BCNU-loaded polymers

Brem H, Ewend MG, Piantadosi S, et al. The safety of interstitial chemotherapy with BCNU-loaded polymer followed by radiation therapy in the treatment of newly diagnosed malignant gliomas phase I trial. J Neurooncol 1995 26 111-123. 

Preclinical studies of BCNU-polymer preparations proceeded in four systematic stages. The first series of experiments examined in vivo release kinetics of BCNU loaded polymers. The initial study involved EVAc copolymer implantation in the rat brain (31). Subsequent to polymer placement, a Brat-ton-Marshall assay measured BCNU concentrations in both cerebral hemispheres, and serum samples were collected at prescribed time points. The hemisphere ipsilateral to polymer placement corresponded with peak BCNU levels at 4 h clinically significant concentrations persisted at day 7. In contrast, both contralateral hemisphere and serum BCNU levels were at least an order of magnitude lower throughout the experiment. Thus, the study served as proof of principle of the ability of polymer technology to simultaneously achieve sustained release and local delivery of chemotherapy within the CNS. 

From an efficacy standpoint, overall median survival times were 46 weeks from implantation and 87 weeks after initial diagnosis 86% of patients lived more than 1 year after diagnosis. Based on this work, the 3.85% BCNU-loaded polymer was chosen for further clinical study. 

Figure 5 Overall survival for patients receiving BCNU-loaded polymers vs. controls at the time of the operation for recurrent malignant ghomas. (From Ref. 94.)...

Figure 6 Kaplan-Meier survival curve for patients with initial therapy for grade III and grade IV gliomas treated with BCNU-loaded polymer implants vs. placebo. (From Ref. 96.)...

Further subset evaluation of GBM patients revealed a median survival advantage of 53.3 weeks vs. 39.9 weeks with placebo ip = 0.008). Interestingly, three of the study s four long-term survivors (still alive 3 years after study termination) received BCNU-loaded polymers. Age and KPS score significantly impacted survival while the survival effect of tumor type failed to achieve statistical significance. The phase III trial reinforced earlier research documenting no local or systemic morbidities with pol5rmer implantation. 

Local quinacrine delivery therefore offers a natural alternative to systemic administration. Figure 7b illustrates that the implantation of 15% (w/w) quinacrine-loaded pCPP SA polymers and BCNU-loaded polymers significantly extend survival. Interestingly, the synergistic benefit of combined quinacrine and BCNU local delivery demonstrates time sensitivity quinacrine polymer implantation 2 days prior to BCNU poljnner placement enhances survival whereas concurrent tmnor bed insertion offers no benefit (Fig. 7 c). The importance of ordered administration of adjuvant quinacrine therapy provides some mechanistic insight, and remains the subject of ongoing research. 

Finally, changes in the brain that occur during the course of therapy are not properly considered in this model. Irradiation can be safely administered when a BCNU-loaded polymer has been implanted in monkey brains, suggesting the feasibility of adjuvant radiotherapy. Flowever, irradiation also causes necrosis in the brain. The necrotic region has a lower perfusion rate and interstitial pressure than tumor tissue thus, the convective interstitial flow due to fluid leakage is expected to be smaller. Interstitial... 

Brem, H., Tamargo, R. J., Finn, M., and Chasin, M., Biocompatibility of a BCNU-loaded biodegradable polymer A toxicity study in primates, Abstracts of the 1988 Annual Meeting of the American Association of Neurological Surgeons, 1988,... 

A third experiment examined 20% (w/w) BCNU loaded pCPP SA polymer release kinetics and biodistribution in a primate intracranial model. Tiunorcidal concentrations of BCNU spread up to 4 cm from the polymer implantation site 24 h post-operatively (86). Taken together, these animal studies established the drug delivery capabihties of pol3rmer technology, and confirmed the viabifity of local, sustained, and clinically significant in vivo delivery of chemotherapeutic agents within the CNS. 

A second study in the same established rat intracranial 9L gliosarcoma model evaluated the efficacy of 20% (w/w) BCNU-loaded pCPPrSA polymers vs. direct stereotactic injec-... 

BG mediated AGT inhibition indeed increases tizmor sensitivity to BCNU. However, concomitant 06-BG and systemic BCNU administration in animal models reduced the maximum tolerated dose 6-fold due to bone marrow toxicity (101). Presumably, 06-BG imparts the same increased BCNU sensitivity to tumor cells and those vulnerable to systemic toxicity. Rhines et al. postulated systemic 06-BG administration with intracranial BCNU polymer delivery, not systemic BCNU, would significantly reduce the side effects of combination therapy (102). In the established rat intracranial F98 gfioma model (a tumor line with high AGT activity), systemic 06-BG with BCNU-loaded pCPPrSA polymers improved median survival over either 06-BG alone (34 vs. 22 days, p = 0.0002) or BCNU polymer alone (34 vs. 25 days, p = 0.0001). Moreover, Rhines et al. showed the reduction in BCNU polymer load was not necessary with the systemic introduction of 06-BG. The animals further demonstrated no gastrointestinal or bone marrow toxicity from combination therapy (95). 

H. Brem, R.J. Tamargo, M. Pinn, M. Chasin, Biocompatibility of BCNU-loaded biodegradable polymer a toxicity study in primates, J. Neurosurg. 68 (1988) 335-336. 

MAJOR APPLICATIONS Biodegradable polymer for controlled drug delivery in a form of implant or injectable microspheres (e.g., Gliadel -BCNU-loaded wafer for the treatment of brain tumors). 

Figure 4 After surgical dehulking, the tumor resection cavity is lined with up to eight 200 mg 3.8% (w/w) BCNU pCPP SA (20 80) (Gliadel ) polymer, where the loaded drug is gradually released as they dissolve.

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