Injectable intratumoral depot of thermally responsive polypeptide-radionuclide conjugates delays tumor progression in a mouse model.
Injectable intratumoral depot of thermally responsive polypeptide-radionuclide conjugates delays tumor progression in a mouse model.
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DOI：
10.1016/j.jconrel.2010.01.032
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发表时间：
2010-05-21
影响因子：
10.8
通讯作者：
Chilkoti, Ashutosh
中科院分区：
文献类型：
--
作者：
Liu, Wenge;MacKay, J. Andrew;Dreher, Matthew R.;Chen, Mingnan;McDaniel, Jonathan R.;Simnick, Andrew J.;Callahan, Daniel J.;Zalutsky, Michael R.;Chilkoti, Ashutosh
关键词：
本研究评价了一种用于局部癌症放射治疗的生物可降解药物递送系统，该系统由热敏弹性蛋白样多肽（ELP）与治疗性放射性核素缀合组成。使用基因工程合成了两种ELP（49 kD），以测试可注射生物聚合物仓库可以局部保留放射性核素并减少肿瘤生长的假设。一种热敏性多肽，ELP1，被设计成在瘤内注射时在室温和体温之间自发地经历可溶性-不溶性相变（形成粘性微粒），而ELP2被设计成在注射时保持可溶性并用作聚集体组装效应的阴性对照。将ELP的放射性核素缀合物瘤内施用到裸鼠中的植入的肿瘤异种移植物中后，量化它们在肿瘤内的保留、时空分布和治疗效果。放射性核素-ELP 1在肿瘤中的停留时间显著长于热不敏感的ELP 2缀合物。此外，ELP1的热转变显着保护共轭放射性核素脱卤，而ELP2上的共轭放射性核素迅速从肿瘤中消除，并从生物聚合物中裂解。与可溶性ELP2对照相比，热敏性ELP1贮库的这些属性改善了碘-131的抗肿瘤功效。这种新型的可注射和可生物降解的贮库具有通过减少不可手术肿瘤的体积来控制晚期癌症的潜力，能够手术切除去体积肿瘤并保留健康组织。
This study evaluated a biodegradable drug delivery system for local cancer radiotherapy consisting of a thermally sensitive elastin-like polypeptide (ELP) conjugated to a therapeutic radionuclide. Two ELPs (49 kD) were synthesized using genetic engineering to test the hypothesis that injectable biopolymeric depots can retain radionuclides locally and reduce the growth of tumors. A thermally sensitive polypeptide, ELP1, was designed to spontaneously undergo a soluble-insoluble phase transition (forming viscous microparticles) between room temperature and body temperature upon intratumoral injection, while ELP2 was designed to remain soluble upon injection and to serve as a negative control for the effect of aggregate assembly. After intratumoral administration of radionuclide conjugates of ELPs into implanted tumor xenografts in nude mice, their retention within the tumor, spatio-temporal distribution, and therapeutic effect were quantified. The residence time of the radionuclide-ELP1 in the tumor was significantly longer than the thermally insensitive ELP2 conjugate. In addition, the thermal transition of ELP1 significantly protected the conjugated radionuclide from dehalogenation, whereas the conjugated radionuclide on ELP2 was quickly eliminated from the tumor and cleaved from the biopolymer. These attributes of the thermally sensitive ELP1 depot improved the antitumor efficacy of iodine-131 compared to the soluble ELP2 control. This novel injectable and biodegradable depot has the potential to control advanced-stage cancers by reducing the bulk of inoperable tumors, enabling surgical removal of de-bulked tumors, and preserving healthy tissues.
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影响因子：
5.3
作者：
Celikoglu, F;Celikoglu, SI;Goldberg, EP
通讯作者：
Goldberg, EP
影响因子：
4.6
作者：
Hruby, Martin;Konak, Cestmir;Ulbrich, Karel
通讯作者：
Ulbrich, Karel
影响因子：
10.3
作者：
Dreher, MR;Liu, WG;Chilkoti, A
通讯作者：
Chilkoti, A
DOI：
10.1073/pnas.91.6.2076
发表时间：
1994-03-15
影响因子：
11.1
作者：
BOBO, RH;LASKE, DW;OLDFIELD, EH
通讯作者：
OLDFIELD, EH
影响因子：
3.5
作者：
Grossman, TH;Kawasaki, ES;Osburne, MS
通讯作者：
Osburne, MS