in the local treatment of GB for drug delivery vehicles that provide sustained local release of small molecules and combination drugs over several months. Herein, key quantitative lessons from the use of local and systemic adjuvant chemotherapy for GB in the clinic are outlined, and it is discussed how these can inform the development of next‐generation therapies. Several recent approaches are highlighted, and it is proposed that long‐lasting soft materials can capture the value of stiff BCNU‐loaded wafers while addressing a number of unmet medical needs. Finally, it is suggested that improved communication between materials scientists, biomedical scientists, and clinicians may facilitate translation of these materials into the clinic and ultimately lead to improved clinical outcomes.

Carmustine

10.1002/adhm.201801391

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Research data supporting "Applying Support-Vector Machine Learning Algorithms towards Predicting Host-Guest Interactions with Cucurbit[7]uril"

Oren A. Scherman Anthony Tabet Thomas Gebhart Guanglu Wu Charlie Readman

DFT simulations were run using Gaussian 09 on organic small molecules that are known guests to cucurbit[7]uril. Controls are also included. This data supports the manuscript entitled Applying Support-Vector Machine Learning Algorithms towards Predicting Host-Guest Interactions with Cucurbit[7]uril.

10.17863/cam.54504

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Low-cost, rapidly-developed, 3D printed in vitro corpus callosum model for mucopolysaccharidosis type I

F1000Research (2016)

Anthony Tabet Matthew Gardner Sebastian Swanson Sydney Crump Austin McMeekin

The rising prevalence of high throughput screening and the general inability of (1) two dimensional (2D) cell culture and (2)in vitrorelease studies to predictin vivoneurobiological and pharmacokinetic responses in humans has led to greater interest in more realistic three dimensional (3D) benchtop platforms. Advantages of 3D human cell culture over its 2D analogue, or even animal models, include taking the effects of microgeometry and long-range topological features into consideration. In the era of personalized medicine, it has become increasingly valuable to screen candidate molecules and synergistic therapeutics at a patient-specific level, in particular for diseases that manifest in highly variable ways. The lack of established standards and the relatively arbitrary choice of probing conditions has limitedin vitrodrug release to a largely qualitative assessment as opposed to a predictive, quantitative measure of pharmacokinetics and pharmacodynamics in tissue. Here we report the methods used in the rapid, low-cost development of a 3D model of a mucopolysaccharidosis type I patient’s corpus callosum, which may be used for cell culture and drug release. The CAD model is developed fromin vivobrain MRI tracing of the corpus callosum using open-source software, printed with poly (lactic-acid) on a Makerbot Replicator 5X, UV-sterilized, and coated with poly (lysine) for cellular adhesion. Adaptations of material and 3D printer for expanded applications are also discussed.

10.12688/f1000research.9861.1

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