Biocompatible Polymer Development An Historical Perspective

Carmustine (BCNU), a member of the nitrosurea family, was widely used as a systemic agent for treating malignant brain tumors. Given its established mechanism of action against 

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. 

A second experiment employed the same rat intracranial model to compare BCNU release kinetics and biodistribution using pCPP SA (20 80) copolymer delivery vs. direct stereotactic injection (85). Following implantation or injection, tritiated BCNU allowed drug distribution assessment by 

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. 

Using rat flank and intracranial 9L gliosarcoma models, Tamargo et al. (70) initially compared the efficacy of polymer and systemically based BCNU. EVAc polymer delivery in the flank model produced significant tumor growth delay relative to systemic administration (15.3 vs. 11.2 days, p 0.05). In the intracranial model, a 10 mg polymer with 20% (w/w) BCNU polymers dramatically improved survival in animals with established 9L gliosarcoma. EVAc and pCPP SA polymers conferred respective survival advantages of 7.3-fold and 5.4-fold over controls. Systemic BCNU, in contrast, increased survival only 2.4-fold compared to controls. 

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