Pharmacokinetic Analysis of 111In-Labeled Liposomal Doxorubicin in Murine Glioblastoma after Blood-Brain Barrier Disruption by Focused Ultrasound

Yang, Feng; Wang, Hsin Ell; Liu, Ru‐Shi; Teng, Ming Che; Li, Jia Je; Lu, Maggie; Wei, Ming Cheng; Wong, Tai-Tong

doi:10.1371/journal.pone.0045468

Cited by 61 publications

(44 citation statements)

References 23 publications

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“…An improved uptake of drugs into the brain after ultrasound-induced BBB disruption has been demonstrated for antineoplastic drugs, such as doxorubicin; 1,24,30,31,41 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU);…”

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confidence: 99%

Ultrasound-induced opening of the blood-brain barrier to enhance temozolomide and irinotecan delivery: an experimental study in rabbits

Beccaria

Canney²,

Goldwirt

et al. 2016

JNS

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C urrently, the prognosis for patients with primary brain tumors, despite aggressive treatment strategies, remains poor. The median survival for patients with high-grade gliomas varies from 1 to 5 years. 26 The failure of the current standard of treatment is due to a combination of incomplete resection of the malignant tissue during surgery (infiltrative disease) and a low penetration of drugs not only into the tumor, but also into the surrounding brain parenchyma, where up to 80% of recurrences happen. 12,35 The low penetration of drugs into the brain is due to the existence of the blood-brain barrier (BBB), which consists of endothelial cells with tight junctions that line the microvasculature of the brain.8 This physiological barrier limits approximately 98% of smallmolecule drugs and 100% of large-molecule drugs from reaching the parenchymal tissue. obJective The blood-brain barrier (BBB) limits the intracerebral penetration of drugs and brain tumor treatment efficacy. The effect of ultrasound-induced BBB opening on the intracerebral concentration of temozolomide (TMZ) and irinotecan (CPT-11) was assessed. methods This study was performed using 34 healthy New Zealand rabbits. Half had unilateral BBB opening, and half served as controls. Sonications were performed by pulsing a 1.05-MHz planar ultrasound transducer with a duty cycle of 2.5% and an in situ acoustic pressure level of 0.6 MPa after injection of a microbubble ultrasound contrast agent. Drugs were injected either 5 minutes before (ChemoPreUS) or 15 minutes after (ChemoPostUS) the ultrasound sonication. The plasma and intracerebral concentrations of both drugs were quantified using ultra-performance liquid chromatography. results The mean intracerebral tissue-to-plasma drug concentration ratio in the control hemispheres was 34% for TMZ and 2% for CPT-11. After BBB opening, these values increased by up to 21% for TMZ and up to 178% for CPT-11. Intracerebral concentrations of drugs were enhanced in regions where the BBB was opened compared with the contralateral hemisphere (p < 0.01 and p < 0.0001 for CPT-11, p = 0.02 and p = 0.03 for TMZ, in ChemoPreUS and ChemoPostUS, respectively) and compared with the control group (p < 0.001 and p < 0.0001 for CPT-11, p < 0.01 and p = 0.02 for TMZ, in ChemoPreUS and ChemoPostUS, respectively). The intracerebral distribution of drugs was heterogeneous, depending on the distance from the ultrasound source. coNclusioNs Ultrasound-induced opening of the BBB significantly enhances the intracerebral concentration of both TMZ and CPT-11 in rabbits.

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confidence: 99%

Ultrasound-induced opening of the blood-brain barrier to enhance temozolomide and irinotecan delivery: an experimental study in rabbits

Beccaria

Canney²,

Goldwirt

et al. 2016

JNS

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“…15,16 In Yang et al's study, DOX liposomes radiolabeled with 111 In-oxine (5 mg/kg) were prepared and delivered using 1.0 MHz FUS with a negative acoustic pressure of 0.7 MPa, PRF of 1 Hz and the duty cycle of 5%. 36 The DOX concentration in the sonicated glioma was determined to be 9 µg/g, which was 2-fold greater than that in unsonicated tumors. In addition, the median survival time of the glioblastoma-bearing mice was extended from 9 to 15 days.…”

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confidence: 91%

Enhanced delivery of paclitaxel liposomes using focused ultrasound with microbubbles for treating nude mice bearing intracranial glioblastoma xenografts

Shen¹,

Pi²,

Yan³

et al. 2017

IJN

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Paclitaxel liposomes (PTX-LIPO) are a clinically promising antineoplastic drug formulation for the treatment of various extracranial cancers, excluding glioblastoma. A main reason for this is the presence of the blood–brain barrier (BBB) or blood–tumor barrier (BTB), preventing liposomal drugs from crossing at a therapeutically meaningful level. Focused ultrasound (FUS) in conjunction with microbubbles (MBs) has been suggested in many studies to be an effective approach to increase the BBB or BTB permeability. In this study, we investigated the feasibility of enhancing the delivery of PTX-LIPO in intracranial glioblastoma-bearing nude mice using pulsed low-intensity FUS exposure in the presence of MBs. Our results showed that the delivery efficiency of PTX-LIPO could be effectively improved in terms of the penetration of both the BBB in vitro and BTB in vivo by pulsed FUS sonication with a 10 ms pulse length and 1 Hz pulse repetition frequency at 0.64 MPa peak-rarefactional pressure in the presence of MBs. Quantitative analysis showed that a 2-fold higher drug concentration had accumulated in the glioblastoma 3 h after FUS treatment, with 7.20±1.18 µg PTX per g glioma tissue. Longitudinal magnetic resonance imaging analysis illustrated that the intracranial glioblastoma progression in nude mice treated with PTX-LIPO delivered via FUS with MBs was suppressed consistently for 4 weeks compared to the untreated group. The medium survival time of these tumor-bearing nude mice was significantly prolonged by 20.8%, compared to the untreated nude mice. Immunohistochemical analysis further confirmed the antiproliferation effect and cell apoptosis induction. Our study demonstrated that noninvasive low-intensity FUS with MBs can be used as an effective approach to deliver PTX-LIPO in order to improve their chemotherapy efficacy toward glioblastoma.

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“…Moreover, it has been demonstrated that boronophenylalanine (BPA) injection in combination with FUS exposure increases the accumulation of boron in brain tumors (29). An evaluation of micro-SPECT/CT imaging showed that FUS not only significantly increased the permeability of the BBB at the sonicated site but also significantly elevated the tumor-to-normal brain ratio for a drug in the focal region (30,31). Nuclear imaging may be useful for offering a good assessment of the extent of BBB-D and identifying the optimum therapeutic window for radiotherapy or chemotherapy of brain tumors with BBB-D induced by sonication.…”

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confidence: 99%

Pharmacokinetic Analysis and Uptake of ¹⁸F-FBPA-Fr After Ultrasound-Induced Blood–Brain Barrier Disruption for Potential Enhancement of Boron Delivery for Neutron Capture Therapy

Yang¹,

Chang²,

Li³

et al. 2014

J Nucl Med

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Boronophenylalanine has been applied in clinical boron neutron capture therapy for the treatment of high-grade gliomas. The purpose of this study was to evaluate the pharmacokinetics of 4-borono-2-18 F-fluoro-L-phenylalanine-fructose ( 18 F-FBPA-Fr) in F98 gliomabearing Fischer 344 rats by means of intravenous injection of 18 F-FBPA-Fr both with and without blood-brain barrier disruption (BBB-D) induced by focused ultrasound (FUS). Methods: Dynamic PET imaging of 18 F-FBPA-Fr was performed on the ninth day after tumor implantation. Blood samples were collected to obtain an arterial input function for tracer kinetic modeling. Ten animals were scanned for approximately 3 h to estimate the uptake of 18 F radioactivity with respect to time for the pharmacokinetic analysis. Rate constants were calculated by use of a 3-compartment model. Results: The accumulation of 18 F-FBPA-Fr in brain tumors and the tumor-to-contralateral brain ratio were significantly elevated after intravenous injection of 18 F-FBPA-Fr with BBB-D. 18 F-FBPA-Fr administration after sonication showed that the tumor-to-contralateral brain ratio for the sonicated tumors (3.5) was approximately 1.75-fold higher than that for the control tumors (2.0). Furthermore, the K 1 /k 2 pharmacokinetic ratio after intravenous injection of 18 F-FBPA-Fr with BBB-D was significantly higher than that after intravenous injection without BBB-D. Conclusion: This study demonstrated that radioactivity in tumors and the tumor-to-normal brain ratio after intravenous injection of 18 F-FBPA-Fr with sonication were significantly higher than those in tumors without sonication. The K 1 /k 2 ratio may be useful for indicating the degree of BBB-D induced by FUS. Further studies are needed to determine whether FUS may be useful for enhancing the delivery of boronophenylalanine in patients with high-grade gliomas. Bor on neutron capture therapy (BNCT) is a binary cancer treatment system that requires the selective delivery of a boroncontaining drug to the tumor and then irradiation with neutrons to yield high-linear-energy-transfer a particles and recoiling 7 Li nuclei (1-5). Successful application of BNCT requires the selective delivery of 10 B to the tumor, low levels in the surrounding tissue, and the delivery of sufficient thermal neutron fluence to the tumor site (6,7). Considerable efforts have been dedicated to the development of boron-delivering agents that could ensure a high tumor-to-normal tissue ratio of uptake of boron in tumors for BNCT (8). With the development of new techniques for the chemical synthesis of an effective agent, several new potential boron-delivering agents have emerged. However, drug delivery will have to be optimized because it is unlikely that any single agent will be capable of targeting most of the tumor cells.Despite the fact that the blood-tumor barrier is more permeable than the blood-brain barrier (BBB), the efficacy of systemic chemotherapy in patients with brain tumors is poor because the selective permeability of the blood-tumor barrier st...

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Pharmacokinetic Analysis of 111In-Labeled Liposomal Doxorubicin in Murine Glioblastoma after Blood-Brain Barrier Disruption by Focused Ultrasound

Cited by 61 publications

References 23 publications

Ultrasound-induced opening of the blood-brain barrier to enhance temozolomide and irinotecan delivery: an experimental study in rabbits

Ultrasound-induced opening of the blood-brain barrier to enhance temozolomide and irinotecan delivery: an experimental study in rabbits

Enhanced delivery of paclitaxel liposomes using focused ultrasound with microbubbles for treating nude mice bearing intracranial glioblastoma xenografts

Pharmacokinetic Analysis and Uptake of ¹⁸F-FBPA-Fr After Ultrasound-Induced Blood–Brain Barrier Disruption for Potential Enhancement of Boron Delivery for Neutron Capture Therapy

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Pharmacokinetic Analysis of 111In-Labeled Liposomal Doxorubicin in Murine Glioblastoma after Blood-Brain Barrier Disruption by Focused Ultrasound

Cited by 61 publications

References 23 publications

Ultrasound-induced opening of the blood-brain barrier to enhance temozolomide and irinotecan delivery: an experimental study in rabbits

Ultrasound-induced opening of the blood-brain barrier to enhance temozolomide and irinotecan delivery: an experimental study in rabbits

Enhanced delivery of paclitaxel liposomes using focused ultrasound with microbubbles for treating nude mice bearing intracranial glioblastoma xenografts

Pharmacokinetic Analysis and Uptake of 18F-FBPA-Fr After Ultrasound-Induced Blood–Brain Barrier Disruption for Potential Enhancement of Boron Delivery for Neutron Capture Therapy

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Pharmacokinetic Analysis and Uptake of ¹⁸F-FBPA-Fr After Ultrasound-Induced Blood–Brain Barrier Disruption for Potential Enhancement of Boron Delivery for Neutron Capture Therapy