Local delivery of temozolomide by biodegradable polymers is superior to oral administration in a rodent glioma model

Brem, S.; Tyler, Betty; Li, Khan; Pradilla, Gustavo; Legnani, Federico; Caplan, Justin M.; Brem, Henry

doi:10.1007/s00280-006-0407-2

Cited by 83 publications

(71 citation statements)

References 17 publications

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“…37 Such a saturation of MGMT would explain the longer survival obtained with protracted and continuous schedules in humans 25 or with increased local brain delivery of TMZ by biodegradable polymers in a rodent glioma model. 4 On the other hand, Jiang et al have recently shown that high doses of CPT-11 may increase the in vivo inhibition of U87 tumor growth in nude mice models. 15 In the same way, some studies suggest that a modest enhancement of either TMZ or CPT-11 may be sufficient to obtain a significant improvement in their antitumoral activity.…”

Section: Discussionmentioning

confidence: 99%

“…28,33 In addition, both clinical and experimental observations confirm that the use of high doses of both TMZ and CPT-11 increase their antitumoral activity. 3,4,15,25,37 For both TMZ and CPT-11, the main limit to high-dose protocols remains the systemic side effects of these drugs. In this context, ultrasound-induced opening of the BBB appears to be an ideal technique that may enhance drug delivery to the brain without having to increase the amount of systemically administered drug.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

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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“…In addition to its benefit in human GBM patients as an oral chemotherapeutic, TMZ has been described as an ideal candidate for local chemotherapy within the brain given its lack of need for hepatic activation, and its lack of neurotoxicity to normal brain tissue. TMZ rapidly hydrolyzes under normal and alkaline pH, while it is stable at an acidic pH, which is typical of an intra-tumoural environment; this allows TMZ to be taken up into tumour cells where its active metabolite is created, but reduces risk to normal tissues [31]. Because of the desirable properties of PLGA and TMZ and the proven benefit of oral TMZ for human GBM, these two agents were chosen for a local chemotherapy protocol that can be developed as a minimallyinvasive treatment option for primary canine brain tumours.…”

Section: Introductionmentioning

confidence: 99%

Clinical, Imaging and Pathological Characteristics of Brain Implanted Polylactic Co-Glycolic Acid Polymers Conjugated with Temozolomide

Hicks¹,

R²

2015

J Veterinar Sci Technol

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Definitive treatments for primary brain tumours are still sought. Slow-release local chemotherapy may provide a good effect and poly (lactide-co-glycolide) (PLGA) microcylinders could allow this. We evaluated the neurological and histopathological consequences, and MRI visibility, of PLGA microcylinders conjugated with temozolomide and gadolinium implanted in normal canine brains. Eight purpose-bred beagles had cerebral implantation of microcylinders combined with temozolomide and gadolinium. MRI was performed following implantation and 28d later prior to necropsy and brain histopathology. All adverse events were associated with implantation and resolved. Dogs with six microcylinders at 0 and 6.25% gadolinium had mild inflammation and all other dogs had greater brain inflammation, which increased with higher gadolinium concentrations and microcylinder number. Microcylinders with gadolinium were identifiable on MRI. Brain implantation of PLGA microcylinders conjugated with gadolinium and temozolomide is tolerated in healthy beagles. The lowest gadolinium percentage and microcylinder number should be used if this therapy is pursued.

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“…In addition, various chemotherapeutic agents other than BCNU have been exploited to deliver through polymeric system. Preclinical studies demonstrated that many drugs such as temozolomide, paclitaxel, taxotere, and camptothecin were efficacious against gliomas through polymeric delivery (46)(47)(48)(49). Further clinical investigation of the safety and efficacy is therefore warranted.…”

Section: Economic Considerationmentioning

confidence: 99%

Interstitial Chemotherapy for Malignant Gliomas

Sai¹,

Sun²,

Chen³

2016

Neurooncology - Newer Developments

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Glioma is the most common primary tumor in the central nervous system (CNS). Even with aggressive treatments, gliomas remain as one of the most devastating tumors. Chemotherapy through oral administration of temozolomide (TMZ) is currently the standard regimen for malignant gliomas. However, the systemic toxicity and drug resistance are frequently observed in glioma patients. In order to improve the efficacy and minimize side effects, multiple strategies have been developed. Interstitial chemotherapy is a promising one. By directly delivering chemotherapeutic agents in tumor bed, interstitial chemotherapy bypasses the blood-brain barrier (BBB) and therefore achieves a higher concentration with less systemic exposure. In this chapter, we will have a thorough review on the development and the application of interstitial chemotherapy in gliomas, with the focus on the biomaterial-based and convection-enhanced delivery system. In addition, the future of interstitial chemotherapy is also be shortly discussed.Keywords: malignant gliomas, local therapy, surgery, adjuvant chemotherapy, temozolomide, Gliadel waffer IntroductionMalignant gliomas account for more than 50% of primary central nervous system (CNS) tumors and are among the most formidable cancers in human beings (1). Although aggressive debulking surgery followed by radiation and chemotherapy is the mainstay for malignant gliomas, the prognosis of malignant gliomas remains far from satisfactory. The 5-year overall survival (OS) is as low as 9.8% for patients with glioblastoma multiforme (GBM), a malignancy classified as grade IV by the world health organization (WHO) (2). The recurrence seems to be inevitable for malignant gliomas. Most patients with recurred GBM will die within 6 months even with salvage treatments.© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.The exact mechanisms underlying the intractability of malignant gliomas have not been fully understood, but the inherent resistance and the sheltering environment of brain have been proposed to protect the disease from conventional treatments. First of all, the infiltrative growth pattern of glioma cells makes the complete surgical resection almost impossible. Second, the existence of blood-brain barrier (BBB), which is tightly formed by capillary endothelial cells together with astrocytes, restricts the entry of most systemically administered chemotherapeutic agents into the tumor parenchyma (3). Third, the inherent and acquired insensitivity to radiation and chemotherapy through the disturbance of signaling pathway in glioma cells results in the resistance to current therapies (4). Because gliomas seldom metastasize outside the CNS and usually recur within 1-2 cm from the original tumor site, it is reasonable to expect the efficacy of directly deliv...

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Local delivery of temozolomide by biodegradable polymers is superior to oral administration in a rodent glioma model

Abstract: The survival of tumor-bearing animals was improved with local delivery of TMZ compared with systemic administration. XRT in combination with intracranial TMZ did not cause additional toxicity and prolonged the survival even further.

Cited by 83 publications

References 17 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

Clinical, Imaging and Pathological Characteristics of Brain Implanted Polylactic Co-Glycolic Acid Polymers Conjugated with Temozolomide

Interstitial Chemotherapy for Malignant Gliomas

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