**3.2. Carmustine implants**

#### *3.2.1. Background information*

Various biodegradable polymers, such as the 1,3‐bis(p‐carboxyphenoxy) propane and sebacic acid (PCPP‐SA), the fatty acid dimer sebacic acid (FAD‐SA), and poly(lactide‐co‐glycolide) (PLGA) polymers, have been investigated in the last 3 decades. But until now, PCPP‐SA is the most successful and widely used polymer for brain tumors. This compound has several advantages as matrix (15). Firstly, PCPP‐SA is hydrophobic and can therefore protect the impregnated drug from inactivation by the surrounding aqueous environment. Secondly, the two‐stage degradation of PCPP‐SA matrix results in the gradual release of the content. At the first stage, the bonds between sebacic acid and sebacic acid or those between sebacic acid and CPP rapidly hydrolyzed, whereas the bonds between CPP and CPP take a longer time to degrade. This initial degradation is followed by a process of inward erosion which starts at the surface of the matrix and goes interiorly into the core. By modulating the ratio of sebacic acid and CPP in the matrix, the speed of degradation can be adjusted from hours to days as required. In addition, the breakdown of the PCPP‐SA does not leave foreign body behind. Currently, the only US Food and Drug Administration (FDA) approved local chemothera‐ peutical agent for brain tumors, that is, Gliadel wafer, is composed by PCPP‐SA as matrix and 1,3‐bis(2‐chloroethyl)‐1‐nitrosurea (carmustine or BCNU) as content.

BCNU is one of the most effective chemotherapeutics against malignant brain tumors at the time when the first local polymeric drug delivery system was being developed. BCNU is a classic alkylating and exerts its anti‐tumor effect by forming inter‐strand crosslink in DNA and subsequently inhibiting the replication and transcription of DNA in tumor cells (16). The highly lipid‐soluble and nonpolar nature of BCNU makes it ideal for cancers in CNS be‐ cause the agent has a good penetration of BBB. The concentration of BCNU in cerebral spinal fluid (CSF) is as high as 30% of that in plasma after intravenous injection. Clinical studies have demonstrated that systemic administration of BCNU is capable of prolonging the survival of patients with malignant gliomas (17). As a result, BCNU alone or combined with other agents has once been the most frequently used chemotherapy regimens for malignant gliomas. Although effective, intravenously administered BCNU is limited by its toxicities (18).

Gastrointestinal adverse effects such as nausea and vomiting can be observed shortly after infusion of BCNU and last for hours. Systemic BCNU therapy also causes myelosuppression. The peak of hematologic suppression may occur 1 month after BCNU administration, and it may take weeks for the recovery of bone marrow. In addition, pulmonary injury is another toxicity caused by BCNU treatment. Although rare, with the occurrence of approximately 5% of the patients, the BCNU‐associated pneumonitis induces restrictive pulmonary disorders and subsequently progressive lung fibrosis, even after the withdrawal of the agent. Some patients terminate the chemotherapy due to the severe and irreversible toxicities. Based on its clinical efficacy against malignant brain tumors and the undesirable adverse effects, BCNU was impregnated into the PCPP‐SA polymers. The BCNU wafers were explored for preclini‐ cal testing followed by clinical investigation.
