Convection enhanced delivery of boronated EGF as a molecular targeting agent for neutron capture therapy of brain tumors.
Convection enhanced delivery of boronated EGF as a molecular targeting agent for neutron capture therapy of brain tumors.
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对流增强硼化 EGF 的递送，作为脑肿瘤中子捕获治疗的分子靶向剂。
DOI：
10.1007/s11060-009-9945-x
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发表时间：
2009
影响因子：
3.9
通讯作者：
Binns,PeterJ
中科院分区：
文献类型：
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作者：
Yang,Weilian;Barth,RolfF;Wu,Gong;Huo,Tianyao;Tjarks,Werner;Ciesielski,Michael;Fenstermaker,RobertA;Ross,BrainD;Wikstrand,CarolJ;Riley,KentJ;Binns,PeterJ
在本研究中，我们评价了一种硼化树状大分子-表皮生长因子(BD-EGF)生物结合物作为分子靶向药物对人EGFR基因转基因的F98大鼠脑胶质瘤F98EGFR进行硼中子俘获治疗(BNCT)。通过异双功能试剂mMBS，将EGF与重硼聚酰胺胺树枝状大分子(BD)进行化学偶联。在肿瘤内(I.T.)后6小时和24小时进行生物分布研究。注射或脑内注射(I.C.)对流增强递送125I标记或未标记的BD-EGF(40μg10B/10μg EGF)给F98胶质瘤荷瘤大鼠。在24小时，与I.T.相比，CED后EGFR(+)肿瘤的放射性增加了43%。注射，并将肿瘤硼浓度翻一番(22.3万μg/g对11.7亿μg/g)。注射BD-EGF后，BD-EGF在脑内的分布体积增加了7.2倍，肿瘤摄取增加了1.9倍。注射。基于这些有利的生物分布数据，在I.C.之后14天，在麻省理工学院核反应堆进行了BNCT。BD-EGF CED后24小时。这些动物的MST为54.1±44.7天，而I.T.后为43.0±22.8天。注射。CED联合静脉注射BD-EGF的大鼠。已在实验和临床研究中使用的硼苯丙氨酸(BPA)的MST为86.0±228.1天，而静脉注射的MST为39.8±11.6天。单纯双酚A(P<；0.0001)，照射对照组30.9±11.4天，未治疗对照组25.10±11.0天(P<；总体)。这些数据表明，与注射BD-EGF相比，BNCT的疗效显著提高(P<；0.006)，并且存活数据与我们先前报道的使用硼化抗人EGF单抗C225(西妥昔单抗)的数据相当。
In the present study, we have evaluated a boronated dendrimer-epidermal growth factor (BD-EGF) bioconjugate as a molecular targeting agent for boron neutron capture therapy (BNCT) of the human EGFR gene-transfected F98 rat glioma, designated F98EGFR. EGF was chemically linked to a heavily boronated polyamidoamine dendrimer (BD) by means of the heterobifunctional reagent, mMBS. Biodistribution studies were carried out at 6 h and 24 h following intratumoral (i.t.) injection or intracerebral (i.c.) convection enhanced delivery (CED) of125I-labeled or unlabeled BD-EGF (40 μg10B/10 μg EGF) to F98 glioma bearing rats. At 24 h. there was 43% more radioactivity in EGFR(+) tumors following CED compared to i.t. injection, and a doubling of the tumor boron concentration (22.3 μg/g vs. 11.7 μg/g). CED of BD-EGF resulted in a 7.2× increase in the volume of distribution within the infused cerebral hemisphere and a 1.9× increase in tumor uptake of BD-EGF compared with i.t. injection. Based on these favorable biodistribution data, BNCT was carried out at the Massachusetts Institute of Technology nuclear reactor 14 days following i.c. tumor implantation and 24 h. after CED of BD-EGF. These animals had a MST of 54.1 ± 4.7 days compared to 43.0 ± 2.8 days following i.t. injection. Rats that received BD-EGF by CED in combination with i.v. boronophenylalanine (BPA), which has been used in both experimental and clinical studies, had a MST of 86.0 ± 28.1 days compared to 39.8 ± 1.6 days for i.v. BPA alone (P< 0.01), 30.9 ± 1.4 days for irradiated controls and 25.1 ± 1.0 days for untreated controls (overallP< 0.0001). These data have demonstrated that the efficacy of BNCT was significantly increased (P< 0.006), following i.c CED of BD-EGF compared to i.t injection, and that the survival data were equivalent to those previously reported by us using the boronated anti-human-EGF mAb, C225 (cetuximab).