First in human nanotechnology doxorubicin delivery system to target epidermal growth factor receptors in recurrent glioblastoma

Whittle, James R.; Lickliter, Jason D.; Gan, Hui; Scott, Andrew M.; Simes, John; Solomon, Benjamin; MacDiarmid, Jennifer; Brahmbhatt, Himanshu; Rosenthal, Mark

doi:10.1016/j.jocn.2015.06.005

Cited by 100 publications

(71 citation statements)

References 29 publications

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“…A recent first-in-human clinical trial in adults showed that EGFR EDV TM packaged with paclitaxel were safe and showed some efficacy. In glioblastoma, a first in human trial using EGFR EDV TM packaged with doxorubicin also found that the delivery system was well tolerated with no severe adverse effects noted (9). As doxorubicin forms part of the chemotherapeutic cocktail used to treat neuroblastoma, in this study we focused on examining the efficacy of EGFR EDV TM Dox in neuroblastoma.…”

Section: Discussionmentioning

confidence: 99%

“…Twenty-two of 28 enrolled patients completed the trial with six patients being withdrawn due to progressive disease with the most common treatment-related side effects being rigors and pyrexia (8). A recent phase I trial of EGFR targeted EDV TM nanocells loaded with doxorubicin in adults with recurrent EGFR-expressing glioblastoma was also well tolerated, with no dose limiting toxicities or withdrawals from the study due to adverse effects (9). To date, the EDV TM nanocells have not been tested for in vitro and in vivo efficacy against solid pediatric tumors.…”

Section: Introductionmentioning

confidence: 99%

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Targeted Doxorubicin-Loaded Bacterially Derived Nano-Cells for the Treatment of Neuroblastoma

Sagnella

Trieu

Brahmbhatt

et al. 2018

Molecular Cancer Therapeutics

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Advanced stage neuroblastoma is an aggressive disease with limited treatment options for patients with drug-resistant tumors. Targeted delivery of chemotherapy for pediatric cancers offers promise to improve treatment efficacy and reduce toxicity associated with systemic chemotherapy. The EnGeneIC Dream Vector (EDV) is a nanocell, which can package chemotherapeutic drugs and target tumors via attachment of bispecific proteins to the surface of the nanocell. Phase I trials in adults with refractory tumors have shown an acceptable safety profile. Herein we investigated the activity of EGFR-targeted and doxorubicin-loaded EDV (EDV) for the treatment of neuroblastoma. Two independent neuroblastoma cell lines with variable expression of EGFR protein [SK-N-BE(2), high; SH-SY-5Y, low] were used. EDV induced apoptosis in these cells compared to control, doxorubicin, or non-doxorubicin loaded EDV In three-dimensional tumor spheroids, imaging and fluorescence life-time microscopy revealed that EDV had a marked enhancement of doxorubicin penetration compared to doxorubicin alone, and improved penetration compared to non-EGFR-targeted EDV, with enhanced spheroid penetration leading to increased apoptosis. In two independent orthotopic human neuroblastoma xenograft models, short-term studies (28 days) of tumor-bearing mice led to a significant decrease in tumor size in EDV-treated animals compared to control, doxorubicin, or non-EGFR EDV There was increased TUNEL staining of tumors at day 28 compared to control, doxorubicin, or non-EGFR EDV Moreover, overall survival was increased in neuroblastoma mice treated with EDV ( < 0007) compared to control. Drug-loaded bispecific-antibody targeted EDVs offer a highly promising approach for the treatment of aggressive pediatric malignancies such as neuroblastoma. .

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Targeted Doxorubicin-Loaded Bacterially Derived Nano-Cells for the Treatment of Neuroblastoma

Sagnella

Trieu

Brahmbhatt

et al. 2018

Molecular Cancer Therapeutics

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“…DOX is used, at present, to treat many cancers with some success, but it has not been used in treating GBM, because of the poor penetration of the blood−brain barrier. There are efforts underway to develop innovative means for delivery of DOX to GBMs (25), in the hopes that DOX can be effective in this grim cancer. We suggest here that, even if it is possible for DOX to be delivered across the blood-brain barrier, it will not be an effective GBM therapy, at least not by itself, because of induced resistance.…”

Section: Discussionmentioning

confidence: 99%

Rapid emergence and mechanisms of resistance by U87 glioblastoma cells to doxorubicin in an in vitro tumor microfluidic ecology

Han

Jun

Kim

et al. 2016

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

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In vitro prediction of the probable rapid emergence of resistance to a drug in tumors could act to winnow out potential candidates for further costly development. We have developed a microfluidic device consisting of ∼500 hexagonal microcompartments that provides a complex ecology with wide ranges of drug and nutrient gradients and local populations. This ecology of a fragmented metapopulation induced the drug resistance in stage IV U87 glioblastoma cells to doxorubicin in 7 d. Exome and transcriptome sequencing of the resistant cells identified mutations and differentially expressed genes. Gene ontology and pathway analyses of the genes identified showed that they were functionally relevant to the established mechanisms of doxorubicin action. Specifically, we identified (i) a frame-shift insertion in the filamin-A gene, which regulates the influx and efflux of topoisomerase II poisons; (ii) the overexpression of aldo-keto reductase enzymes, which convert doxorubicin into doxorubicinol; and (iii) activation of NF-κB via alterations in the nucleotide-binding oligomerization domain (NOD)-like receptor signaling pathway from mutations in three genes (CARD6, NSD1, and NLRP13) and the overexpression of inflammatory cytokines. Functional experiments support the in silico analyses and, together, demonstrate the effects of these genetic changes. Our findings suggest that, given the rapid evolution of resistance and the focused response, this technology could act as a rapid screening modality for genetic aberrations leading to resistance to chemotherapy as well as counter selection of drugs unlikely to be successful ultimately.

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“…The study was then conducted in phase I with small groups of patients. Minicells loaded with doxorubicin were also continuously tested in phase II in patients with glioblastoma (a type of brain tumor) [128,129]. However, Lactobacillus species being the safe microorganisms with many biological activities in anticancer and immunotherapy, they were used to generate nanosized minicells tested in drug delivery.…”

Section: Minicell Loading With Different Drugsmentioning

confidence: 99%

Nanosized Minicells Generated by Lactic Acid Bacteria for Drug Delivery

Nguyen

Jovel

Nguyen

2017

Journal of Nanomaterials

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Nanotechnology has the ability to target specific areas of the body, controlling the drug release and significantly increasing the bioavailability of active compounds. Organic and inorganic nanoparticles have been developed for drug delivery systems. Many delivery systems are through clinical stages for development and market. Minicell, a nanosized cell generated by bacteria, is a potential particle for drug delivery because of its size, safety, and biodegradability. Minicells produced by bacteria could drive therapeutic agents against cancer, microbial infection, and other diseases by targeting. In addition, minicells generated by lactic acid bacteria being probiotics are more interesting than others because of their benefits like safety, immunological improvement, and biodegradation. This review aims to highlight the stages of development of nanoparticle for drug delivery and discuss their advantages and limitations to clarify minicells as a new opportunity for the development of potential nanoparticle for drug delivery.

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First in human nanotechnology doxorubicin delivery system to target epidermal growth factor receptors in recurrent glioblastoma

Cited by 100 publications

References 29 publications

Targeted Doxorubicin-Loaded Bacterially Derived Nano-Cells for the Treatment of Neuroblastoma

Targeted Doxorubicin-Loaded Bacterially Derived Nano-Cells for the Treatment of Neuroblastoma

Rapid emergence and mechanisms of resistance by U87 glioblastoma cells to doxorubicin in an in vitro tumor microfluidic ecology

Nanosized Minicells Generated by Lactic Acid Bacteria for Drug Delivery

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