Journal of Controlled Release 61 (1999) 21–41 The delivery of BCNU to brain tumors a, a a b * Chi-Hwa Wang , Jian Li , Chee Seng Teo , Timothy Lee a Department of Chemical Engineering, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260, Singapore b Division of Neurosurgery, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260, Singapore Received 15 October 1998; received in revised form 3 February 1999; accepted 2 April 1999 Abstract This paper reports the development of three-dimensional simulations to study the effect of various factors on the delivery of 1-3-bis(2-chloroethyl)-1-nitrosourea (BCNU) to brain tumors. The study yields information on the efficacy of various delivery methods, and the optimal location of polymer implantation. Two types of drug deliveries, namely, systemic administration and controlled release from polymers, were simulated using fluid dynamics analysis package (FIDAP) to predict the temporal and spatial variation of drug distribution. Polymer-based delivery provides higher mean concentration, longer BCNU exposure time and reduced systemic toxicity than bolus injection. Polymer implanted in the core gives higher concentration of drug in both the core and viable zone than the polymer in the viable zone case. The penetration depth of BCNU is very short. This is because BCNU can get drained out of the system before diffusing to any appreciable distance. Since transvascular permeation is the dominant means of BCNU delivery, the interstitial convection has minor effect because of the extremely small transvascular Peclet number. The reaction of BCNU with brain tissues reduces the drug concentration in all regions and its effect increases with rate constant. The implantation of BCNU / ethylene–vinyl acetate copolymer (EVAc) matrix at the lumen of the viable zone immediately following the surgical removal of 80% of the tumor may be an effective treatment for the chemotherapy of brain tumors. The present study provides a quantitative examination on the  working principle of Gliadel wafer for the treatment of brain tumors.  1999 Elsevier Science B.V. All rights reserved. Keywords: Tumor; 1-3-Bis(2-chloroethyl)-1-nitrosourea; Polymeric delivery; Systemic administration; Simulation 1. Introduction ciated with it are the systemic toxicities characterized by delayed hematopoietic depression, cytotoxic ef- BCNU (1-3-bis(2-chloroethyl)-1-nitrosourea (car- fects on kidney, liver and central nervous system, mustine)) is an important chemotherapeutic drug in and the short exposure time of tumor tissue to BCNU treating brain tumors. Its main function is to inhibit [1]. The research work of Blasberg et al. [2] showed the synthesis of DNA, RNA and protein similar to that the intravenous perfusion of BCNU results in its other alkylating agents. The traditional method of penetration through only a short distance ( |2 mm) delivering BCNU to the pathological site is mainly from the ependymal surface into the local brain through intravenous perfusion. The drawbacks asso- tissues, and hence the efficacy of this kind of drug delivery appears to be quite low. In an effort to overcome these disadvantages, *Corresponding author. E-mail address: chewch@nus.edu.sg (C.-H. Wang) intensive research has been undertaken by the sci- 0168-3659 / 99 / $ – see front matter  1999 Elsevier Science B.V. All rights reserved. PII: S0168-3659(99)00098-X