Combination of paclitaxel thermal gel depot with temozolomide and radiotherapy significantly prolongs survival in an experimental rodent glioma model

Vellimana, Ananth K.; Recinos, Violette Renard; Hwang, Lee; Fowers, Kirk D.; Li, Khan W.; Zhang, Yonggang; Okonma, Saint; Eberhart, Charles G.; Brem, Henry; Tyler, Betty

doi:10.1007/s11060-012-1014-1

Cited by 73 publications

(50 citation statements)

References 33 publications

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“…In a recent study, 35 μL of Oncogel ™ (6.3 mg/mL) was tested in an intracranial 9L gliosarcoma rat model in combination with oral temozolomide, locally implanted temozolomide incorporated in a biodegradable polyanhydride and radiation treatment [67]. Control rats and rats treated with radiation after 5 days with 20 Gy had a mean survival time of 15 and 19 days, respectively.…”

Section: Plga-b-peg-b-plga Sol-gelsmentioning

confidence: 99%

PEG- b -PLA micelles and PLGA- b -PEG- b -PLGA sol–gels for drug delivery

Cho

Gao

Kwon

2016

Journal of Controlled Release

145

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Poly(ethylene glycol)-block-poly(D,L-lactic acid) (PEG-b-PLA) micelles and poly(D,L-lactic-co-glycolic acid)-block-polyethylene glycol)-block-poly(D,L-lactic-co-glycolic acid) (PLGA-b-PEG-b-PLGA) sol-gels have been extensively researched for systemic and localized drug delivery applications, respectively, and they have both progressed into humans for paclitaxel, an important yet poorly water-soluble chemotherapeutic agent. In this review article, preclinical and clinical research on PEG-b-PLA micelles and PLGA-b-PEG-b-PLGA sol-gels that has focused on paclitaxel will be updated, and recent research on other poorly water-soluble anticancer agents and delivery of drug combinations (i.e. multi-drug delivery) that seeks synergistic anticancer efficacy will be summarized. PEG-b-PLA micelles are a first-generation platform for the systemic multi-delivery of poorly water soluble anticancer agents. PLGA-b-PEG-b-PLGA sol-gels are a first-generation platform for the localized multi-drug delivery of water-soluble and/or poorly water-soluble anticancer agents. In summary, PEG-b-PLA micelles and PLGA-b-PEG-b-PLGA sol-gels may safely enable pre-clinical evaluation and clinical translation of poorly water-soluble anticancer agents, especially for promising, rapidly emerging anticancer combinations.

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Section: Plga-b-peg-b-plga Sol-gelsmentioning

confidence: 99%

PEG- b -PLA micelles and PLGA- b -PEG- b -PLGA sol–gels for drug delivery

Cho

Gao

Kwon

2016

Journal of Controlled Release

145

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“…35 Despite the overall significance of this study, further studies involving human xenografts and larger animals are necessary to support these conclusions.…”

Section: Combination Of Minocycline Polymer and Oral Temozolomidementioning

confidence: 85%

Local delivery of angiogenesis-inhibitor minocycline combined with radiotherapy and oral temozolomide chemotherapy in 9L glioma

Ho¹,

Hwang²,

Schildhaus³

et al. 2014

JNS

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Object Over the past several years, there has been increasing interest in combining angiogenesis inhibitors with radiotherapy and temozolomide chemotherapy in the treatment of glioblastoma. Although the US FDA approved bevacizumab for the treatment of glioblastoma in 2009, the European Medicines Agency rejected its use due to its questionable impact on patient survival. One factor contributing to the failure of angiogenesis inhibitors to increase overall patient survival may be their inability to cross the blood-brain barrier. Here the authors examined in a 9L glioma model whether intracranial polymer-based delivery of the angiogenesis inhibitor minocycline potentiates the effects of both radiotherapy and temozolomide chemotherapy in increasing median survival. The authors also investigated whether the relative timing of minocycline polymer implantation with respect to radiotherapy affects the efficacy of radiotherapy. Methods Minocycline was incorporated into the biodegradable polymer polyanhydride poly(1,3-bis-[p-carboxyphenoxy propane]-co-[sebacic anhydride]) (CPP:SA) at a ratio of 50:50 by weight. Female Fischer 344 rats were implanted with 9L glioma on Day 0. The minocycline polymer was then implanted on either Day 3 or Day 5 posttumor implantation. Cohorts of rats were exposed to 20 Gy focal radiation on Day 5 or were administered oral temozolomide (50 mg/kg daily) on Days 5–9. Results Both minocycline polymer implantations on Days 3 and 5 increased survival from 14 days to 19 days (p < 0.001 vs control). Treatment with a combination of both minocycline polymer and radiotherapy on Day 5 resulted in a 139% increase in median survival compared with treatment with radiotherapy alone (p < 0.005). There was not a statistically significant difference in median survival between the group that received minocycline implanted on the same day as radiotherapy and the group that received minocycline polymer 2 days prior to radiotherapy. Lastly, treatment with a combination of minocycline polymer with oral temozolomide resulted in a 38% extension of median survival compared with treatment of oral temozolomide alone (p < 0.001). Conclusions These results show that minocycline delivered locally potentiates the effects of both radiotherapy and oral temozolomide in increasing median survival in a rodent glioma model. More generally, these results suggest that traditional therapy in combination with local, as opposed to systemic, delivery of angiogenesis inhibitors may be able to increase median survival for patients with glioblastoma.

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“…Briefly, 1 × 10 5 F98 GBM or 9L GS cells in 10 μl of phosphate buffer saline were administered over 5 min at a depth of 3.5 mm using a Hamilton Neuro Syringe (Hamilton, Reno, NV) mounted on a small animal stereotactic frame (Stoelting, Wood Dale, Il). To establish brain tumor models mimicking high-grade gliomas characterized by rapid tumor growth rates, we orthotopically inoculated rat brains with the maximum numbers of tumor cells, similar to the calculations used as the basis of clinical translation [48,49]. …”

Section: Methodsmentioning

confidence: 99%

Biodegradable brain-penetrating DNA nanocomplexes and their use to treat malignant brain tumors

Mastorakos

Zhang

Song

et al. 2017

Journal of Controlled Release

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The discovery of powerful genetic targets has spurred clinical development of gene therapy approaches to treat patients with malignant brain tumors. However, lack of success in the clinic has been attributed to the inability of conventional gene vectors to achieve gene transfer throughout highly disseminated primary brain tumors. Here, we demonstrate ex vivo that small nanocomplexes composed of DNA condensed by a blend of biodegradable polymer, poly(β-amino ester) (PBAE), with PBAE conjugated with 5 kDa polyethylene glycol (PEG) molecules (PBAE-PEG) rapidly penetrate healthy brain parenchyma and orthotopic brain tumor tissues in rats. Rapid diffusion of these DNA-loaded nanocomplexes observed in fresh tissues ex vivo demonstrated that they avoided adhesive trapping in the brain owing to their dense PEG coating, which was critical to achieving widespread transgene expression throughout orthotopic rat brain tumors in vivo following administration by convection enhanced delivery. Transgene expression with the PBAE/PBAE-PEG blended nanocomplexes (DNA-loaded brain-penetrating nanocomplexes, or DNA-BPN) was uniform throughout the tumor core compared to nanocomplexes composed of DNA with PBAE only (DNA-loaded conventional nanocomplexes, or DNA-CN), and transgene expression reached beyond the tumor edge, where infiltrative cancer cells are found, only for the DNA-BPN formulation. Finally, DNA-BPN loaded with anti-cancer plasmid DNA provided significantly enhanced survival compared to the same plasmid DNA loaded in DNA-CN in two aggressive orthotopic brain tumor models in rats. These findings underscore the importance of achieving widespread delivery of therapeutic nucleic acids within brain tumors and provide a promising new delivery platform for localized gene therapy in the brain.

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Combination of paclitaxel thermal gel depot with temozolomide and radiotherapy significantly prolongs survival in an experimental rodent glioma model

Cited by 73 publications

References 33 publications

PEG- b -PLA micelles and PLGA- b -PEG- b -PLGA sol–gels for drug delivery

PEG- b -PLA micelles and PLGA- b -PEG- b -PLGA sol–gels for drug delivery

Local delivery of angiogenesis-inhibitor minocycline combined with radiotherapy and oral temozolomide chemotherapy in 9L glioma

Biodegradable brain-penetrating DNA nanocomplexes and their use to treat malignant brain tumors

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