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Protein-Engineered Fibers For Drug Encapsulation Traceable via 19F Magnetic Resonance

Britton, Dustin; Legocki, Jakub; Aristizabal, Orlando; Mishkit, Orin; Liu, Chengliang; Jia, Sihan; Renfrew, Paul Douglas; Bonneau, Richard; Wadghiri, Youssef Z; Montclare, Jin Kim
Theranostic materials research is experiencing rapid growth driven by the interest in integrating both therapeutic and diagnostic modalities. These materials offer the unique capability to not only provide treatment but also track the progression of a disease. However, to create an ideal theranostic biomaterial without compromising drug encapsulation, diagnostic imaging must be optimized for improved sensitivity and spatial localization. Herein, we create a protein-engineered fluorinated coiled-coil fiber, Q2TFL, capable of improved sensitivity to 19F magnetic resonance spectroscopy (MRS) detection. Leveraging residue-specific noncanonical amino acid incorporation of trifluoroleucine (TFL) into the coiled-coil, Q2, which self-assembles into nanofibers, we generate Q2TFL. We demonstrate that fluorination results in a greater increase in thermostability and 19F magnetic resonance detection compared to the nonfluorinated parent, Q2. Q2TFL also exhibits linear ratiometric 19F MRS thermoresponsiveness, allowing it to act as a temperature probe. Furthermore, we explore the ability of Q2TFL to encapsulate the anti-inflammatory small molecule, curcumin (CCM), and its impact on the coiled-coil structure. Q2TFL also provides hyposignal contrast in 1H MRI, echogenic signal with high-frequency ultrasound and sensitive detection by 19F MRS in vivo illustrating fluorination of coiled-coils for supramolecular assembly and their use with 1H MRI, 19F MRS and high frequency ultrasound as multimodal theranostic agents.
PMCID:10682962
PMID: 38037605
ISSN: 2574-0970
CID: 5591272

Towards reliable reconstruction of the mouse brain corticothalamic connectivity using diffusion MRI

Arefin, Tanzil Mahmud; Lee, Choong Heon; Liang, Zifei; Rallapalli, Harikrishna; Wadghiri, Youssef Z; Turnbull, Daniel H; Zhang, Jiangyang
Diffusion magnetic resonance imaging (dMRI) tractography has yielded intriguing insights into brain circuits and their relationship to behavior in response to gene mutations or neurological diseases across a number of species. Still, existing tractography approaches suffer from limited sensitivity and specificity, leading to uncertain interpretation of the reconstructed connections. Hence, in this study, we aimed to optimize the imaging and computational pipeline to achieve the best possible spatial overlaps between the tractography and tracer-based axonal projection maps within the mouse brain corticothalamic network. We developed a dMRI-based atlas of the mouse forebrain with structural labels imported from the Allen Mouse Brain Atlas (AMBA). Using the atlas and dMRI tractography, we first reconstructed detailed node-to-node mouse brain corticothalamic structural connectivity matrices using different imaging and tractography parameters. We then investigated the effects of each condition for accurate reconstruction of the corticothalamic projections by quantifying the similarities between the tractography and the tracer data from the Allen Mouse Brain Connectivity Atlas (AMBCA). Our results suggest that these parameters significantly affect tractography outcomes and our atlas can be used to investigate macroscopic structural connectivity in the mouse brain. Furthermore, tractography in mouse brain gray matter still face challenges and need improved imaging and tractography methods.
PMCID:10149621
PMID: 37060936
ISSN: 1095-9572
CID: 5464322

Evaluation of cellular water exchange in a mouse glioma model using dynamic contrast-enhanced MRI with two flip angles

Kiser, Karl; Zhang, Jin; Das, Ayesha Bharadwaj; Tranos, James A; Wadghiri, Youssef Zaim; Kim, Sungheon Gene
This manuscript aims to evaluate the robustness and significance of the water efflux rate constant (kio) parameter estimated using the two flip-angle Dynamic Contrast-Enhanced (DCE) MRI approach with a murine glioblastoma model at 7 T. The repeatability of contrast kinetic parameters and kio measurement was assessed by a test-retest experiment (n = 7). The association of kio with cellular metabolism was investigated through DCE-MRI and FDG-PET experiments (n = 7). Tumor response to a combination therapy of bevacizumab and fluorouracil (5FU) monitored by contrast kinetic parameters and kio (n = 10). Test-retest experiments demonstrated compartmental volume fractions (ve and vp) remained consistent between scans while the vascular functional measures (Fp and PS) and kio showed noticeable changes, most likely due to physiological changes of the tumor. The standardized uptake value (SUV) of tumors has a linear correlation with kio (R2 = 0.547), a positive correlation with Fp (R2 = 0.504), and weak correlations with ve (R2 = 0.150), vp (R2 = 0.077), PS (R2 = 0.117), Ktrans (R2 = 0.088) and whole tumor volume (R2 = 0.174). In the treatment study, the kio of the treated group was significantly lower than the control group one day after bevacizumab treatment and decreased significantly after 5FU treatment compared to the baseline. This study results support the feasibility of measuring kio using the two flip-angle DCE-MRI approach in cancer imaging.
PMCID:9945648
PMID: 36810898
ISSN: 2045-2322
CID: 5448162

Locus coeruleus activity improves cochlear implant performance

Glennon, Erin; Valtcheva, Silvana; Zhu, Angela; Wadghiri, Youssef Z; Svirsky, Mario A; Froemke, Robert C
Cochlear implants (CIs) are neuroprosthetic devices that can provide hearing to deaf people1. Despite the benefits offered by CIs, the time taken for hearing to be restored and perceptual accuracy after long-term CI use remain highly variable2,3. CI use is believed to require neuroplasticity in the central auditory system, and differential engagement of neuroplastic mechanisms might contribute to the variability in outcomes4-7. Despite extensive studies on how CIs activate the auditory system4,8-12, the understanding of CI-related neuroplasticity remains limited. One potent factor enabling plasticity is the neuromodulator noradrenaline from the brainstem locus coeruleus (LC). Here we examine behavioural responses and neural activity in LC and auditory cortex of deafened rats fitted with multi-channel CIs. The rats were trained on a reward-based auditory task, and showed considerable individual differences of learning rates and maximum performance. LC photometry predicted when CI subjects began responding to sounds and longer-term perceptual accuracy. Optogenetic LC stimulation produced faster learning and higher long-term accuracy. Auditory cortical responses to CI stimulation reflected behavioural performance, with enhanced responses to rewarded stimuli and decreased distinction between unrewarded stimuli. Adequate engagement of central neuromodulatory systems is thus a potential clinically relevant target for optimizing neuroprosthetic device use.
PMID: 36544024
ISSN: 1476-4687
CID: 5395022

Open-source versatile 3D-print animal conditioning platform design for in-vivo preclinical brain imaging in awake mice and anesthetized mice and rats

Gironda, Zakia Ben Youss; Arefin, Tanzil Mahmud; Qayyum, Sawwal; Zhang, Jiangyang; Wadghiri, Youssef Zaim; Alon, Leeor; Yaghmazadeh, Omid
ORIGINAL:0016470
ISSN: 2692-8205
CID: 5417732

Melanoma-secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis

Kleffman, Kevin; Levinson, Grace; Rose, Indigo V L; Blumenberg, Lili M; Shadaloey, Sorin A A; Dhabaria, Avantika; Wong, Eitan; Galan-Echevarria, Francisco; Karz, Alcida; Argibay, Diana; Von Itter, Richard; Floristan, Alfredo; Baptiste, Gillian; Eskow, Nicole M; Tranos, James A; Chen, Jenny; Vega Y Saenz de Miera, Eleazar C; Call, Melissa; Rogers, Robert; Jour, George; Wadghiri, Youssef Zaim; Osman, Iman; Li, Yue-Ming; Mathews, Paul; DeMattos, Ronald; Ueberheide, Beatrix; Ruggles, Kelly V; Liddelow, Shane A; Schneider, Robert J; Hernando, Eva
Brain metastasis is a significant cause of morbidity and mortality in multiple cancer types and represents an unmet clinical need. The mechanisms that mediate metastatic cancer growth in the brain parenchyma are largely unknown. Melanoma, which has the highest rate of brain metastasis among common cancer types, is an ideal model to study how cancer cells adapt to the brain parenchyma. Our unbiased proteomics analysis of melanoma short-term cultures revealed that proteins implicated in neurodegenerative pathologies are differentially expressed in melanoma cells explanted from brain metastases compared to those derived from extracranial metastases. We showed that melanoma cells require amyloid beta (AB) for growth and survival in the brain parenchyma. Melanoma-secreted AB activates surrounding astrocytes to a pro-metastatic, anti-inflammatory phenotype and prevents phagocytosis of melanoma by microglia. Finally, we demonstrate that pharmacological inhibition of AB decreases brain metastatic burden.
PMID: 35262173
ISSN: 2159-8290
CID: 5183542

A Robust Discovery Platform for the Identification of Novel Mediators of Melanoma Metastasis

Shadaloey, Arman Alberto Sorin; Karz, Alcida; Moubarak, Rana S; Agrawal, Praveen; Levinson, Grace; Kleffman, Kevin; Aristizabal, Orlando; Osman, Iman; Wadghiri, Youssef Z; Hernando, Eva
Metastasis is a complex process, requiring cells to overcome barriers that are only incompletely modeled by in vitro assays. A systematic workflow was established using robust, reproducible in vivo models and standardized methods to identify novel players in melanoma metastasis. This approach allows for data inference at specific experimental stages to precisely characterize a gene's role in metastasis. Models are established by introducing genetically modified melanoma cells via intracardiac, intradermal, or subcutaneous injections into mice, followed by monitoring with serial in vivo imaging. Once preestablished endpoints are reached, primary tumors and/or metastases-bearing organs are harvested and processed for various analyses. Tumor cells can be sorted and subjected to any of several 'omics' platforms, including single-cell RNA sequencing. Organs undergo imaging and immunohistopathological analyses to quantify the overall burden of metastases and map their specific anatomic location. This optimized pipeline, including standardized protocols for engraftment, monitoring, tissue harvesting, processing, and analysis, can be adopted for patient-derived, short-term cultures and established human and murine cell lines of various solid cancer types.
PMID: 35343960
ISSN: 1940-087x
CID: 5200892

Rapid in Vitro Quantification of a Sensitized Gadolinium Chelate via Photoinduced Triplet Harvesting

Tranos, James A.; Das, Ayesha; Zhang, Jin; Hafeez, Sonia; Arvanitakis, Georgios N.; Thomson, Stuart A.J.; Khan, Suleiman; Pandya, Neelam; Kim, Sungheon Gene; Wadghiri, Youssef Z.
Gadolinium (Gd) based contrast agents (GBCAs) are widely used in magnetic resonance imaging (MRI) and are paramount to cancer diagnostics and tumor pharmacokinetic analysis. Accurate quantification of gadolinium concentration is essential to monitoring the biodistribution, clearance, and pharmacodynamics of GBCAs. However, current methods of quantifying gadolinium in blood or plasma (biological media) are both low throughput and clinically unavailable. Here, we have demonstrated the use of a sensitized gadolinium chelate, Gd[DTPA-cs124], as an MRI contrast agent that can be used to measure the concentration of gadolinium via luminescence quantification in biological media following transmetalation with a terbium salt. Gd[DTPA-cs124] was synthesized by conjugating carbostyril-124 (cs124) to diethylenetriaminepentaacetic acid (DTPA) and chelating to gadolinium. We report increases in both stability and relaxivity compared to the clinically approved analog Gd[DTPA] (gadopentetic acid or Magnevist). In vivo MRI experiments were conducted using C57BL6 mice in order to further illustrate the performance of Gd[DTPA-cs124] as an MRI contrast agent in comparison to Magnevist. Our results indicate that similar chemical modification to existing clinically approved GBCA may likewise provide favorable property changes, with the ability to be used in a gadolinium quantification assay. Furthermore, our assay provides a straightforward and high-throughput method of measuring gadolinium in biological media using a standard laboratory plate reader.
SCOPUS:85146178614
ISSN: 2470-1343
CID: 5408602

Engineered protein-iron oxide hybrid biomaterial for MRI-traceable drug encapsulation

Hill, Lindsay K.; Britton, Dustin; Jihad, Teeba; Punia, Kamia; Xie, Xuan; Delgado-Fukushima, Erika; Liu, Che Fu; Mishkit, Orin; Liu, Chengliang; Hu, Chunhua; Meleties, Michael; Renfrew, P. Douglas; Bonneau, Richard; Wadghiri, Youssef Z.; Montclare, Jin Kim
ISI:000796594500001
ISSN: 2058-9689
CID: 5245772

Engineering Fluorinated Thermo-responsive Assembled Protein (F-TRAP) for Theranostic Applications in Glioblastoma Multiforme [Meeting Abstract]

Bhattacharya, A; Mishkit, O; Tranos, J; Morales, L; Wang, A; Frenster, J; Bready, D; Boess, N; Lee, F; Wadghiri, Y; Placantonakis, D; Montclare, J K
Background Gliomas account for roughly 27% of all brain tumors and there is an urgent need to develop new therapeutic modalities. A glioblastoma multiforme (GBM) prognosis signifies a survival time of 14-16 months with only 5% of patients surviving more than 5 years. (1) A significant challenge for traditional GBM drug delivery is the inability to: a) treat tumor cells with cytotoxic drugs due to their poor solubility and lack of blood brain barrier (BBB) permeation; b) specifically target tumor cells while avoiding normal tissue with such cytotoxic agents c) stimulate drug release; and d) monitor GBM status and therapy non-invasively. (2) Theranostic agents are being developed for their ability to diagnose disease and improve therapeutic delivery and can address these requirements because treatments specific to GBM do not currently exist. (3) While considerable efforts have been made in developing protein-based systems as drug-delivery carriers or as diagnostic agents (4), we are investigating a fundamental new insight that is helping us develop a single protein-based system combining drug delivery capabilities with the ability to cross the BBB and remain at cancer site due to the enhanced permeation and retention (EPR) effect. This biomaterial also incorporates functional groups detectable via magnetic resonance (MR) spectroscopy and imaging as well as near-infrared fluorescence (NIR) to enable visualization during chemotherapy. The protein-based theranostic agent we have engineered is called fluorinated thermo-responsive assembled protein (F-TRAP) that bears a non-canonical fluorinated amino acid (trifluoroleucine or TFL), can self-assemble into micellar structures, and encapsulate hydrophobic drugs. Methods and Materials Circular dichroism and dynamic light scattering have been performed to observe F-TRAP's secondary structure and micelle formation respectively (2). Additionally, 19F magnetic resonance imaging (MRI) has been carried out to visualize F-TRAP (5) and near infra-red fluorescence imaging (NIRF) has been utilized to determine its pharmacokinetic properties in a glioblastoma (GBM) mouse model. Results Results indicate that F-TRAP has an ?-helical secondary structure and forms micelles 30 nm in size. F-TRAP shows favorable pharmacokinetic data with a half-life of 123 minutes and high plasma retention. Importantly, animal data also reveals the ability of F-TRAP to cross the BBB and to be imaged inside the brain. Conclusions F-TRAP is capable of encapsulating small hydrophobic molecules, such as dox. It crosses the BBB and undergoes EPR effect allowing it to accumulate therein and be visualized NIRF imaging and is capable of undergoing MR imaging due to an appropriate half-life of about 123 min
EMBASE:640493195
ISSN: 1860-2002
CID: 5512132