Local delivery of temozolomide by biodegradable polymers is superior to oral administration in a rodent glioma model.
OBJECTIVE
Dose-limiting adverse effects of thrombocytopenia and leukopenia prevent augmentation of current temozolomide (TMZ) dosing protocols; therefore, we hypothesized that the direct intracranial delivery of TMZ would lead to improved efficacy in an animal model of malignant glioma in an animal model.


METHODS
Temozolomide was incorporated into biodegradable polymers and the active drug was released over 80 h. Intracranial toxicity was assessed in F344 rats and a maximally tolerated dose was not achieved.


RESULTS
In vivo drug biodistribution demonstrated that intracranial concentrations of TMZ increased threefold compared with orally delivered TMZ. In a rodent glioma model, animals treated with a single TMZ polymer (50% w/w) had a median survival of 28 days (P < 0.001 vs. controls, P < 0.001 vs. oral treatment), whereas animals treated with oral TMZ had a median survival of 22 days compared to control animals (median survival of 13 days). Animals treated with two TMZ polymers (50% w/w) had a median survival of 92 days (P < 0.001 vs. controls, P < 0.001 vs. oral treatment). The percentage of long-term survivors (LTS) for groups receiving intracranial TMZ ranged from 25 to 37.5%; there were no LTS with oral TMZ treatment. Animals treated with radiation therapy (XRT) and intracranial TMZ (median survival not reached, LTS = 87.5%) demonstrated improved survival compared to those with intracranial TMZ alone (median survival, 41 days; LTS = 37.5%), or oral TMZ and XRT (median survival, 43 days, LTS = 38.9%).


CONCLUSIONS
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.
Brem
Sarah
S
Department of Neurosurgery, Johns Hopkins School of Medicine, Baltimore, MD, USA. hbrem@jhmi.edu
Tyler
Betty
B
Li
Khan
K
Pradilla
Gustavo
G
Legnani
Federico
F
Caplan
Justin
J
Brem
Henry
H
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001672:Biocompatible Materials / Q000008:administration & dosage*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy; D003131:Combined Modality Therapy; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D003692:Delayed-Action Preparations / Q000008:administration & dosage; D004343:Drug Implants / Q000008:administration & dosage; D004354:Drug Screening Assays, Antitumor; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy; D020714:Maximum Tolerated Dose; D011108:Polymers; D051381:Rats; D011916:Rats, Inbred F344; D000077204:Temozolomide
D000970:Antineoplastic Agents; D001672:Biocompatible Materials; D003692:Delayed-Action Preparations; D004343:Drug Implants; D011108:Polymers; D003606:Dacarbazine; D000077204:Temozolomide