Incomplete copolymer degradation of in situ chemotherapy

Abstract

In situ carmustine wafers containing 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) are commonly used for the treatment of recurrent glioblastoma to overcome the brain-blood barrier. In theory, this chemotherapy diffuses into the adjacent parenchyma and the excipient degrades in maximum 8 weeks but no clinical data confirms this evolution, because patients are rarely operated again. A 75-year-old patient was operated twice for recurrent glioblastoma, and a carmustine wafer was implanted during the second surgery. Eleven months later, a third surgery was performed, revealing unexpected incomplete degradation of the wafer. 1H-Nuclear Magnetic Resonance was performed to compare this wafer to pure BCNU and to an unused copolymer wafer. In the used wafer, peaks corresponding to hydrophobic units of the excipient were no longer noticeable, whereas peaks of the hydrophilic units and traces of BCNU were still present. These surprising results could be related to the formation of a hydrophobic membrane around the wafer, thus interfering with the expected diffusion and degradation processes. The clinical benefit of carmustine wafers in addition to the standard radio-chemotherapy remains limited, and in vivo behavior of this treatment is not completely elucidated yet. We found that the wafer may remain after several months. Alternative strategies to deal with the blood-brain barrier, such as drug-loaded liposomes or ultrasound-opening, must be explored to offer larger drug diffusion or allow repetitive delivery.

Established and Emerging Strategies for Drug Delivery Across the Blood-Brain Barrier in Brain Cancer

“…Gliadel ® consists of the copolymer polifeposan (1,3-bis(p-carboxyphenoxy) propane and sebacic acid, 4:1 molar ratio) [72] loaded with the alkylating agent carmustine (3.85% w / w ). The wafers are disk-shaped of 14 mm in diameter and 1 mm in thickness, with an overall weight of 200 mg. A previous investigation in primates (without tumor or tissue removal) receiving the wafers demonstrated that carmustine can diffuse in the brain parenchyma between 2 and 8 mm from the implantation site [73]. These wafers are FDA approved in many countries and they are designed for being completely biodegradable and support a sustained release of at least five days after implantation [74], while the wafer is supposed to be completely degraded in 2–3 weeks.…”

“…Infection is another documented potential adverse effect of the wafers even though a large study performed by the group of Chaichana, demonstrated that the previous presence of diabetes mellitus, multiple resections, and prolonged hospitalization are probably the main causes at the base of this phenomenon [78]. In addition, the group of Carpentier described a clinical case in which they analyzed not fully degraded wafers removed from the brain of a patient that underwent a second surgery due to a tumor recurrence [73]. The analysis demonstrated that incomplete degradation occurred at the level of the sebacic acid units (hydrophilic material), causing the scientists to speculate that a hydrophobic layer of unspecified biological material generated on the surface of the wafers reducing their degradation.…”

Biodegradable gemcitabine-loaded microdevice with sustained local drug delivery and improved tumor recurrence inhibition abilities for postoperative pancreatic tumor treatment

“…Gliadel ® is the first implantable microdevice approved by the US Food and Drug Administration (FDA) (in 1996) for the treatment of malignant glioma after surgery and has been shown to extend median survival (Westphal et al., 2006 ; Jelonek & Kasperczyk, 2013 ). Although the local implantation of Gliadel ® can ignore the blood–brain barrier to achieve a good therapeutic effect, the product has the disadvantages that the degradation time (3 weeks) is much longer than the release time (five days) and the drug release behavior is unknown (Fleming & Saltzman, 2002 ; Bourdillon et al., 2018 ). Zoladex ® is a sufficiently mature goserelin acetate (a luteinizing hormone analog) sustained-release implant developed by AstraZeneca for the treatment of prostate cancer, breast cancer and uterine fibroids (Sartor, 2003 ; Zhang et al., 2012 ).…”