Implantable Polymers

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The use of biodegradable wafers and microspheres combined with a variety of chemotherapeutic and immunotherapeutic agents has established this local treatment modality as a versatile investigative approach for interstitial treatment of CNS lesions. The investigation culminated with US Food and Drug

Fig. 2. Gliadel wafers placed into a tumor cavity following resection of a recurrent malignant glioma.

Administration (FDA) approval of wafers (Gliadel) impregnated with 1,3-bis (2,chloroethyl)-1-nitrosurea (BCNU; also called carmustine) in 1996 for use in the treatment of malignant gliomas (Fig. 2) (38). The clinical results validate efforts to utilize local delivery as a feasible strategy for treating gliomas; however, its impact on survival has not lived up to expectations.

Principles of Interstitial Polymer Therapy

Polymer technology was introduced with development of a polymer that would release drug at a timed rate from the intact polymer matrix. This led to the design of a polymer matrix that would degrade within the interstitium of the CNS, releasing its impregnated drug into the brain's parenchyma (4). These approaches depend on diffusion for distribution within the brain (2).

The prototype polymer developed using an intact matrix was the ethylene-vinyl acetate copolymer (EVAc). This matrix is capable of releasing a host of drugs ranging from high- to low-molecular-weight compounds (4). The release rate of drug is largely governed by the properties of the matrix, its permeability, its reactivity to the surrounding interstitium, and its interaction with the loaded drug. The EVAc matrix has been subsequently used in clinical treatment for glaucoma with pilocarpine, vaginal contraception with progesterone, and intratumoral glioma therapy with BCNU (5). Silicone rubber, a long-lasting matrix, has also been used with 5-fluoruracil (5-FU) in clinical efforts (4,12).

The degradable poly-[bzs(p-carboxyphenoxy)propane]-sebacic acid copolymer (PCPP-SA) was used for glioma therapy in clinical trials. PCPP-SA and its metabolites have been shown to be nonmutagenic, noncytotoxic, and non-ter-atogenic (4) and to elicit only a minimal inflammatory reaction (gliosis) in vivo (5,8). This matrix is degraded by alteration of the polyanhydride bonds that constitute the matrix. The release of drugs from the biodegradable polymer system depends on diffusion of the drug from the polymer and degradation properties of the matrix (4). A variety of drugs can be incorporated into the matrix provided they do not chemically modify or interact with the backbone PCPP-SA (5).

PCPP-SA is primarily designed for hydrophobic agents, such as BCNU, but its use with hydrophilic agents has been complicated by degradation of the impregnated drug (5). An additional matrix fatty acid dimer-sebacic acid (FAD-SC) was approved for clinical trials for the delivery of hydrophilic agents. The FAD-SC polymer prevents degradation of the loaded drug and allows for its delivery to a lesion (5). An additional polymer matrix has been developed using a poly(lactide-co-glyoclide) polymer (5,29,67), which enables the polymer to form microspheres (29). Microspheres can be introduced into a lesion with stereotactic placement or during surgical resection (5,57). Animal and clinical studies with microspheres loaded with 5-FU or various cytokines have shown promise in the treatment of malignant gliomas and the development of tumor vaccines (29,30,68).

The volume of distribution of drug and its sustained delivery are largely dependent on concentration gradients established by drug diffusion (7,28). These properties are determined primarily by the drug loaded into the polymer matrix (51). This mechanism is ultimately responsible for the limited volume of distribution that can be achieved since diffusion is exceedingly slow in solid tissues. A transient increase in interstitial fluid may promote a limited degree of convection that may occur as a result of increased ICP at the site of polymer insertion (7,61). Diffusion remains the primary mechanism by which drugs are delivered with polymer implants and can be verified with experiments that show an exponential decrease in drug concentration as distance from the polymer implant is increased (2,12). This is the likely explanation for the limited efficacy in clinical trials.

Experiments to optimize the therapeutic delivery and volume of distribution with polymers have focused on two facets. The first is altering the matrix and its structure. The second is changing the concentration of the drug loaded into the polymer (8,10,28,51,56). Subsequent studies revealed that changing to 50% PCPP and 50% SA offered no improvement in survival, but when the BCNU was increased to 20%, an increase in survival was possible while maintaining limited toxicity (8).

Although most studies report a mild gliosis to the polymer at autopsy, there may be more significant adverse effects. Severe brain edema unresponsive to corticosteroid therapy, perioperative seizures, wound infections, CSF leaks, sepsis, wound dehiscence, and cyst formation have all been reported (3,8,28). Intracranial air collection and fragments of a degradable polymer are a concern, as they may migrate through the parenchyma and penetrate the ventricular system, contributing to the observed CSF leaks and chemical meningitis (28). Wound dehiscence is thought to be caused by inhibition of epidermal cell growth by BCNU leaking from the wafer. Gliosis in response to the polymer may, however, be advantageous, as it may help to recruit components of the inflammatory response, further suppressing tumor growth (28,58).

A further limiting factor is that the polymers, unlike pumps, CED, and reservoirs, cannot be refilled with the therapeutic agent of choice. This translates into subsequent surgeries for placement of additional drug wafers if the therapeutic response is suboptimal. Finally, the possibility of developing tumor resistance to a single therapeutic agent when it is released from a polymer has been explored (5).

Clinical Applications of Polymer Technology

Research investigations with polymer technology have included its use in the treatment of malignant gliomas, cerebral infections (51), Parkinson's disease (57,60), Huntington's disease (59), cerebral edema with dexamethasone release (57), and models of tumor metastasis with breast cancer. The diversity is a reflection of the unique versatility of polymer technology to address a wide range of CNS disorders.

The initial studies completed with polymer wafers centered on the treatment of malignant gliomas. Initial animal studies (13,51) and phase I/II clinical studies (10) focused on establishing the safety, efficacy, and combination of drug and polymer that would be optimal. These initial studies were responsible for the FDA's approval of Gliadel wafers, 3.85% BCNU impregnated in a 20% PPCA, and 80% SA polymer (10). Early results from phase I/II clinical trials revealed that the wafers could be used safely in a population of patients with histologi-cally graded III and IV astrocytomas. This study helped to establish the aforementioned BCNU dose of 3.85% and helped elucidate that increased dose did not necessarily result in improved clinical outcome. Patients did experience cerebral edema; however, no significant adverse events were found to be attributable to the wafers.

A subsequent prospective clinical study randomized placebo-controlled patients and 222 patients with malignant gliomas from 27 centers in the United States and Canadal (56). Patients with glioblastoma multiforme (GBM) had the most significant improvement with the drug-loaded wafers, although overall results showed minimal improvement in survival. As with the previous study,

Fig. 3. Diagram demonstrating convection-enhanced delivery. Therapeutic compounds are slowly pumped into a catheter implanted in brain tissue. A pressure gradient is established that distributes the compound through the interstitial space by bulk flow.

cerebral edema occurred and was treated with corticosteroids (28,56). Subsequent studies helped to establish Gliadel wafers as acceptable treatments for patients undergoing their initial surgery for GBM (28). Further studies, repeated in 1997 (53 )and 1999 (28), revealed that a significant complication rate is associated with polymer treatment using Gliadel wafers.

These studies elucidated the pharmacokinetics of the Gliadel system, demonstrating that BCNU was released in vivo over a period of three weeks with 50% of the drug being released within the first 24 h and 95% of the BCNU being released in 120 h (3,61). Wafers were found to degrade within 6-8 wk. Further characterization of the pharmacokinetics revealed that the depth of BCNU was predicted to be limited to 5mm at 100 h, owing to a high transvascular permeability and rapid reabsorption into the systemic circulation (28). Measurable penetration of BCNU may be limited to 1 to 2 cm from the site of implantation (28), but effective therapeutic concentrations are even more limited, with a millimeter range that limits its effect on invaded brain tissue.

Additional clinical research with BCNU wafers has explored its use in a model of breast cancer metastasis to the brain (43) and in combination with radiation (9). Initial results have shown promise in combining radiation therapy with polymer technology including the use of halogenated pyrimidines as potent radiosensitizers for human gliomas (63). Studies using IUdR impregnated in a PCPP-SA polymer coupled with radiation to treat malignant gliomas are currently under way (63). Additional chemotherapeutic agents being investigated include mitoxanthrone, doxetaxel, and platinum base (3).

As polymer technology moves into the future, its versatility as a treatment modality may make it suitable for targeting specific molecular proteins and signal transduction cascades. One such example is the use of O6-benzylguanine to potentiate the antitumor effect of BCNU polymers (55). Recent studies coupling immunotherapy and polymer technology have utilized IL-2 coupled with BCNU or carboplatin wafers (58,60). This combined approach to treatment may be helpful when one is trying to avoid tumor cell resistance.

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