Biology subjects

Sheybani, N. D.

Publications and source records attributed to Sheybani, N. D..

5 recordsLinked to original sources

bioRxiv2026

Multimodal PET Defines a Goldilocks Thermal Window for Focused Ultrasound Ablation and Immunotherapy Combinations

BackgroundThermally ablative focused ultrasound (T-FUS) offers a noninvasive, spatially precise strategy for local tumor destruction, with the added potential to remodel tumor architecture and immune dynamics in ways that influence downstream therapeutic delivery and efficacy. Despite promising preclinical and clinical findings, the T-FUS parameters that best balance tumor debulking with preservation of local biologic, e.g. immunotherapy, penetrance remain unclear. Thermal dose, defined by the relationship between tissue heating, exposure duration, and biological effect, is likely a critical determinant of this balance. Excessive thermal dose may eliminate the vascular and stromal features needed to support immunotherapy access, whereas insufficient thermal dose may fail to achieve meaningful cytoreduction. Here, we deploy multimodal PET, contrast-enhanced ultrasound, and tissue profiling to define a "Goldilocks Zone" for T-FUS that balances bulk tumor destruction with immunotherapy delivery. MethodSubtotal T-FUS was applied to 4T1 tumors using three thermal dose regimens resolved by in silico modeling. Ablation was quantified by H&E and TTC staining. Post-ablative perfusion and microvascular coverage were assessed by contrast-enhanced ultrasound and immunofluorescence, respectively. Tumor oxygenation was measured by intravenous hypoxyprobe labeling. After T-FUS, mice underwent dynamic [18F]-FDG PET and immunoPET with a model tumor-targeted antibody, [89Zr]-CD47, to relate cytoreduction to antibody penetrance. ImmunoPET findings were further evaluated by ex vivo biodistribution analysis. ResultsIn silico modeling established three T-FUS regimens that generated distinct thermal dose profiles and were deployed in vivo in a solid breast tumor model. Histopathology, perfusion imaging, and hypoxia analysis revealed dose-dependent and dose-divergent biological effects that informed a candidate Goldilocks thermal window. Low thermal dose produced measurable but limited tumor debulking, whereas high thermal dose caused disproportionate functional perfusion collapse. An intermediate thermal dose achieved robust partial ablation, broad hypoxia relief, and preservation of residual tumor physiology sufficient to support antibody access. Dynamic [18F]-FDG PET confirmed a marked reduction in metabolically active tumor burden after Goldilocks T-FUS. Serial [89Zr]-CD47 immunoPET showed that bulk antibody signal was maintained after ablation, and integration of immunoPET with matched [18F]-FDG PET revealed approximately 3-fold enrichment of antibody exposure within the residual viable tumor compartment of ablated tumors. These findings demonstrate that appropriately tuned thermal ablation can debulk tumor while preserving, and potentially concentrating, immunotherapy access within the remaining targetable tumor niche. ConclusionThis study identifies thermal dose as a critical consideration for T-FUS immunotherapy combinations and establishes a PET-informed framework for balancing cytoreduction with therapeutic delivery. Rather than functioning solely as a local debulking modality, we demonstrate that T-FUS can be tuned to yield a post-ablation tumor state that remains accessible to large biologics. These findings provide timely, translationally relevant guidance for tailoring T-FUS regimens to achieve local tumor destruction while preserving an immunotherapy-permissive niche for combination treatment.

bioengineering↗

bioRxiv2026

Focused Ultrasound Thermal Ablation and CD40 Agonism Reprograms Breast Tumor Immunity to Drive Regression and Memory

Focused ultrasound thermal ablation (T-FUS) is a clinically accessible, non-invasive modality capable of inducing rapid tumor cytoreduction while mobilizing early immunologic danger signals. However, its capacity to synergize with potent co-stimulatory immunotherapies in breast cancer (BC) remains undefined. Here, we demonstrate that subtotal T-FUS cooperates with CD40 agonism to elicit durable, T cell-dependent tumor control across four immunologically and hormonally distinct murine BC models. Partial thermal ablation triggered canonical immunogenic cell-death signatures and acute remodeling of intratumoral myeloid populations, while expanding circulating CD4+ and CD8+ T cells. When layered onto this immunogenic milieu, CD40 markedly constrained tumor outgrowth, yielding significant reductions in tumor burden across all models and complete tumor eradication in 33% of E0771 tumors, with additional complete responses in BRPKP110 and EMT6. Efficacy required both CD4+ and CD8+ T cells, and complete responders mounted robust systemic immunity, rejecting contralateral tumor rechallenge with 100% protection and displaying persistent effector-memory T cell activation. Together, these findings establish T-FUS as an immune-potentiating partner for CD40 agonism, capable of driving durable, robust BC regression and immunological memory. This work positions T-FUS+CD40 agonism as a clinically scalable, in situ vaccination-like strategy with potential to benefit breast cancers, including luminal subtypes, that remain largely refractory to immune checkpoint blockade.

cancer biology↗

bioRxiv2023

Solid Tumor Treatment via Augmentation of Bioactive C6 Ceramide Levels with Thermally Ablative Focused Ultrasound

Sparse scan partial thermal ablation (TA) with focused ultrasound (FUS) may be deployed to treat solid tumors and increase delivery of systemically administered therapeutics. Further, C6-ceramide-loaded nanoliposomes (CNLs), which rely upon the enhanced permeation and retention (EPR) effect for delivery, have shown promise for treating solid tumors and are being tested in clinical trials. Here, our objective was to determine whether CNLs synergize with TA in the control of 4T1 breast tumors. CNL-monotherapy of 4T1 tumors yielded significant intratumoral bioactive C6 accumulation by the EPR effect, but tumor growth was not controlled. TA increased bioactive C6 accumulation by [~]12.5-fold over the EPR effect. In addition, TA+CNL caused shifts in long-chain to very-long-chain ceramide ratios (i.e., C16/24 and C18/C24) that could potentially contribute to tumor control. Nonetheless, these changes in intratumoral ceramide levels were still insufficient to confer tumor growth control beyond that achieved when combining with TA with control "ghost" nanoliposomes (GNL). While this lack of synergy could be due to increased "pro-tumor" sphingosine-1-phosphate (S1P) levels, this is unlikely because S1P levels exhibited only a moderate and statistically insignificant increase with TA+CNL. In vitro studies showed that 4T1 cells are highly resistant to C6, offering the most likely explanation for the inability of TA to synergize with CNL. Thus, while our results show that sparse scan TA is a powerful approach for markedly enhancing CNL delivery and generating "anti-tumor" shifts in long-chain to very-long-chain ceramide ratios, resistance of the tumor to C6 can still be a rate-limiting factor for some solid tumor types.

bioengineering↗

bioRxiv2020

ImmunoPET-informed sequence for focused ultrasound-targeted mCD47 blockade controls glioma

Phagocytic immunotherapies such as CD47 blockade have emerged as promising strategies for glioblastoma (GB) therapy, but the blood brain/tumor barriers (BBB/BTB) pose a persistent challenge for mCD47 delivery that can be overcome by focused ultrasound (FUS)-mediated BBB/BTB disruption. We here leverage immuno-PET imaging to determine how timing of [89Zr]-mCD47 injection relative to FUS impacts antibody penetrance into orthotopic murine gliomas. We then design and implement a rational paradigm for combining FUS and mCD47 for glioma therapy. We demonstrate that timing of antibody injection relative to FUS BBB/BTB disruption is a critical determinant of mCD47 access, with post-FUS injection conferring superlative antibody delivery to gliomas. We also show that mCD47 delivery across the BBB/BTB with repeat sessions of FUS can significantly constrain tumor outgrowth and extend survival in glioma-bearing mice. This study generates provocative insights for ongoing pre-clinical and clinical evaluations of FUS-mediated antibody delivery to brain tumors. Moreover, our results confirm that mCD47 delivery with FUS is a promising therapeutic strategy for GB therapy.

bioengineering↗

bioRxiv2020

Transcriptomic Response of Brain Tissue to Focused Ultrasound-Mediated Blood-Brain Barrier Disruption Depends Strongly on Anesthesia

Focused ultrasound (FUS) mediated blood brain barrier disruption (BBBD) is a promising strategy for the targeted delivery of systemically-administered therapeutics to the central nervous system (CNS). Pre-clinical investigations of BBBD have been performed on different anesthetic backgrounds; however, the potential influence of the choice of anesthetic on the molecular response to BBBD is unknown, despite its potential to critically affect interpretation of experimental therapeutic outcomes. Here, using bulk RNA sequencing approaches, we comprehensively examined the transcriptomic response of both normal brain tissue and brain tissue exposed to FUS-induced BBBD in mice anesthetized with either isoflurane with medical air (Iso) or ketamine/dexmedetomidine (KD). In normal murine brain tissue, Iso alone elicited minimal differential gene expression (DGE) and repressed pathways associated with neuronal signaling. KD alone, however, led to massive DGE and enrichment of pathways associated with protein synthesis. In brain tissue exposed to BBBD (1 MHz, 0.5 Hz pulse repetition frequency, 0.4 MPa peak-negative pressure), we systematically evaluated the relative effects of anesthesia, microbubbles, and FUS on the transcriptome. Of particular interest, we observed that gene sets associated with sterile inflammatory responses and cell-cell junctional activity were induced by BBBD, regardless of the choice of anesthesia. Meanwhile, gene sets associated with metabolism, platelet activity, tissue repair, and signaling pathways, were differentially affected by BBBD, with a strong dependence on the anesthetic. We conclude that the underlying transcriptomic response to FUS-mediated BBBD may be powerfully influenced by anesthesia. These findings raise considerations for the translation of FUS-BBBD delivery approaches that impact, in particular, metabolism, tissue repair, and intracellular signaling.

bioengineering↗