Imperial College London

Dr Sophie V Morse

Faculty of EngineeringDepartment of Bioengineering

Imperial College Research Fellow
 
 
 
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Contact

 

sophie.morse11

 
 
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Location

 

B324Royal School of MinesSouth Kensington Campus

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Summary

 

Publications

Publication Type
Year
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15 results found

Grewal S, Goncalves de Andrade E, Hahn Kofoed R, Matthews PM, Aubert I, Tremblay M-E, Morse Set al., 2023, Using focused ultrasound to modulate microglial structure and function, Frontiers in Cellular Neuroscience, Vol: 17, ISSN: 1662-5102

Transcranial focused ultrasound (FUS) has the unique ability to target regions of the brain with high spatial precision, in a minimally invasive manner. Neuromodulation studies have shown that FUS can excite or inhibit neuronal activity, demonstrating its tremendous potential to improve the outcome of neurological diseases. Recent evidence has also shed light on the emerging promise that FUS has with and without the use of intravenously injected microbubbles, in modulating the blood-brain barrier and the immune cells of the brain. As the resident immune cells of the central nervous system, microglia are at the forefront of the brain's maintenance and immune defense. Notably, microglia are highly dynamic and continuously survey the brain parenchyma by extending and retracting their processes. This surveillance activity aids microglia in performing key physiological functions required for brain activity and plasticity. In response to stressors, microglia rapidly alter their cellular and molecular profile to help facilitate a return to homeostasis. While the underlying mechanisms by which both FUS and FUS + microbubbles modify microglial structure and function remain largely unknown, several studies in adult mice have reported changes in the expression of the microglia/macrophage marker ionized calcium binding adaptor molecule 1, and in their phagocytosis, notably of protein aggregates, such as amyloid beta. In this review, we discuss the demonstrated and putative biological effects of FUS and FUS + microbubbles in modulating microglial activities, with an emphasis on the key cellular and molecular changes observed in vitro and in vivo across models of brain health and disease. Understanding how this innovative technology can modulate microglia paves the way for future therapeutic strategies aimed to promote beneficial physiological microglial roles, and prevent or treat maladaptive responses.

Journal article

Perryman R, Renziehausen A, Shaye H, Kostagianni AD, Tsiailanis AD, Thorne T, Chatziathanasiadou MV, Sivolapenko GB, El Mubarak MA, Won Han G, Zarzycka B, Katritch V, Lebon G, Nigro CL, Lattanzio L, Morse S, Choi J, ONeill K, Kanaki Z, Klinakis A, Crook T, Cherezov V, Tzakos A, Syed Net al., 2023, Inhibition of the angiotensin II type 2 receptor AT2R is a novel therapeutic strategy for glioblastoma, Proceedings of the National Academy of Sciences of USA, Vol: 119, ISSN: 0027-8424

Glioblastoma (GBM) is an aggressive malignant primary brain tumor with limited therapeutic options. We show that the angiotensin II (AngII) type 2 receptor (AT2R) is a novel therapeutic target for GBM and that AngII, endogenously produced in GBM cells, promotes proliferation through AT2R. We repurposed EMA401, an AT2R antagonist originally developed as a peripherally restricted analgesic, for GBM and showed that it inhibits the proliferation of AT2R-expressing GBM spheroids and blocks their invasiveness and angiogenic capacity. The crystal structure of AT2R bound to EMA401 was determined and revealed the receptor to be in an active-like conformation with helix-VIII blocking G protein or β-arrestin recruitment. The architecture and interactions of EMA401 in AT2R differ drastically from complexes of AT2R with other relevant compounds. To enhance central nervous system (CNS) penetration of EMA401, we exploited the crystal structure to design an angiopep-2 tethered EMA401 derivative, A3E. A3E exhibited enhanced CNS penetration, leading to reduced tumor volume, inhibition of proliferation and increased levels of apoptosis in an orthotopic xenograft model of GBM.

Journal article

Lim Kee Chang W, Chan T, Raguseo F, Mishra A, Chattenton D, de Rosales RTM, Long N, Morse Set al., 2023, Rapid short-pulses of focused ultrasound and microbubbles deliver a range of agent sizes to the brain, Scientific Reports, Vol: 13, ISSN: 2045-2322

Focused ultrasound and microbubbles can non-invasively and locally deliver therapeutics and imaging agents across the blood–brain barrier. Uniform treatment and minimal adverse bioeffects are critical to achieve reliable doses and enable safe routine use of this technique. Towards these aims, we have previously designed a rapid short-pulse ultrasound sequence and used it to deliver a 3 kDa model agent to mouse brains. We observed a homogeneous distribution in delivery and blood–brain barrier closing within 10 min. However, many therapeutics and imaging agents are larger than 3 kDa, such as antibody fragments and antisense oligonucleotides. Here, we evaluate the feasibility of using rapid short-pulses to deliver higher-molecular-weight model agents. 3, 10 and 70 kDa dextrans were successfully delivered to mouse brains, with decreasing doses and more heterogeneous distributions with increasing agent size. Minimal extravasation of endogenous albumin (66.5 kDa) was observed, while immunoglobulin (~ 150 kDa) and PEGylated liposomes (97.9 nm) were not detected. This study indicates that rapid short-pulses are versatile and, at an acoustic pressure of 0.35 MPa, can deliver therapeutics and imaging agents of sizes up to a hydrodynamic diameter between 8 nm (70 kDa dextran) and 11 nm (immunoglobulin). Increasing the acoustic pressure can extend the use of rapid short-pulses to deliver agents beyond this threshold, with little compromise on safety. This study demonstrates the potential for deliveries of higher-molecular-weight therapeutics and imaging agents using rapid short-pulses.

Journal article

Morse SV, Chan TG, Cudeiro-Blanco J, Pouliopoulos ANet al., 2023, Ultrasound-Mediated Delivery of Therapeutics, Emerging Drug Delivery and Biomedical Engineering Technologies, Publisher: CRC Press, Pages: 181-193

Book chapter

Al Musaimi O, Morse SV, Lombardi L, Serban S, Basso A, Williams DRet al., 2023, Successful synthesis of a glial-specific blood-brain barrier shuttle peptide following a fragment condensation approach on a solid-phase resin, Journal of Peptide Science, Vol: 29, Pages: 1-9, ISSN: 1075-2617

Successful manual synthesis of the TD2.2 peptide acting as a blood-brain barrier shuttle was achieved. TD2.2 was successfully synthesised by sequential condensation of four protected peptide fragments on solid-phase settings, after several unsuccessful attempts using the stepwise approach. These fragments were chosen to minimize the number of demanding amino acids (in terms of coupling, Fmoc removal) in each fragment that are expected to hamper the overall synthetic process. Thus, the hydrophobic amino acids as well as Fmoc-Arg (Pbf)-OH were strategically spread over multiple fragments rather than having them congested in one fragment. This study shows how a peptide that shows big challenges in the synthesis using the common stepwise elongation methodology can be synthesised with an acceptable purity. It also emphasises that choosing the right fragment with certain amino acid constituents is key for a successful synthesis. It is worth highlighting that lower amounts of reagents were required to synthesise the final peptide with an identical purity to that obtained by the automatic synthesiser.

Journal article

Symington J, Perryman R, Morse S, O'Neill K, Want E, Syed Net al., 2022, ADI-PEG20 RESTORES IMMUNITY IN THE TUMOR MICROENVIRONMENT AND ERADICATES GBM TUMORS IN MICE WHEN COMBINED WITH RADIATION, 27th Annual Scientific Meeting and Education Day of the Society-for-Neuro-Oncology (SNO), Publisher: OXFORD UNIV PRESS INC, Pages: 278-278, ISSN: 1522-8517

Conference paper

Morse SV, Mishra A, Chan TG, T M de Rosales R, Choi JJet al., 2021, Liposome delivery to the brain with rapid short-pulses of focused ultrasound and microbubbles., Journal of Controlled Release, Vol: 341, Pages: 605-615, ISSN: 0168-3659

Liposomes are clinically used drug carriers designed to improve the delivery of drugs to specific tissues while minimising systemic distribution. However, liposomes are unable to cross the blood-brain barrier (BBB) and enter the brain, mostly due to their large size (ca. 100 nm). A noninvasive and localised method of delivering liposomes across the BBB is to intravenously inject microbubbles and apply long pulses of ultrasound (pulse length: >1 ms) to a targeted brain region. Recently, we have shown that applying rapid short pulses (RaSP) (pulse length: 5 μs) can deliver drugs with an improved efficacy and safety profile. However, this was tested with a relatively smaller 3-kDa molecule (dextran). In this study, we examine whether RaSP can deliver liposomes to the murine brain in vivo. Fluorescent DiD-PEGylated liposomes were synthesized and injected intravenously alongside microbubbles. The left hippocampus of mice was then sonicated with either a RaSP sequence (5 μs at 1.25 kHz in groups of 10 ms at 0.5 Hz) or a long pulse sequence (10 ms at 0.5 Hz), with each pulse having a 1-MHz centre frequency (0.35 and 0.53 MPa). The delivery and distribution of the fluorescently-labelled liposomes were assessed by fluorescence imaging of the brain sections. The safety profile of the sonicated brains was assessed by histological staining. RaSP was shown to locally deliver liposomes across the BBB at 0.53 MPa with a more diffused and safer profile compared to the long pulse ultrasound sequence. Cellular uptake of liposomes was observed in neurons and microglia, while no uptake within astrocytes was observed in both RaSP and long pulse-treated brains. This study shows that RaSP allows a targeted and safe delivery of liposomal drugs into the murine brain with potential to deliver drugs into neuronal and glial targets.

Journal article

Chan TG, Ruehl CL, Morse SV, Simon M, Rakers V, Watts H, Aprile FA, Choi JJ, Vilar Ret al., 2021, Modulation of amyloid-beta aggregation by metal complexes with a dual binding mode and their delivery across the blood-brain barrier using focused ultrasound, Chemical Science, Vol: 12, Pages: 9485-9493, ISSN: 2041-6520

One of the key hallmarks of Alzheimer's disease is the aggregation of the amyloid-β peptide to form fibrils. Consequently, there has been great interest in studying molecules that can disrupt amyloid-β aggregation. While a handful of molecules have been shown to inhibit amyloid-β aggregation in vitro, there remains a lack of in vivo data reported due to their inability to cross the blood–brain barrier. Here, we investigate a series of new metal complexes for their ability to inhibit amyloid-β aggregation in vitro. We demonstrate that octahedral cobalt complexes with polyaromatic ligands have high inhibitory activity thanks to their dual binding mode involving π–π stacking and metal coordination to amyloid-β (confirmed via a range of spectroscopic and biophysical techniques). In addition to their high activity, these complexes are not cytotoxic to human neuroblastoma cells. Finally, we report for the first time that these metal complexes can be safely delivered across the blood–brain barrier to specific locations in the brains of mice using focused ultrasound.

Journal article

Davies HJ, Morse SV, Copping MJ, Sujarittam K, Bourgin VD, Tang M-X, Choi JJet al., 2021, Imaging with therapeutic acoustic wavelets–short pulses enable acoustic localization when time of arrival is combined with delay and sum, IEEE Transactions on Ultrasonics, Ferroelectrics, and Frequency Control, Vol: 68, Pages: 178-190, ISSN: 0885-3010

—Passive acoustic mapping (PAM) is an algorithm that reconstructs the location of acoustic sourcesusing an array of receivers. This technique can monitor therapeutic ultrasound procedures to confirm the spatial distribution and amount of microbubble activity induced. CurrentPAM algorithms have an excellentlateral resolution but havea poor axial resolution, making it difficult to distinguishacoustic sources within the ultrasound beams. With recentstudies demonstrating that short-length and low-pressurepulses—acoustic wavelets—have the therapeutic function,we hypothesizedthat the axial resolution could be improvedwith a quasi-pulse-echo approach and that the resolutionimprovement would depend on the wavelet’s pulse length.This article describes an algorithm that resolves acousticsources axially using time of flight and laterally using delayand-sum beamforming, which we named axial temporalposition PAM (ATP-PAM). The algorithm accommodates arapid short pulse (RaSP) sequence that can safely deliverdrugs across the blood–brain barrier. We developed ouralgorithm with simulations (k-wave) and in vitro experiments for one-, two-, and five-cycle pulses, comparingour resolution against that of two current PAM algorithms.We then tested ATP-PAM in vivo and evaluated whether thereconstructed acoustic sources mapped to drug delivery

Journal article

Morse SV, Boltersdorf T, Chan TG, Gavins FNE, Choi JJ, Long NJet al., 2020, In vivo delivery of a fluorescent FPR2/ALX-targeted probe using focused ultrasound and microbubbles to image activated microglia, RSC Chemical Biology, Vol: 1, Pages: 385-389, ISSN: 2633-0679

To image activated microglia, a small-molecule FPR2/ALX-targeted fluorescent probe was locally delivered into the brain using focused ultrasound and microbubbles. The probe did not co-localise with neurons or astrocytes but accumulated in activated microglia, making this a potential imaging tool for future drug discovery programs focused on neurological disorders.

Journal article

Choi J, Pouliopoulos A, Smith C, Bezer J, El Ghamrawy A, Boulding C, Morse SV, Meng-Xing Tet al., 2020, Doppler passive acoustic mapping, IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control, Vol: 67, Pages: 2692-2703, ISSN: 0885-3010

In therapeutic ultrasound using microbubbles, it is essential to drive the microbubbles into the correct type of activity and the correct location to produce the desired biological response. Although passive acoustic mapping (PAM) is capable of locating where microbubble activities are generated, it is well known that microbubbles move rapidly within the ultrasound beam. We propose a technique that can image microbubble movement by estimating their velocities within the focal volume. Microbubbles embedded within a wall-less channel of a tissue-mimicking material were sonicated using 1-MHz focused ultrasound. The acoustic emissions generated by the microbubbles were captured with a linear array (L7-4). PAM with robust Capon beamforming was used to localize the microbubble acoustic emissions. We spectrally analyzed the time trace of each position and isolated the higher harmonics. Microbubble velocity maps were constructed from the position-dependent Doppler shifts at different time points during sonication. Microbubbles moved primarily away from the transducer at velocities on the order of 1 m/s due to primary acoustic radiation forces, producing a time-dependent velocity distribution. We detected microbubble motion both away and towards the receiving array, revealing the influence of acoustic radiation forces and fluid motion due to the ultrasound exposure. High-speed optical images confirmed the acoustically-measured microbubble velocities. Doppler PAM enables passive estimation of microbubble motion and may be useful in therapeutic applications, such as drug delivery across the blood-brain barrier, sonoporation, sonothrombolysis and drug release.

Journal article

Morse SV, Boltersdorf T, Harriss BI, Chan TG, Baxan N, Hee Seok J, Pouliopoulos AN, Choi J, Long NJet al., 2020, Neuron labeling with rhodamine-conjugated Gd-based MRI contrast agents delivered to the brain via focused ultrasound, Theranostics, Vol: 10, Pages: 2659-2674, ISSN: 1838-7640

Gadolinium-based magnetic resonance imaging contrast agents can provide information regarding neuronal function, provided that these agents can cross the neuronal cell membrane. Such contrast agents are normally restricted to extracellular domains, however, by attaching cationic fluorescent dyes, they can be made cell-permeable and allow for both optical and magnetic resonance detection. To reach neurons, these agents also need to cross the blood-brain barrier. Focused ultrasound combined with microbubbles has been shown to enhance the permeability of this barrier, allowing molecules into the brain non-invasively, locally and transiently. The goal of this study was to investigate whether combining fluorescent rhodamine with a gadolinium complex would form a dual-modal contrast agent that could label neurons in vivo when delivered to the mouse brain with focused ultrasound and microbubbles.Methods: Gadolinium complexes were combined with a fluorescent, cationic rhodamine unit to form probes with fluorescence and relaxivity properties suitable for in vivo applications. The left hemisphere of female C57bl/6 mice (8-10 weeks old; 19.07 ± 1.56 g; n = 16) was treated with ultrasound (centre frequency: 1 MHz, peak-negative pressure: 0.35 MPa, pulse length: 10 ms, repetition frequency: 0.5 Hz) while intravenously injecting SonoVue microbubbles and either the 1 kDa Gd(rhodamine-pip-DO3A) complex or a conventionally-used lysine-fixable Texas Red® 3 kDa dextran. The opposite right hemisphere was used as a non-treated control region. Brains were then extracted and either sectioned and imaged via fluorescence or confocal microscopy or imaged using a 9.4 T magnetic resonance imaging scanner. Brain slices were stained for neurons (NeuN), microglia (Iba1) and astrocytes (GFAP) to investigate the cellular localization of the probes.Results: Rhodamine fluorescence was detected in the left hemisphere of all ultrasound treated mice, while none was detected in the right contr

Journal article

Morse SV, Pouliopoulos AN, Chan TG, Copping MJ, Lin J, Long NJ, Choi JJet al., 2019, Rapid short-pulse ultrasound delivers drugs uniformly across the murine blood-brain barrier with negligible disruption, Radiology, Vol: 291, Pages: 459-466, ISSN: 0033-8419

Background Previous work has demonstrated that drugs can be delivered across the blood-brain barrier by exposing circulating microbubbles to a sequence of long ultrasound pulses. Although this sequence has successfully delivered drugs to the brain, concerns remain regarding potentially harmful effects from disrupting the brain vasculature. Purpose To determine whether a low-energy, rapid, short-pulse ultrasound sequence can efficiently and safely deliver drugs to the murine brain. Materials and Methods Twenty-eight female wild-type mice underwent focused ultrasound treatment after injections of microbubbles and a labeled model drug, while three control mice were not treated (May-November 2017). The left hippocampus of 14 mice was exposed to low-energy short pulses (1 MHz; five cycles; peak negative pressure, 0.35 MPa) of ultrasound emitted at a rapid rate (1.25 kHz) in bursts (0.5 Hz), and another 14 mice were exposed to standard long pulses (10 msec, 0.5 Hz) containing 150 times more acoustic energy. Mice were humanely killed at 0 (n = 5), 10 (n = 3), or 20 minutes (n = 3) after ultrasound treatment. Hematoxylin-eosin (H-E) staining was performed on three mice. The delivered drug dose and distribution were quantified with the normalized optical density and coefficient of variation. Safety was assessed by H-E staining, the amount of albumin released, and the duration of permeability change in the blood-brain barrier. Statistical analysis was performed by using the Student t test. Results The rapid short-pulse sequence delivered drugs uniformly throughout the parenchyma. The acoustic energy emitted from the microbubbles also predicted the delivered dose (r = 0.97). Disruption in the blood-brain barrier lasted less than 10 minutes and 3.4-fold less albumin was released into the brain than with long pulses. No vascular or tissue damage from rapid short-pulse exposure was observable using H-E staining. Conclusion The rapid short-pulse ultrasound sequence is a minimally

Journal article

Chan T, Morse S, Copping M, Choi J, Vilar Compte Ret al., 2018, Targeted delivery of DNA-Au nanoparticles across the blood-brain barrier using focused ultrasound, ChemMedChem, Vol: 13, Pages: 1311-1314, ISSN: 1860-7187

Nanoparticles have been widely studied as versatile platforms for in vivo imaging and therapy. However, their use to image and/or treat the brain is limited, as they are often unable to cross the blood–brain barrier (BBB). To overcome this problem, herein we report the use of focused ultrasound in vivo to successfully deliver DNA‐coated gold nanoparticles to specific locations in the brains of mice.

Journal article

Morse SV, Pouliopoulos AN, Chan T, Lin J, Copping M, Long NJ, Choi JJet al., 2017, Rapid short-pulse (RaSP) sequences improve the distribution of drug delivery to the brain in vivo, IEEE UFFC, Publisher: IEEE, ISSN: 1948-5719

Focused ultrasound and microbubbles have been shown to locally and noninvasively open the blood-brain barrier. Despite encouraging results in human patients, several performance and safety features, such as poor drug distribution, high drug accumulation along vessels and small sites of red blood cell extravasation, have been unavoidable. We have recently developed a new ultrasound sequence - rapid short-pulse (RaSP) sequence - designed to suppress these adverse features by promoting safer modes of cavitation activity throughout capillaries. In our RaSP sequences, low-pressure short ultrasonic pulses are emitted at kHz pulse repetition frequencies (PRF) and grouped into bursts. We have shown in vitro that RaSP sequences prolong microbubble lifetime and increase their mobility, enhancing the distribution of acoustic cavitation activity. Here we evaluate the ability of RaSP sequences to improve the in vivo performance and safety of ultrasound-mediated drug delivery to the brain.

Conference paper

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