Pharmacokinetics of doxorubicin in glioblastoma multiforme following ultrasound-Induced blood-brain barrier disruption as determined by microdialysis

Lin, Yi-Wei; Wu, Meng; Yang, Feng

doi:10.1016/j.jpba.2017.11.047

Cited by 34 publications

(17 citation statements)

References 20 publications

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“…Although Doxorubicin efficiently kills glioblastoma cells in vitro, its use for the treatment of brain tumors is limited due to poor penetration of the drug through the BBB and severe side effects in normal tissue, including dose-limiting cardiotoxicity. Previously, researchers have developed various formulations such as liposomes, nanoparticles, and polymer conjugates to improve transport of Doxorubicin through the BBB and delivery to glioblastoma tumors [11,12]. Additionally, complementary approaches, which include ultrasound, pH difference, and application of heat, have been used to disrupt the BBB [13,14,15].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Elastin-Like Polypeptides for Tumor Targeted Delivery of Doxorubicin to Glioblastoma

2019

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To increase treatment efficiency for glioblastoma, we have developed a system to selectively deliver chemotherapeutic doxorubicin (Dox) to Glioblastoma (GBM) tumors. This carrier is based on elastin-like polypeptide (ELP), which is soluble at physiological temperatures but undergoes a phase transition and accumulates at tumor sites with externally applied, mild (40–41 °C) hyperthermia. The CPP-ELP-Dox conjugate consists of a cell penetrating peptide (CPP), which facilitates transcytosis through the blood brain barrier and cell entry, and a 6-maleimidocaproyl hydrazone derivative of doxorubicin at the C-terminus of ELP. The acid-sensitive hydrazone linker ensures release of Dox in the lysosomes/endosomes after cellular uptake of the drug conjugate. We have shown that CPP-ELP-Dox effectively inhibits cell proliferation in three GBM cell lines. Both the free drug and CPP-ELP-Dox conjugate exhibited similar in vitro cytotoxicity, although their subcellular localization was considerably different. The Dox conjugate was mainly dispersed in the cytoplasm, while free drug had partial nuclear accumulation in addition to cytoplasmic distribution. The intracellular Dox concentration was increased in the CPP-ELP-Dox cells compared to that in the cells treated with free Dox, which positively correlates with cytotoxic activity. In summary, our findings demonstrate that CPP-ELP-Dox effectively kills GBM cells. Development of such a drug carrier has the potential to greatly improve current therapeutic approaches for GBM by increasing the specificity and efficacy of treatment and reducing cytotoxicity in normal tissues.

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Section: Introductionmentioning

confidence: 99%

Evaluation of Elastin-Like Polypeptides for Tumor Targeted Delivery of Doxorubicin to Glioblastoma

2019

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“…We and other researchers showed that brain microdialysis is useful to evaluate the pharmacokinetics of ultrasound-mediated drugs delivered. 125,126) We measured the concentration of 5-fluorouracil (5-FU) in the brain after intravenous injection of 5-FU and nanobubbles followed by ultrasound irradiation. 125) Lin et al evaluated the pharmacokinetics of ultrasound-mediated doxorubicin delivery to glioma lesions.…”

Section: Brain Microdialysis Methodsmentioning

confidence: 99%

“…125,126) We measured the concentration of 5-fluorouracil (5-FU) in the brain after intravenous injection of 5-FU and nanobubbles followed by ultrasound irradiation. 125) Lin et al evaluated the pharmacokinetics of ultrasound-mediated doxorubicin delivery to glioma lesions. 126) Brain microdialysis can measure the time course of drug concentrations in targeted regions with high quantitative accuracy because the microdialysis probe is inserted directly into the brain.…”

Section: Brain Microdialysis Methodsmentioning

confidence: 99%

Recent Strategies for Targeted Brain Drug Delivery

2020

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Because the brain is the most important human organ, many brain disorders can cause severe symptoms. For example, glioma, one type of brain tumor, is progressive and lethal, while neurodegenerative diseases cause severe disability. Nevertheless, medical treatment for brain diseases remains unsatisfactory, and therefore innovative therapies are desired. However, the development of therapies to treat some cerebral diseases is difficult because the blood-brain barrier (BBB) or blood-brain tumor barrier prevents drugs from entering the brain. Hence, drug delivery system (DDS) strategies are required to deliver therapeutic agents to the brain. Recently, brain-targeted DDS have been developed, which increases the quality of therapy for cerebral disorders. This review gives an overview of recent brain-targeting DDS strategies. First, it describes strategies to cross the BBB. This includes BBB-crossing ligand modification or temporal BBB permeabilization. Strategies to avoid the BBB using local administration are also summarized. Intrabrain drug distribution is a crucial factor that directly determines the therapeutic effect, and thus it is important to evaluate drug distribution using optimal methods. We introduce some methods for evaluating drug distribution in the brain. Finally, applications of brain-targeted DDS for the treatment of brain tumors, Alzheimer's disease, Parkinson's disease, and stroke are explained.

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“…Delivery of doxorubicin to a brainstem was also recently shown to be feasible and safe for animals after histological and behavioral tests (50). Other chemotherapies investigated in conjunction with MRgFUS BBB opening in small (e.g., rat, rabbit) to large (e.g., nonhuman primates) animals include paclitaxel (60), methotrexate (61, 62), doxorubicin (50, 63, 64), cisplatin (65), bevacizumab (66), and carmustine (67) (Table 1). …”

Section: Chemotherapiesmentioning

confidence: 99%

Low-Intensity MR-Guided Focused Ultrasound Mediated Disruption of the Blood-Brain Barrier for Intracranial Metastatic Diseases

et al. 2018

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Low-intensity MR-guided focused ultrasound in combination with intravenously injected microbubbles is a promising platform for drug delivery to the central nervous system past the blood-brain barrier. The blood-brain barrier is a key bottleneck for cancer therapeutics via limited inter- and intracellular transport. Further, drugs that cross the blood-brain barrier when delivered in a spatially nonspecific way, result in adverse effects on normal brain tissue, or at high concentrations, result in increasing risks to peripheral organs. As such, various anti-cancer drugs that have been developed or to be developed in the future would benefit from a noninvasive, temporary, and repeatable method of targeted opening of the blood-brain barrier to treat metastatic brain diseases. MR-guided focused ultrasound is a potential solution to these design requirements. The safety, feasibility and preliminary efficacy of MRgFUS aided delivery have been demonstrated in various animal models. In this review, we discuss this preclinical evidence, mechanisms of focused ultrasound mediated blood-brain barrier opening, and translational efforts to neuro-oncology patients.

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Pharmacokinetics of doxorubicin in glioblastoma multiforme following ultrasound-Induced blood-brain barrier disruption as determined by microdialysis

Cited by 34 publications

References 20 publications

Evaluation of Elastin-Like Polypeptides for Tumor Targeted Delivery of Doxorubicin to Glioblastoma

Evaluation of Elastin-Like Polypeptides for Tumor Targeted Delivery of Doxorubicin to Glioblastoma

Recent Strategies for Targeted Brain Drug Delivery

Low-Intensity MR-Guided Focused Ultrasound Mediated Disruption of the Blood-Brain Barrier for Intracranial Metastatic Diseases

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