New Jersey Center for Biomaterials and Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, 145 Bevier Road, Piscataway, NJ 08854, USA.
J Control Release. 2013 Nov 10;171(3):315-21. doi: 10.1016/j.jconrel.2013.06.017. Epub 2013 Jun 20.
Targeted delivery of anti-cancer agents to cancer cells is a mature line of investigation that has yet to realize its full potential. In this study we report on the development of a delivery platform with the future goal of merging two thus far parallel methods for selective elimination of cancer cells: targeted nanospheres and pretargeted radioimmunotherapy. Several clinical trials have shown the promise of pretargeted radioimmunotherapy, which leverages the specificity of antibodies for targeted cell populations and delivers a localized dose of a biotinylated radionuclide that is most often administered following binding of a biotinylated antibody and streptavidin (StA) to the target cells. The work presented here describes the development of biotinylated nanospheres based on an ABA-type copolymer comprised of a tyrosine-derived oligomer as the B-block and poly(ethylene glycol) (PEG) A-blocks. The biotinylated nanospheres encapsulate paclitaxel (PTX) to the same extent as unbiotinylated nanospheres. Efficacy of targeting was shown on CD44 positive cells in the SUM159 breast cancer cell line by incubating the cells sequentially with a biotinylated anti-CD44 antibody, StA and the biotinylated nanospheres encapsulating PTX. Targeted nanospheres achieved the half maximal inhibitory concentration of PTX on SUM159 cells at a 5-10 fold lower concentration than that of PTX applied in either non-targeted nanospheres or free drug approaches. Moreover, targeted nanospheres selectively eliminated CD44 positive SUM159 cells compared to free PTX and untargeted nanospheres. This new generation of nano-sized carrier offers a versatile platform that can be adopted for a wide variety of drug and target specific applications and has the potential to be combined with the clinically emerging method of pretargeted radioimmunotherapy.
将抗癌药物靶向递送至癌细胞是一条成熟的研究路线，但尚未充分发挥其潜力。在这项研究中，我们报告了一种递药平台的开发，其未来目标是合并两种迄今平行的选择性消除癌细胞的方法：靶向纳米球和预靶向放射免疫疗法。几项临床试验表明，预靶向放射免疫疗法具有广阔的应用前景，该疗法利用抗体对靶向细胞群的特异性，并递送至生物素化放射性核素的局部剂量，通常在生物素化抗体与链霉亲和素（StA）结合至靶细胞后给予。这里描述的工作是基于由酪氨酸衍生的低聚物作为 B 嵌段和聚乙二醇（PEG）A 嵌段组成的 ABA 型嵌段共聚物开发的生物素化纳米球。与非生物素化纳米球相比，生物素化纳米球同样可以包封紫杉醇（PTX）。通过依次用生物素化抗 CD44 抗体、StA 和包封 PTX 的生物素化纳米球孵育 CD44 阳性细胞，在 SUM159 乳腺癌细胞系中证明了靶向作用的效果。与非靶向纳米球或游离药物方法相比，靶向纳米球在 CD44 阳性 SUM159 细胞上达到 PTX 的半最大抑制浓度所需的浓度低 5-10 倍。此外，与游离 PTX 和非靶向纳米球相比，靶向纳米球选择性地消除了 CD44 阳性 SUM159 细胞。这种新一代纳米载体提供了一种多功能平台，可用于广泛的药物和靶向特异性应用，并且具有与临床新兴的预靶向放射免疫疗法相结合的潜力。
