Ning S, Trisler K, Brown D M, Yu N Y, Kanekal S, Lundsten M J, Knox S J
Department of Radiation Oncology, Stanford University Medical Center, CA 94305-5105, USA.
Radiother Oncol. 1996 May;39(2):179-89. doi: 10.1016/0167-8140(96)01718-5.
Low tumor uptake and normal tissue toxicity limit the efficacy of RIT for the treatment of solid tumors. In this study, an intratumoral injectable gel drug delivery system for local administration of RIT was evaluated using the LS174T human colon cancer xenograft model in SCID mice. The injectable gel is a collagen-based drug delivery system designed for intratumoral (i.t.) administration, which has previously been shown to enhance drug retention at the injection site and reduce systemic drug exposure. We compared the local (tumor) retention and biodistribution of 111In-labeled NR-LU-10 monoclonal antibody given i.t. in the injectable gel versus simple aqueous solution. 111In gel given i.t. and 111In-NR-LU-10 given intraperitoneally (i.p.) were used as controls. The results showed that tumors treated with 111In-NR-LU-10 gel maintained the highest levels of radioactivity for up to 96 h. At 48 h after the administration of 111In-NR-LU-10 gel i.t., 111In-NR-LU-10 solution i.t., 111In gel i.t., or 111In-NR-LU-10 i.p., the level of radioactivity remaining in each gram of tumor was 98, 49, 45, and 16% of the injected dose, respectively. It was estimated that if 100 microCi of 90Y-NR-LU-10 were administered similarly, tumor treated with 90Y-NR-LU-10 gel i.t. would receive a dose of 90.0 Gy, whereas normal tissues in the same animal would receive a dose of approximately 2.43 Gy. In contrast, if 90Y-NR-LU-10 were delivered i.p., a comparable tumor would receive a dose of 16.8 Gy and corresponding normal tissues would receive 3.36 Gy. Consistent with these estimates, enhanced antitumor efficacy was observed when 90Y-NR-LU-10 gel was administered i.t. Tumor growth delay time was 6.9-fold (P < 0.01) longer in these animals (14.4 days) than in animals treated with 90Y-NR-LU-10 i.p. (2.1 days). Systemic toxicity was also significantly reduced in gel-treated animals as monitored by loss of body weight. This study demonstrated that intratumoral delivery of 90Y-NR-LU-10 gel markedly increased the retention of the radioisotope in tumors, enhanced the antitumor efficacy, and reduced systemic toxicity compared to systemic administration of the radiolabeled antibody. This injectable gel drug delivery system may allow for improvement in the therapeutic index for RIT.
肿瘤摄取率低和正常组织毒性限制了放射性免疫疗法（RIT）治疗实体瘤的疗效。在本研究中，使用SCID小鼠的LS174T人结肠癌异种移植模型，对用于局部给药RIT的瘤内注射凝胶药物递送系统进行了评估。该可注射凝胶是一种基于胶原蛋白的药物递送系统，设计用于瘤内（i.t.）给药，此前已证明其可增强药物在注射部位的保留并减少全身药物暴露。我们比较了瘤内注射可注射凝胶与简单水溶液中给予的111In标记的NR-LU-10单克隆抗体的局部（肿瘤）保留和生物分布。瘤内注射111In凝胶和腹腔内（i.p.）注射111In-NR-LU-10用作对照。结果显示，用111In-NR-LU-10凝胶治疗的肿瘤在长达96小时内保持最高放射性水平。在瘤内注射111In-NR-LU-10凝胶、瘤内注射111In-NR-LU-10溶液、瘤内注射111In凝胶或腹腔内注射111In-NR-LU-10后48小时，每克肿瘤中剩余的放射性水平分别为注射剂量的98%、49%、45%和16%。据估计，如果以类似方式给予100微居里的90Y-NR-LU-10，瘤内注射90Y-NR-LU-10凝胶治疗的肿瘤将接受90.0戈瑞的剂量，而同一动物的正常组织将接受约2.43戈瑞的剂量。相比之下，如果腹腔内递送90Y-NR-LU-10，类似的肿瘤将接受16.8戈瑞的剂量，相应的正常组织将接受3.36戈瑞的剂量。与这些估计一致，当瘤内注射90Y-NR-LU-10凝胶时观察到抗肿瘤疗效增强。这些动物的肿瘤生长延迟时间（14.4天）比腹腔内注射90Y-NR-LU-10治疗的动物（2.1天）长6.9倍（P < 0.01）。通过体重减轻监测发现，凝胶治疗动物的全身毒性也显著降低。本研究表明，与放射性标记抗体的全身给药相比，瘤内递送90Y-NR-LU-10凝胶显著增加了放射性同位素在肿瘤中的保留，增强了抗肿瘤疗效，并降低了全身毒性。这种可注射凝胶药物递送系统可能会提高RIT的治疗指数。
