Effectiveness of controlled release of a cyclophosphamide derivative with polymers against rat gliomas

Abstract

Most malignant gliomas grow despite treatment by standard chemotherapeutic agents. The authors explored the use of an innovative drug, 4-hydroperoxycyclophosphamide (4HC), delivered via a controlled-release biodegradable polymer to determine whether local delivery would enhance efficacy. This drug is an alkylator-type chemotherapeutic agent derived from cyclophosphamide. Unlike the parent drug, which requires activation by hepatic microsomes, 4HC is active in vitro. Two rat glioma cell lines, 9L and F98, were treated in cell culture with medium containing 4HC. Both cell lines were more sensitive to 4HC than to a nitrosourea, BCNU, an agent of established value in the local therapy of gliomas. Ninety Fischer 344 rats implanted with 9L or F98 gliomas were treated with an intracranial polymer implant containing 0% to 50% loaded 4HC in the polymer, and it was found that 20% 4HC-loaded polymers caused minimum local brain toxicity and maximum survival. These polymers were then used to compare the in vivo efficacy of 4HC to BCNU in rats implanted with 9L glioma. Animals with brain tumors treated with 4HC had a median survival span of 77 days compared to the median survival of 21 days in BCNU-treated animals and median survival of 14 days in untreated animals. Long-term survival for more than 80 days was 40% in the 4HC-treated rats versus 30% in the BCNU-treated rats. The polymer carrier used in this study was a copolyanhydride of dimer erucic acid and sebacic acid 1:1, which was able to maintain the hydrolytically unstable 4HC in a stable state for local delivery. Thus, it is concluded that 4HC-impregnated polymers provide an effective and safe local treatment for rat glioma.

Polymeric controlled-release amsacrine chemotherapy in an experimental glioma model

“…It should therefore be possible to increase this dosage several times while avoiding toxicity to the normal brain. Long-term survival was 50% in the in vivo model, which is similar to that reported in other studies by Brem and co-workers using different devices and drugs [17,29]. It is difficult to apply these animal results to the human situation where the tumour volume is about 1000 times larger.…”

Intralesionally implanted cisplatin plus systemic carmustine for the treatment of brain tumor in rats

“…Theoretically, this strategy is expected to deliver a high drug concentration to the tumor center (by local drug implantation) and a constant level to the periphery (through systemic administration). Ideally, the drug implanted intralesionally should have a poor permeability through the BBB to prevent escape [26,27], with the systemically administered drug having a relatively high permeability through the BBB. As the permeability of cisplatin through the BBB is poor and the permeability of carmustine is relatively high, cisplatin implanted ic in polymer plus carmustine administered systemically theoretically makes good sense.…”

Enhanced therapeutic agent delivery through magnetic resonance imaging–monitored focused ultrasound blood-brain barrier disruption for brain tumor treatment: an overview of the current preclinical status

“…Chemotherapeutic agents can also be delivered interstitially by local injection 51 or by direct implantation of drug-carrying biodegradable matrices into the debulked tumor cavity. 33,64 A 30-month trial in 240 patients found median survival times of 13.9 and 11.6 months for patients implanted with BCNU wafers or placebos, respectively. 64 However, Gliadel wafer (Eisai) implantation was found to cause adverse effects, including CSF leakage, intracranial hypertension, seizures, brain edema, healing abnormalities, and intracranial infection.…”