NanoFerrite particle based radioimmunonanoparticles: Binding affinity and in vivo pharmacokinetics
NanoFerrite particle based radioimmunonanoparticles: Binding affinity and in vivo pharmacokinetics
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DOI：
10.1021/bc800015n
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发表时间：
2008-06-01
影响因子：
4.7
通讯作者：
DeNardo, S. J.
中科院分区：
文献类型：
--
作者：
Natarajan, A.;Gruettner, C.;DeNardo, S. J.
葡聚糖和PEG包被的氧化铁纳米颗粒（NP），当被适当修饰以能够与分子靶向剂缀合时，提供靶向癌细胞的机会。已经报道了与20 nm NP缀合的单克隆抗体、scFv和肽靶向癌症用于成像和交变磁场（AMF）治疗。纳米颗粒的物理特性会影响其在体内的性能。表面形态、表面电荷密度和粒度被认为是决定药代动力学、毒性和生物分布的重要因素。研究了具有改进的特定AMF吸收率和30和100 nm直径的新纳米铁氧体（NF）颗粒，以评估与先前研究的20 nm超顺磁性氧化铁（SPIO）NP相比其体外和体内特性的变化。将SPIO NP 20 nm和NF NP 30和100 nm与In-111-DOTA-ChL 6（放射免疫缀合物）缀合。通过碳二亚胺化学，使用25 μ g RIC/mg NP将放射免疫缀合物缀合至NP。放射免疫纳米颗粒（RINP）进行纯化，其特征在于聚丙烯酰胺凝胶电泳，醋酸纤维素电泳（CAE），活细胞结合试验，并在无胸腺小鼠荷人乳腺癌（HBT 3477）异种移植物的药代动力学。静脉注射和全身注射RINP（2.2 mg）;在4、24和48 h采集血液和组织数据。通过PAGE和CAE，用于动物研究的制剂>90%为单体。与In-111-ChL 6相比，RINP的免疫反应性为40-60%。剂量的比活性为20-25 μ Ci/2.2 ml和6-11 μ g mAb/2.2 mg NP。平均肿瘤摄取48 h时，SPIO 20 nm、NF 30 nm和100 nm RINP各自的（% ID/g +/- SD）分别为9.00 +/- 0.8（20 nm）、3.0 +/- 0.3（30 nm）和4.5 +/- 0.8（100 nm）;组织摄取的范围是肝（16-32 +/-1-8）、肾（7.0-15 +/-1）、脾（8-17 +/-3-8）、淋巴结（5-6 +/-1-2）和肺（2.0-4 +/-0.1-2）。总之，本研究表明，100 nm NF NP可以与In-111-mAb偶联，因此所得RINP具有适合AMF治疗的特性。尽管100 nm RINP靶向的肿瘤小于20 nm SPIO RINP，但它们的加热能力通常是20 nm SPIO RINP的6倍，这表明100 nm NF RINP仍然可以用AMF提供更好的治疗。
Dextran and PEG-coated iron oxide nanoparticles (NP), when suitably modified to enable conjugation with molecular targeting agents, provide opportunities to target cancer cells. Monoclonal antibodies, scFv, and peptides conjugated to 20 nm NP have been reported to target cancer for imaging and alternating magnetic field (AMF) therapy. The physical characteristics of NPs can affect their in vivo performance. Surface morphology, surface charge density, and particle size are considered important factors that determine pharmacokinetics, toxicity, and biodistribution. New NanoFerrite (NF) particles having improved specific AMF absorption rates and diameters of 30 and 100 nm were studied to evaluate the variation in their in vitro and in vivo characteristics in comparison to the previously studied 20 nm superparamagnetic iron oxide (SPIO) NP. SPIO NP 20 nm and NF NP 30 and 100 rim were conjugated to In-111-DOTA-ChL6, a radioirnmunoconjugate. Radioimmunoconjugates were conjugated to NPs using 25 mu g of RIC/mg of NP by carbodiimide chemistry. The radioimmunonanoparticles (RINP) were purified and characterized by PAGE, cellulose acetate electrophoresis (CAE), live cell binding assays, and pharmacokinetics in athymic mice bearing human breast cancer (HBT 3477) xenografts. RINP (2.2 mg) were injected iv and whole body; blood and tissue data were collected at 4, 24, and 48 h. The preparations used for animal Study were >90% monomeric by PAGE and CAE. The immunoreactivity of the RINP was 40-60% compared to In-111-ChL6. Specific activities of the doses were 20-25 mu Ci/2.2 m I and 6-11 mu g of mAb/2.2 mg of NP. Mean tumor uptakes (% ID/g +/- SD) of each SPIO 20 nm, NF 30 nm, and 100 nm RINP at 48 h were 9.00 +/- 0.8 (20 nm), 3.0 +/- 0.3 (30 nm), and 4.5 +/- 0.8 (100 rim), respectively; the ranges of tissue uptakes were liver (16-32 +/- 1-8), kidney (7.0-15 +/- 1), spleen (8-17 +/- 3-8), lymph nodes 5-6 +/- 1-2), and lung (2.0-4 +/- 0.1-2). In conclusion, this study demonstrated that 100 nm NF NP could be conjugated to In-111-mAb so that the resulting RINP had characteristics suitable for AMF therapy. Although, 100 nm RINP targeted tumor less than 20 nm SPIO RINP, their heating capacity is typically 6 times greater, suggesting the 100 nm NF RINP could still deliver better therapy with AMF.