Augmentation of brain tumor interstitial flow via focused ultrasound promotes brain-penetrating nanoparticle dispersion and transfection

Curley, Colleen T.; Mead, Brian; Negron, Karina; Kim, Namho; Garrison, William J.; Miller, G. Wilson; Kingsmore, Kathryn M.; Thim, E. Andrew; Song, Ji Sun; Munson, Jennifer M.; Klibanov, Alexander L.; Hanes, Justin; Price, Richard J.

doi:10.1126/sciadv.aay1344

Cited by 83 publications

(57 citation statements)

References 44 publications

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“…The 0.5 MPa peak-negative pressure value was chosen to be well within the safe (i.e. stable cavitation) range at 1 MHz when used with this MB formulation in mice with brain tumors 15 . For FUS+MBs treated animals, contrast enhanced MRI was performed prior to FUS+MBs treatment to visualize and target the tumor tissue and immediately following treatment to confirm BTB/BBB disruption, as shown in Figure 1 A.…”

Section: Resultsmentioning

confidence: 99%

“…The increased percentage of ZsGreen-positive DCs in the tumors of FUS+MBs treated mice suggests increased antigen uptake within the tumor following FUS+MBs BTB/BBB opening. Factors such as increased antigen from cell death, increased phagocytosis, or enhanced distribution of antigen throughout the tumor from FUS+MBs induced changes in interstitial transport could contribute to this finding 15 . Staining for the MHC-SIINFEKL complex on DCs revealed a trend towards increased abundance within the superficial cervical lymph nodes of FUS+MBs treated animals.…”

Section: Discussionmentioning

confidence: 96%

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Immunomodulation of intracranial melanoma in response to blood-tumor barrier opening with focused ultrasound

Curley¹,

Stevens²,

Mathew³

et al. 2020

Theranostics

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Background: Focused ultrasound (FUS) activation of microbubbles (MBs) for blood-brain (BBB) and blood-tumor barrier (BTB) opening permits targeted therapeutic delivery. While the effects of FUS+MBs mediated BBB opening have been investigated for normal brain tissue, no such studies exist for intracranial tumors. As this technology advances into clinical immunotherapy trials, it will be crucial to understand how FUS+MBs modulates the tumor immune microenvironment. Methods and Results: Bulk RNA sequencing revealed that FUS+MBs BTB/BBB opening (1 MHz, 0.5 MPa peak-negative pressure) of intracranial B16F1cOVA tumors increases the expression of genes related to proinflammatory cytokine and chemokine signaling, pattern recognition receptor signaling, and antigen processing and presentation. Flow cytometry revealed increased maturation (i.e. CD86) of dendritic cells (DCs) in the meninges and altered antigen loading of DCs in both the tumor and meninges. For DCs in tumor draining lymph nodes, FUS+MBs had no effect on maturation and elicited only a trend towards increased presentation of tumor-derived peptide by MHC. Neither tumor endothelial cell adhesion molecule expression nor homing of activated T cells was affected by FUS+MBs. Conclusion: FUS+MBs-mediated BTB/BBB opening elicits signatures of inflammation; however, the response is mild, transient, and unlikely to elicit a systemic response independent of administration of immune adjuvants.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 96%

Immunomodulation of intracranial melanoma in response to blood-tumor barrier opening with focused ultrasound

Curley¹,

Stevens²,

Mathew³

et al. 2020

Theranostics

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“…The dogmatic approach within the domain of FUS BBB/BTB-D has been to systemically inject therapeutic agents immediately prior to sonications [25,[36][37][38]. We hypothesized that the FUSPRE protocol would significantly increase [ 89 Zr]-mCD47 uptake in GL261 tumors.…”

Section: Discussionmentioning

confidence: 99%

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

Sheybani

Paul

McCauley

et al. 2020

Preprint

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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.

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“…Technologies that may augment nanomedicine delivery such as ultrasound‐mediated, transient disruption of the blood–brain barrier are discussed in more detail elsewhere. [ 105,144 ]…”

Section: Introductionmentioning

confidence: 99%

Nanomedicine Revisited: Next Generation Therapies for Brain Cancer

Bhargav

Mondal

Garcia

et al. 2020

Advanced Therapeutics

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Brain cancer persists as a difficult-to-treat condition. In particular, metastatic brain cancer and malignant primary brain tumors such as glioblastoma (GBM) are among the most deadly and still carry a dismal prognosis despite current standard of care with surgery and chemo-radiation. Recent advances in nanotechnology have led to innovative nanomedicine strategies for the treatment of brain cancers and specifically for GBM. These strategies represent promising alternative or adjunctive therapies for conventional treatment modalities and are increasingly designed to target specific cell types such as brain tumor-initiating cells and immune cells. This review provides an update on emerging insights into these nanomedicine strategies with a focus on nanoparticles as tools that facilitate 1) drug delivery 2) gene therapy, and 3) engineered-cellular therapy for GBM and future directions for brain cancer treatment.

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Augmentation of brain tumor interstitial flow via focused ultrasound promotes brain-penetrating nanoparticle dispersion and transfection

Cited by 83 publications

References 44 publications

Immunomodulation of intracranial melanoma in response to blood-tumor barrier opening with focused ultrasound

Immunomodulation of intracranial melanoma in response to blood-tumor barrier opening with focused ultrasound

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

Nanomedicine Revisited: Next Generation Therapies for Brain Cancer

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