Emerich Dwaine F, Winn Shelley R, Bartus Raymond T
Alkermes, Inc., Cambridge, MA 02139, USA.
Cell Transplant. 2002;11(1):47-54.
Polymer microspheres can be easily injected into the brain to provide a local and sustained delivery of chemotherapeutics to a tumor or surrounding tissue subject to high rates of tumor recurrence following surgery. Building on previous studies that established the clear advantage of local, peritumoral injections of sustained release microspheres, the following experiments utilized two different approaches for maximizing the survival benefit in glioma-bearing rats. In the first experiment, a previously grown cortical tumor was debulked and animals received either one or two treatments with carboplatin-loaded microspheres (either 200 or 800 microg total carboplatin per treatment). In each case, the microspheres were injected along the perimeter of the resection cavity with each treatment separated by 20 days. Survival studies clearly demonstrated that two, temporally spaced injections were superior to a single series of injections. At the lowest dose tested (200 microg), median survival was increased an additional 40% over that in animals receiving one treatment. At the higher dose (800 microg), one third of the animals receiving two separate treatments were long-term survivors (> 150 days) and showed complete eradication of the tumor on histological examination. In the second experiment, we directly compared the efficacy produced by sustained release carboplatin or 1,3-bis[2-chloroethyl]-1-nitrourea (BCNU) alone versus injecting carboplatin and BCNU-loaded microspheres blended together as a single suspension. Carboplatin and BCNU both enhanced survival, with BCNU being significantly less effective than carboplatin. However, the greatest improvements in survival were seen when a blended suspension of carboplatin and BCNU microspheres was injected around the surgical cavity. In contrast, spatially alternating injections of BCNU and carboplatin microspheres was significantly less effective and the increase in survival was no greater than that achieved with BCNU alone. These data offer further support for the potential utility of local, sustained release chemotherapeutic microspheres for treating glioma. Moreover, they suggest that injectable chemotherapeutic microspheres may offer important advantages by (a) permitting multiple, temporally spaced injections to be made, as needed, and (b) providing the opportunity to deliver combinations of several different efficacious drugs directly to the tumor site to enhance survival beyond what can be achieved with delivery of any single chemotherapeutic agent.
聚合物微球可以很容易地注入大脑，以向肿瘤或手术后肿瘤复发率高的周围组织提供局部和持续的化疗药物递送。基于先前的研究，即局部瘤周注射缓释微球具有明显优势，以下实验采用了两种不同方法来最大化荷胶质瘤大鼠的生存获益。在第一个实验中，对先前生长的皮质肿瘤进行减瘤手术，动物接受一次或两次卡铂负载微球治疗（每次治疗卡铂总量为200或800微克）。在每种情况下，微球沿着切除腔的周边注射，每次治疗间隔20天。生存研究清楚地表明，两次时间间隔注射优于单次系列注射。在测试的最低剂量（200微克）下，中位生存期比接受一次治疗的动物增加了40%。在较高剂量（800微克）下，接受两次单独治疗的动物中有三分之一是长期存活者（>150天），组织学检查显示肿瘤完全消除。在第二个实验中，我们直接比较了单独使用缓释卡铂或1,3-双[2-氯乙基]-1-硝基脲（BCNU）与注射混合在一起作为单一悬浮液的卡铂和BCNU负载微球所产生的疗效。卡铂和BCNU都提高了生存率，BCNU的效果明显低于卡铂。然而，当在手术腔周围注射卡铂和BCNU微球的混合悬浮液时，生存率有最大的提高。相比之下，空间交替注射BCNU和卡铂微球的效果明显较差，生存率的提高不超过单独使用BCNU时。这些数据进一步支持了局部缓释化疗微球治疗胶质瘤的潜在效用。此外，它们表明可注射化疗微球可能具有重要优势，即（a）允许根据需要进行多次时间间隔注射，以及（b）提供机会将几种不同有效药物的组合直接递送至肿瘤部位，以提高生存率，超过任何单一化疗药物递送所能达到的效果。
