Abstract:
A pretargeted strategy that decouples targeting vectors from radionuclides has shown promise for nuclear imaging and/or therapy in vivo. However, the current pretargeted approach relies on the use of antibodies or nanoparticles as the targeting vectors, which may be compromised by poor tissue penetration and limited accumulation of targeting vectors in the tumor tissues. Herein, we present an orthogonal dual-pretargeted approach by combining stimuli-triggered in situ self-assembly strategy with fast inverse electron demand Diels-Alder (IEDDA) reaction and strong biotin-streptavidin (SA) interaction for near-infrared fluorescence (NIR FL) and magnetic resonance (MR) imaging of tumors. This approach uses a small-molecule probe (P-Cy-TCO&Bio) containing both biotin and trans-cyclooctene (TCO) as a tumor-targeting vector. P-Cy-TCO&Bio can efficiently penetrate subcutaneous HeLa tumors through biotin-assisted targeted delivery and undergo in situ self-assembly to form biotinylated TCO-bearing nanoparticles (Cy-TCO&Bio NPs) on tumor cell membranes. Cy-TCO&Bio NPs exhibited an \"off-on\" NIR FL and retained in the tumors, offering a high density of TCO and biotin groups for the concurrent capture of Gd-chelate-labeled tetrazine (Tz-Gd) and IR780-labeled SA (SA-780) via the orthogonal IEDDA reaction and SA-biotin interaction. Moreover, Cy-TCO&Bio NPs offered multiple-valent binding modes toward SA, which additionally regulated the cross-linking of Cy-Gd&Bio NPs into microparticles (Cy-Gd&Bio/SA MPs). This process could significantly (1) increase r1 relaxivity and (2) enhance the accumulation of Tz-Gd and SA-780 in the tumors, resulting in strong NIR FL, bright MR contrast, and an extended time window for the clear and precise imaging of HeLa tumors.
摘要:
将靶向载体与放射性核素分离的预靶向策略已显示出用于体内核成像和/或治疗的希望。然而,当前的预靶向方法依赖于使用抗体或纳米颗粒作为靶向载体,这可能会受到不良的组织穿透性和靶向载体在肿瘤组织中的有限积累的损害。在这里,我们通过将刺激触发的原位自组装策略与快速反电子需求DiDDA(IEDDA)反应和强生物素-链霉亲和素(SA)相互作用相结合,提出了一种正交双预靶向方法,用于肿瘤的近红外荧光(NIRFL)和磁共振(MR)成像。该方法使用含有生物素和反式环辛烯(TCO)的小分子探针(P-Cy-TCO&Bio)作为肿瘤靶向载体。P-Cy-TCO&Bio可通过生物素辅助靶向递送有效穿透皮下HeLa肿瘤,并进行原位自组装,在肿瘤细胞膜上形成含生物素化TCO的纳米颗粒(Cy-TCO&BioNP)。Cy-TCO&BioNPs表现出“非开启”NIRFL并保留在肿瘤中,通过正交IEDDA反应和SA-生物素相互作用,提供高密度的TCO和生物素基团,用于同时捕获Gd螯合物标记的四嗪(Tz-Gd)和IR780标记的SA(SA-780)。此外,Cy-TCO和BioNP为SA提供了多价结合模式,其另外调节Cy-Gd&BioNP交联成微粒(Cy-Gd&Bio/SAMPs)。此过程可以显着(1)增加r1弛豫率和(2)增强Tz-Gd和SA-780在肿瘤中的积累,导致强烈的NIRFL,明亮的MR对比,和一个延长的时间窗口为HeLa肿瘤的清晰和精确的成像。