Interventional Molecular Imaging Laboratory, Department of Radiology, Leiden University Medical Center, 2300 RC Leiden, Netherlands.
Department of Parasitology and Infectious Diseases, Leiden University Medical Center, 2300 RC Leiden, Netherlands.
Bioconjug Chem. 2021 Mar 17;32(3):607-614. doi: 10.1021/acs.bioconjchem.1c00061. Epub 2021 Feb 23.
Cyclodextrin (CD)-based host-guest interactions with adamantane (Ad) have demonstrated use for functionalizing living cells . The next step in this supramolecular functionalization approach is to explore the concept to deliver chemical cargo to living cells , e.g., inoculated bacteria, in order to study their dissemination. We validated this concept in two rodent models. Bacteria (1 × 10 viable ) were inoculated by (1) intramuscular injection or (2) intrasplenic injection followed by dissemination throughout the liver. The bacteria were prefunctionalized with Tc-UBI-Ad (primary vector), which allowed us to both determine the bacterial load and create an target for the secondary host-vector (24 h post-inoculation). The secondary vector, i.e., chemical cargo delivery system, made use of a In-Cy5CDPIBMA polymer that was administered intravenously. Bacteria-specific cargo delivery as a result of vector complexation was evaluated by dual-isotope SPECT imaging and biodistribution studies (In), and by fluorescence (Cy5); these evaluations were performed 4 h post-injection of the secondary vector. Mice inoculated with nonfunctionalized and mice without an infection served as controls. Dual-isotope SPECT imaging demonstrated that In-Cy5CDPIBMA colocalized with Tc-UBI-Ad-labeled bacteria in both muscle and liver. In inoculated muscle, a 2-fold higher uptake level (3.2 ± 1.0%ID/g) was noted compared to inoculation with nonfunctionalized bacteria (1.9 ± 0.4%ID/g), and a 16-fold higher uptake level compared to noninfected muscle (0.2 ± 0.1%ID/g). The hepatic accumulation of the host-vector was nearly 10-fold higher (27.1 ± 11.1%ID/g) compared to the noninfected control (2.7 ± 0.3%ID/g; < 0.05). Fluorescence imaging of the secondary vector corroborated SPECT-imaging and biodistribution findings. We have demonstrated that supramolecular host-guest complexation can be harnessed to achieve an cargo delivery strategy, using two different bacterial models in soft tissue and liver. This proof-of-principle study paves a path toward developing innovative drug delivery concepts via cell functionalization techniques.
环糊精（CD）与金刚烷（Ad）的主体-客体相互作用已被证明可用于对活细胞进行功能化。在这种超分子功能化方法的下一步中，探索将化学货物递送到活细胞（例如接种的细菌）的概念，以便研究它们的传播。我们在两种啮齿动物模型中验证了这一概念。通过（1）肌肉内注射或（2）脾内注射将细菌（1×10 个活菌）接种，然后将其传播到整个肝脏。细菌预先用 Tc-UBI-Ad（主要载体）进行功能化，这使我们能够确定细菌负荷并为二级宿主载体创建一个 目标（接种后 24 小时）。二级载体，即化学货物递送系统，利用静脉内给予的 In-Cy5CDPIBMA 聚合物。通过双同位素 SPECT 成像和生物分布研究（In）以及荧光（Cy5）评估由于载体络合而导致的细菌特异性货物递送；这些评估是在二级载体注射后 4 小时进行的。用未功能化的 和未感染的小鼠作为对照接种的小鼠。双同位素 SPECT 成像显示，In-Cy5CDPIBMA 与 Tc-UBI-Ad 标记的细菌在肌肉和肝脏中均发生共定位。在接种的肌肉中，与接种未功能化细菌（1.9±0.4%ID/g）相比，摄取水平高 2 倍（3.2±1.0%ID/g），与未感染的肌肉相比高 16 倍（0.2±0.1%ID/g）。与未感染的对照（2.7±0.3%ID/g； < 0.05）相比，载体的肝积累高近 10 倍（27.1±11.1%ID/g）。二级载体的荧光成像证实了 SPECT 成像和生物分布的结果。我们已经证明，超分子主体-客体络合可以被利用来实现 货物递送策略，使用两种不同的软组织和肝脏细菌模型。这项初步研究为通过细胞功能化技术开发创新药物递送概念铺平了道路。
