Prolonged survival upon ultrasound-enhanced doxorubicin delivery in two syngenic glioblastoma mouse models

Kovács, Zsófia; Werner, Beat; Rassi, Anahita; Sass, Jörn Oliver; Martin-Fiori, Ernst; Bernasconi, Michele

doi:10.1016/j.jconrel.2014.05.033

Cited by 103 publications

(72 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In summary, image-guided pFUS+MB is a clinically relevant, noninvasive technique that can effectively cause transient opening of the BBB and has been used to enhance the retention and permeability of drugs or gene therapy materials within targeted regions in the brain (6,20,30,39). Previous studies have indicated that the mechanical effects of pFUS+MB were confined primarily to the endothelium and vessel wall and were associated with cerebral vasculature vasospasm (31).…”

Section: Discussionmentioning

confidence: 99%

Disrupting the blood–brain barrier by focused ultrasound induces sterile inflammation

Kovács

Kim

Jikaria

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

371

388

View full text Add to dashboard Cite

MRI-guided pulsed focused ultrasound (pFUS) combined with systemic infusion of ultrasound contrast agent microbubbles (MB) causes localized blood-brain barrier (BBB) disruption that is currently being advocated for increasing drug or gene delivery in neurological diseases. The mechanical acoustic cavitation effects of opening the BBB by low-intensity pFUS+MB, as evidenced by contrast-enhanced MRI, resulted in an immediate damage-associated molecular pattern (DAMP) response including elevations in heat-shock protein 70, IL-1, IL-18, and TNFα indicative of a sterile inflammatory response (SIR) in the parenchyma. Concurrent with DAMP presentation, significant elevations in proinflammatory, antiinflammatory, and trophic factors along with neurotrophic and neurogenesis factors were detected; these elevations lasted 24 h. Transcriptomic analysis of sonicated brain supported the proteomic findings and indicated that the SIR was facilitated through the induction of the NFκB pathway. Histological evaluation demonstrated increased albumin in the parenchyma that cleared by 24 h along with TUNEL + neurons, activated astrocytes, microglia, and increased cell adhesion molecules in the vasculature. Infusion of fluorescent beads 3 d before pFUS+MB revealed the infiltration of CD68 + macrophages at 6 d postsonication, as is consistent with an innate immune response. pFUS+MB is being considered as part of a noninvasive adjuvant treatment for malignancy or neurodegenerative diseases. These results demonstrate that pFUS+MB induces an SIR compatible with ischemia or mild traumatic brain injury. Further investigation will be required before this approach can be widely implemented in clinical trials.pulsed focused ultrasound | microbubbles | blood-brain barrier | sterile inflammation | magnetic resonance imaging T he temporal proteomic profile in response to blood-brain barrier disruption (BBBD) consists of molecular features that are common across noninfectious insults such as ischemia, trauma, or autoimmune diseases (1-7). The main purpose of the bloodbrain barrier (BBB) is to maintain homeostasis, preventing the passive crossing of cells and molecules that could induce inflammation or damage to cells. The BBB consists of specialized endothelial cells connected through various tight junction proteins (TJP), astrocyte endplates, and a basement membrane. These components form part of the neurovascular unit (NVU) that is comprised of vessels, pericytes, microglia, astrocytes, and neurons along with the extracellular matrix (1,3,4,8). BBBD secondary to ischemia or trauma leads to increases in endothelial caveolae and down-regulation of TJP, transcytosis of plasma proteins (i.e., albumin), and vasogenic edema (1,6,(8)(9)(10)(11). The presence of albumin in the parenchyma following BBBD can activate astrocytes and microglia and induce the production of cytokines, chemokines, and trophic factors (CCTFs) and cell adhesion molecules (CAMs) as observed with a sterile inflammatory response (SIR) to injury (12-15). The release of CCTFs and inte...

show abstract

Section: Discussionmentioning

confidence: 99%

Disrupting the blood–brain barrier by focused ultrasound induces sterile inflammation

Kovács

Kim

Jikaria

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

371

388

View full text Add to dashboard Cite

show abstract

“…[31][32][33][34][35][36] However, the interaction between microbubbles and FUS can produce unnecessary side effects, such as erythrocyte extravasations, intracerebral microhemorrhages, edema, and inflammation. [37][38][39] Moreover, therapeutic agents will accumulate in normal brain tissues leading to serious side effects when the normal brain tissues are sonicated.…”

Section: Ki67mentioning

confidence: 99%

Short-time focused ultrasound hyperthermia enhances liposomal doxorubicin delivery and antitumor efficacy for brain metastasis of breast cancer

Wu¹,

Chiang²,

Hsu³

et al. 2014

IJN

View full text Add to dashboard Cite

The blood–brain/tumor barrier inhibits the uptake and accumulation of chemotherapeutic drugs. Hyperthermia can enhance the delivery of chemotherapeutic agent into tumors. In this study, we investigated the effects of short-time focused ultrasound (FUS) hyperthermia on the delivery and therapeutic efficacy of pegylated liposomal doxorubicin (PLD) for brain metastasis of breast cancer. Murine breast cancer 4T1-luc2 cells expressing firefly luciferase were injected into female BALB/c mice striatum tissues and used as a brain metastasis model. The mice were intravenously injected with PLD (5 mg/kg) with/without 10-minute transcranial FUS hyperthermia on day 6 after tumor implantation. The amounts of doxorubicin accumulated in the normal brain tissues and tumor tissues with/without FUS hyperthermia were measured using fluorometry. The tumor growth for the control, hyperthermia, PLD, and PLD + hyperthermia groups was measured using an IVIS spectrum system every other day from day 3 to day 11. Cell apoptosis and tumor characteristics were assessed using immunohistochemistry. Short-time FUS hyperthermia was able to significantly enhance the PLD delivery into brain tumors. The tumor growth was effectively inhibited by a single treatment of PLD + hyperthermia compared with both PLD alone and short-time FUS hyperthermia alone. Immunohistochemical examination further demonstrated the therapeutic efficacy of PLD plus short-time FUS hyperthermia for brain metastasis of breast cancer. The application of short-time FUS hyperthermia after nanodrug injection may be an effective approach to enhance nanodrug delivery and improve the treatment of metastatic cancers.

show abstract

“…While FUS was capable of delivering up to 17-fold increases in DOX concentration in healthy brain tissue, in the GL261 mouse model of GBM, treatment with FUS and free DOX increased DOX concentrations in the tumors by only 4-fold compared to contralateral controls, although this increase was significant. Animals treated with FUS + free DOX had improved survival times (ISTmedian = 68%) as well, and did not show effects of systemic drug toxicities 5 . While this work indicates that FUS can improve the delivery of free drug across the blood-tumor barrier, it is also apparent that FUS parameters may need to be optimized for tumor biology rather than healthy brain tissue.…”

Section: Drug Deliverymentioning

confidence: 96%

“…Ultrasound is a multifunctional treatment platform that can increase both the delivery 1,2 and efficacy 3 of therapeutics. Ultrasound is FDA approved for therapeutic applications 4 and is capable of being combined with existing 5 and experimental 6 therapies, creating a low barrier for clinical translation and offering great potential for improvements in therapeutic outcomes. Here, we investigate two different ultrasound-mediated cancer treatments: delivery of drug loaded biodegradable polymeric nanoparticles across the BBB using FUS in an intracranial glioma model and enhancement of T cell infiltration in a subcutaneous murine melanoma model.…”

Section: Specific Aimsmentioning

confidence: 99%

“…The BBB is essential for the maintenance of the CNS environment and regulates the traffic of most molecules to and from the brain [1,2]. Unfortunately, the BBB also limits systemically administered drugs from reaching the brain in therapeutically relevant concentrations [3,4]; thus, drug dose and efficacy are often limited by systemic side effects [5]. In the case of some CNS disorders, such as glioblastoma, Alzheimer's, Parkinson's, cerebral palsy, epilepsy and stroke, the BBB can be impaired and "leaky" [6,7]; however, this impairment is often heterogeneous and diseased cells are often found in normal brain parenchyma in regions supplied by healthy blood vessels with normal BBB function [8].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Ultrasound-Based Therapies for the Treatment of Cancer

Timbie

View full text Add to dashboard Cite

Prolonged survival upon ultrasound-enhanced doxorubicin delivery in two syngenic glioblastoma mouse models

Cited by 103 publications

References 55 publications

Disrupting the blood–brain barrier by focused ultrasound induces sterile inflammation

Disrupting the blood–brain barrier by focused ultrasound induces sterile inflammation

Short-time focused ultrasound hyperthermia enhances liposomal doxorubicin delivery and antitumor efficacy for brain metastasis of breast cancer

Ultrasound-Based Therapies for the Treatment of Cancer

Contact Info

Product

Resources

About