EVAc polymer delivery

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. 

The second general strategy for local cytokine delivery involves direct loading onto polymers. In 1998, Wiranowska et al. established, as proof of principle, that polymers were capable of the sustained release of biologically active cytokines (116). Both in vitro and in vivo experiments documented the release of active murine IFN-a/j8 by loaded EVAc polymers. In vitro assays determined the majority of activity release occurred in the first 4 days in vivo trials suggested most of activity release spanned the first 24 h with gradual tapering over the next 3 days. 

Among the many classes of polymeric materials now available for use as biomaterials, non-degradable, hydrophobic polymers are the most widely used. Silicone, polyethylene, polyurethanes, PMMA, and EVAc account for the majority of polymeric materials currently used in clinical applications. Consider, for example, the medical applications listed in Table A.l most of these applications require a polymer that does not change substantially during the period of use. This chapter describes some of the most commonly used non-degradable polymers that are used as biomaterials, with an emphasis on their use in drug delivery systems. 

EVAc has been used in the fabrication of a variety of devices for drug delivery. For example, EVAc was used by Alza in devices to deliver pilocarpine to the surface of the eye for glaucoma treatment (Ocusert). Currently, EVAc is used in the Progestasert intra-uterine device for the delivery of contraceptive hormones to the female reproductive tract and as a rate-controlling membrane in a number of transdermal devices. Since EVAc is one of the most biocompatible of the polymers that have been tested as implant materials [30], it has been widely studied as a matrix for controlled drug delivery (see [31, 32] for reviews). 

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. 

One particular hydrophobic polymer, EVAc, has been investigated extensively as a matrix system for protein delivery. This polymer is biocompatible, a major consideration because of the interest in developing systems for human health. Other classes of hydrophobic polymers, like silicone elastomers and polyurethanes, may also be useful for controlled protein delivery, although there are fewer examples available in the literature. Nondegradable, hydrophilic polymers, such as poly(2-hydroxyethyl methacrylate) [p(HEMA)], are also biocompatible but usually release proteins over a relatively short period. However, a few examples oflong-term release of peptides and proteins from hydrophilic polymers are available. Longterm release of peptides from devices that employ cross-linked p(HEMA) as rate-limiting barriers has been reported (Davidson et al, 1988). The use of hydrophilic polymers for protein release is discussed in more detail elsewhere in this volume. 

Many proteins have short half-lives and must be administered frequently to produce continuous therapeutic concentrations in the blood. Nondeg-radable polymer matrices can be used for extended delivery of proteins to the systemic circulation. For example, insulin has been delivered systemi-cally using EVAc matrix systems (Fischel-Ghodsian et al, 1988 Brown et al, 1986 Langer and Folkman, 1977, Creque eta/., 1980). 

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