Slastnikova Tatiana A, Rosenkranz Andrey A, Morozova Natalia B, Vorontsova Maria S, Petriev Vasiliy M, Lupanova Tatiana N, Ulasov Alexey V, Zalutsky Michael R, Yakubovskaya Raisa I, Sobolev Alexander S
Laboratory of Molecular Genetics of Intracellular Transport, Institute of Gene Biology, Russian Academy of Sciences.
Laboratory of Molecular Genetics of Intracellular Transport, Institute of Gene Biology, Russian Academy of Sciences; Department of Biophysics, Biological Faculty, Lomonosov Moscow State University.
Int J Nanomedicine. 2017 Jan 10;12:395-410. doi: 10.2147/IJN.S125359. eCollection 2017.
Modular nanotransporters (MNTs) are a polyfunctional platform designed to achieve receptor-specific delivery of short-range therapeutics into the cell nucleus by receptor-mediated endocytosis, endosome escape, and targeted nuclear transport. This study evaluated the potential utility of the MNT platform in tandem with Auger electron emitting In for cancer therapy.
Three MNTs developed to target either melanocortin receptor-1 (MC1R), folate receptor (FR), or epidermal growth factor receptor (EGFR) that are overexpressed on cancer cells were modified with p-SCN-Bn-NOTA and then labeled with In in high specific activity. Cytotoxicity of the In-labeled MNTs was evaluated on cancer cell lines bearing the appropriate receptor target (FR: HeLa, SK-OV-3; EGFR: A431, U87MG.wtEGFR; and MC1R: B16-F1). In vivo micro-single-photon emission computed tomography/computed tomography imaging and antitumor efficacy studies were performed with intratumoral injection of MC1R-targeted In-labeled MNT in B16-F1 melanoma tumor-bearing mice.
The three NOTA-MNT conjugates were labeled with a specific activity of 2.7 GBq/mg with nearly 100% yield, allowing use without subsequent purification. The cytotoxicity of In delivered by these MNTs was greatly enhanced on receptor-expressing cancer cells compared with In nontargeted control. In mice with B16-F1 tumors, prolonged retention of In by serial imaging and significant tumor growth delay (82% growth inhibition) were found.
The specific in vitro cytotoxicity, prolonged tumor retention, and therapeutic efficacy of MC1R-targeted In-NOTA-MNT suggest that this Auger electron emitting conjugate warrants further evaluation as a locally delivered radiotherapeutic, such as for ocular melanoma brachytherapy. Moreover, the high cytotoxicity observed with FR- and EGFR-targeted In-NOTA-MNT suggests further applications of the MNT delivery strategy should be explored.
模块化纳米转运体（MNTs）是一种多功能平台，旨在通过受体介导的内吞作用、内体逃逸和靶向核转运，实现将短程治疗药物特异性递送至细胞核。本研究评估了MNT平台与俄歇电子发射体铟联用在癌症治疗中的潜在效用。
开发了三种靶向黑色素皮质素受体-1（MC1R）、叶酸受体（FR）或表皮生长因子受体（EGFR）的MNTs，这些受体在癌细胞上过度表达，用对异硫氰酸苄基-氮杂环十二烷四乙酸（p-SCN-Bn-NOTA）进行修饰，然后用高比活度的铟进行标记。在携带相应受体靶点的癌细胞系（FR：HeLa、SK-OV-3；EGFR：A431、U87MG.wtEGFR；MC1R：B16-F1）上评估铟标记的MNTs的细胞毒性。在荷B16-F1黑色素瘤肿瘤的小鼠中，通过瘤内注射MC1R靶向的铟标记MNT进行体内微单光子发射计算机断层扫描/计算机断层扫描成像和抗肿瘤疗效研究。
三种NOTA-MNT缀合物的比活度为2.7 GBq/mg，产率近100%，无需后续纯化即可使用。与非靶向铟对照相比，这些MNTs递送的铟对表达受体的癌细胞的细胞毒性大大增强。在患有B16-F1肿瘤的小鼠中，通过系列成像发现铟的保留时间延长，并且肿瘤生长明显延迟（生长抑制82%）。
MC1R靶向的铟-NOTA-MNT的特异性体外细胞毒性、延长的肿瘤滞留时间和治疗效果表明，这种俄歇电子发射缀合物作为局部递送的放射治疗剂，如用于眼黑色素瘤近距离治疗，值得进一步评估。此外，FR和EGFR靶向的铟-NOTA-MNT观察到的高细胞毒性表明应探索MNT递送策略的进一步应用。
