【文章內(nèi)容簡介】 relationship between rates of drug release from polymer implants and drug concentration in brain tissue is unknown. This work presents a pharmacokiic framework for application of this new modality of chemotherapy delivery in primates. Either [3H]carmustine, 4hydroperoxycyclophosphamide (4HC), or paclitaxel was encapsulated in a polyanhydride pellet (2841 micro Ci/animal, 40 mg/animal), which was implanted intracranially in cynomolgus monkeys (Macaca fascicularis)。 (n = 17) for up to 30 days. Drug concentrations in the brain, blood, and cerebrospinal fluid were measured by quantitative autoradiography, TLC, and scintillation counting. High drug concentrations ( mM for carmustine, mM for 4HC, and mM for paclitaxel) were measured within the first 3 mm from the polymer implant。 significant ( microM for carmustine, 3 microM for 4HC, and microM for paclitaxel) concentrations were measured up to approximately 5 cm from the implant as long as 30 days after implantation. Pharmacokiic analysis indicated that tissue exposure to carmustine area under concentrationtime curve achieved by polymeric delivery was 41200 times higher than that produced by . administration of a higher dose. 15 Optimizing interstitial delivery of BCNU from controlled release polymers for the treatment of brain tumors. Eric P. Sipos, Betty Tyler, Peter C. Burger, H. Brem， et al Cancer Chemotherapy and Pharmacology Vol 39, Number 5 / Feb, 1997 Two approaches for improving the interstitial administration of carmustine (BCNU) using % loaded poly(carboxyphenoxypropanesebacic acid), an implantable biodegradable anhydride which significantly prolongs survival in patients with recurrent malignant gliomas, were evaluated. First, increasing the ratio of carboxyphenoxypropane (CPP) to sebacic acid (SA) in the polymer increases its hydrolytic stability, thus prolonging its halflife in vivo, and extending the period of drug release. A second approach is to increase the dose of drug loaded into the polymer. This study evaluated the relative merits of these two approaches by paring release kiics, safety, and efficacy of escalating BCNU doses in polymers with 20:80 and 50:50 ratios of CPP to SA. At the highest dose tested, the 50:50 polymer released BCNU times as long in vitro as the 20:80 polymer. Both formulations were nontoxic in rat brains for all BCNU doses tested except 32%. The 20:80 and 50:50 polymers were equally effective in the rat intracranial 9Lglioma model. A doseresponse relationship for BCNU was observed (hazard ratio for each mg/kg increase, P). The two highest loading doses of BCNU improved survival 40fold (P). The 20% BCNUloaded 20:80 polymer achieved the best balance of toxicity and antitumor efficacy, yielding a 75% longterm survival rate. Further evaluation of this polymer in monkeys suggests that it might be used with acceptable toxicity. This study establishes that a doseescalation strategy for improving BCNU controlledrelease polymers is more effective than adjusting the ratio of CPP to SA to prolong drug release. 16 Biodegradable polymer implants to treat brain tumors. Brem H, Gabikian P. J Control Release. 2020 Jul 6。74(13):637. We have developed a systematic approach for the discovery and evaluation of local treatment strategies for brain tumors using polymers. We demonstrated the feasibility of polymermediated drug delivery by using the standard chemotherapeutic agent 1,3bis(2chloroethyl)1nitrosourea (BCNU) and showed that local treatment of gliomas by this method is effective in animal models of intracranial tumors. This led to clinical trials for glioma patients, and subsequent approval of Gliadel [(% BCNU): p(CPP:SA)] by the FDA and other worldwide regulatory agencies. Twentytwo additional clinical trials are currently underway evaluating other issues related to the BCNU polymer, such as dosage, bination with systemic treatments, and bination with various forms of radiation and resistance modifiers. These trials are a result of laboratory investigations using brain tumor models。 based on these models, other research groups have initiated clinical trials with novel binations of different drugs and new polymers for both intracranial tumors (5fluorouracil delivered via poly(DL lactidecoglycolide) polymer) and for tumors outside the brain (paclitaxel in PPE microspheres for ovarian cancer). Since only 1/3 of patients with glioblastoma multiforme (GBM) are sensitive to BCNU, the need to search for additional drugs continues. Although we are attacking major resistance mechanisms, there still will be tumors that do not respond to BCNU therapy but are sensitive to agents with different mechanisms of action, such as taxanes, camptothecin, platinum drugs, and antiangiogenic agents. Thus, it is necessary to explore multiple single agents and ultimately to bine the most effective agents for the clinical treatment of GBM. Furthermore, multimodal approaches bining radiotherapy with microsphere delivery of cytokines and antiangiogenic agents have demonstrated encouraging results. 17 6 、 Chemotherapeutic Drugs Released from Polymers: Distribution of 1,3bis(2chloroethyl)lnitrosourea in the Rat Brain Lawrence K. Fung, Marian Shin, Henry Brem and W. Mark Saltzman,et al. Journal Pharmaceutical Research. 1996 13(5)： 671682 Abstract Purpose. The distribution of [3H]BCNU following release from polymer implants in the rat brain was measured and evaluated by using mathematical models. Methods. [3H]BCNU was loaded into p(CPP:SA) pellets, which were subsequently implanted intracerebrally in rats。 [3H]BCNU was also directly injected into the brains of normal rats and rats with intracranially transplanted 9L gliomas. Concentrations of [3H]BCNU on coronal sections of the brain were measured by autoradiography and i