State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, People's Republic of China.
Department of Radiology, Shanghai Songjiang District Central Hospital, Shanghai 201600, People's Republic of China.
Biomacromolecules. 2021 May 10;22(5):2181-2188. doi: 10.1021/acs.biomac.1c00262. Epub 2021 Apr 13.
Development of nanoplatforms that can amplify the passive tumor targeting effect based on enhanced permeability and retention (EPR) effect is crucial for precision cancer nanomedicine applications. Herein, we present the development of core-shell tecto dendrimers (CSTDs) as a platform for enhanced tumor magnetic resonance (MR) imaging through an amplified EPR effect. In this work, poly(amidoamine) (PAMAM) dendrimers of generation 5 (G5) were decorated with β-cyclodextrin (CD) and then assembled with G3 PAMAM dendrimers premodified with adamantane (Ad) via supramolecular recognition of CD and Ad. The formed G5-CD/Ad-G3 CSTDs were conjugated with tetraazacyclododecane tetraacetic acid (DOTA)-Gd(III) chelators and further acetylated to neutralize the remaining CSTD periphery amines. We reveal that the formed CSTD.NHAc-DOTA(Gd) (CSTD-D-Gd) complexes have a narrow size distribution and satisfactory colloidal stability, and are cytocompatible within the concentration range studied. Compared to the single dendrimer counterpart of G5.NHAc-DOTA(Gd) (G5-D-Gd) complexes, the CSTD-D-Gd complexes with a higher molecular weight and volume possess a longer rotation correlation time, hence having a longitudinal relaxivity () of 7.34 mM s, which is 1.5 times larger than that of G5-D-Gd complexes (4.92 mM s). More importantly, the CSTD-D-Gd complexes display better permeability in the three-dimensional (3D) cell spheroids through fluorescence imaging and a more significant EPR effect for improved tumor MR imaging than the G5-DOTA-Gd complexes. The generated CSTD-D-Gd complexes may be adopted for enhanced tumor MR imaging through an amplified passive EPR effect and also be further extended for different cancer theranostic applications.
基于增强的通透性和保留（EPR）效应的被动肿瘤靶向效果的纳米平台的发展对于精准癌症纳米医学的应用至关重要。在此，我们提出了一种基于超分子识别的核壳状树枝状大分子（CSTDs）作为通过放大 EPR 效应增强肿瘤磁共振（MR）成像的平台的发展。在这项工作中，用β-环糊精（CD）修饰了第五代（G5）聚酰胺胺（PAMAM）树枝状大分子，然后通过 CD 和金刚烷（Ad）的超分子识别与预先用 Ad 修饰的 G3 PAMAM 树枝状大分子组装。形成的 G5-CD/Ad-G3 CSTDs 与四氮杂环十二烷四乙酸（DOTA）-Gd（III）螯合剂偶联，并进一步乙酰化以中和 CSTD 外围剩余的胺。我们发现形成的 CSTD.NHAc-DOTA（Gd）（CSTD-D-Gd）复合物具有较窄的粒径分布和良好的胶体稳定性，并且在研究浓度范围内具有细胞相容性。与单树枝大分子对照物 G5.NHAc-DOTA（Gd）（G5-D-Gd）复合物相比，具有更高分子量和体积的 CSTD-D-Gd 复合物具有更长的旋转相关时间，因此具有更长的纵向弛豫率（）为 7.34 mM s，是 G5-D-Gd 复合物（4.92 mM s）的 1.5 倍。更重要的是，CSTD-D-Gd 复合物通过荧光成像在三维（3D）细胞球体中显示出更好的通透性，并且通过增强的 EPR 效应改善了肿瘤的 MR 成像，优于 G5-DOTA-Gd 复合物。生成的 CSTD-D-Gd 复合物可通过放大的被动 EPR 效应用于增强肿瘤 MR 成像，并且还可进一步扩展用于不同的癌症治疗应用。
