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Cyclodextrin/Adamantane-Mediated Targeting of Inoculated Bacteria in Mice
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2021-02-23 , DOI: 10.1021/acs.bioconjchem.1c00061 Mick M Welling 1 , Nikolas Duszenko 1, 2 , Danny M van Willigen 1 , Wiep Klaas Smits 3 , Tessa Buckle 1 , Meta Roestenberg 2 , Fijs W B van Leeuwen 1
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2021-02-23 , DOI: 10.1021/acs.bioconjchem.1c00061 Mick M Welling 1 , Nikolas Duszenko 1, 2 , Danny M van Willigen 1 , Wiep Klaas Smits 3 , Tessa Buckle 1 , Meta Roestenberg 2 , Fijs W B van Leeuwen 1
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Cyclodextrin (CD)-based host–guest interactions with adamantane (Ad) have demonstrated use for functionalizing living cells in vitro. The next step in this supramolecular functionalization approach is to explore the concept to deliver chemical cargo to living cells in vivo, e.g., inoculated bacteria, in order to study their dissemination. We validated this concept in two rodent Staphylococcus aureus models. Bacteria (1 × 108 viable S. aureus) were inoculated by (1) intramuscular injection or (2) intrasplenic injection followed by dissemination throughout the liver. The bacteria were prefunctionalized with 99mTc-UBI29–41-Ad2 (primary vector), which allowed us to both determine the bacterial load and create an in vivo target for the secondary host-vector (24 h post-inoculation). The secondary vector, i.e., chemical cargo delivery system, made use of a 111In-Cy50.5CD9PIBMA39 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 (111In), and by fluorescence (Cy5); these evaluations were performed 4 h post-injection of the secondary vector. Mice inoculated with nonfunctionalized S. aureus and mice without an infection served as controls. Dual-isotope SPECT imaging demonstrated that 111In-Cy50.5CD9PIBMA39 colocalized with 99mTc-UBI29–41-Ad2-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; p < 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 in vivo 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.
中文翻译：
环糊精/金刚烷介导的小鼠接种细菌靶向
基于环糊精 (CD) 的宿主-客体与金刚烷 (Ad) 的相互作用已证明可用于体外功能化活细胞。这种超分子功能化方法的下一步是探索将化学物质输送到体内活细胞（例如接种的细菌）的概念，以研究它们的传播。我们在两个啮齿动物金黄色葡萄球菌模型中验证了这个概念。细菌（1 × 10 8 个活的金黄色葡萄球菌）通过（1）肌肉注射或（2）脾内注射接种，然后传播到整个肝脏。细菌用99m Tc-UBI 29-41 -Ad 2预功能化（初级载体），这使我们能够确定细菌负荷并为次级宿主载体（接种后 24 小时）创建体内靶标。二级载体，即化学货物递送系统，使用静脉内施用的111 In-Cy5 0.5 CD 9 PIBMA 39聚合物。通过双同位素 SPECT 成像和生物分布研究 ( 111 In) 和荧光 (Cy5)评估作为载体复合结果的细菌特异性货物递送；这些评估是在注射二级载体后 4 小时进行的。接种非功能化金黄色葡萄球菌的小鼠没有感染的小鼠作为对照。双同位素 SPECT 成像表明111 In-Cy5 0.5 CD 9 PIBMA 39与肌肉和肝脏中的99m Tc-UBI 29–41 -Ad 2标记细菌共定位。在接种的肌肉中，与接种非功能化细菌 (1.9 ± 0.4%ID/g) 相比，注意到摄取水平高 2 倍 (3.2 ± 1.0%ID/g)，与未感染肌肉相比，摄取水平高 16 倍(0.2 ± 0.1% ID/g)。与未感染的对照 (2.7 ± 0.3% ID/g; p< 0.05)。次级载体的荧光成像证实了 SPECT 成像和生物分布的发现。我们已经证明，在软组织和肝脏中使用两种不同的细菌模型，可以利用超分子宿主 - 客体复合来实现体内货物递送策略。这项原理验证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。
更新日期：2021-03-17
中文翻译：
环糊精/金刚烷介导的小鼠接种细菌靶向
基于环糊精 (CD) 的宿主-客体与金刚烷 (Ad) 的相互作用已证明可用于体外功能化活细胞。这种超分子功能化方法的下一步是探索将化学物质输送到体内活细胞（例如接种的细菌）的概念，以研究它们的传播。我们在两个啮齿动物金黄色葡萄球菌模型中验证了这个概念。细菌（1 × 10 8 个活的金黄色葡萄球菌）通过（1）肌肉注射或（2）脾内注射接种，然后传播到整个肝脏。细菌用99m Tc-UBI 29-41 -Ad 2预功能化（初级载体），这使我们能够确定细菌负荷并为次级宿主载体（接种后 24 小时）创建体内靶标。二级载体，即化学货物递送系统，使用静脉内施用的111 In-Cy5 0.5 CD 9 PIBMA 39聚合物。通过双同位素 SPECT 成像和生物分布研究 ( 111 In) 和荧光 (Cy5)评估作为载体复合结果的细菌特异性货物递送；这些评估是在注射二级载体后 4 小时进行的。接种非功能化金黄色葡萄球菌的小鼠没有感染的小鼠作为对照。双同位素 SPECT 成像表明111 In-Cy5 0.5 CD 9 PIBMA 39与肌肉和肝脏中的99m Tc-UBI 29–41 -Ad 2标记细菌共定位。在接种的肌肉中，与接种非功能化细菌 (1.9 ± 0.4%ID/g) 相比，注意到摄取水平高 2 倍 (3.2 ± 1.0%ID/g)，与未感染肌肉相比，摄取水平高 16 倍(0.2 ± 0.1% ID/g)。与未感染的对照 (2.7 ± 0.3% ID/g; p< 0.05)。次级载体的荧光成像证实了 SPECT 成像和生物分布的发现。我们已经证明，在软组织和肝脏中使用两种不同的细菌模型，可以利用超分子宿主 - 客体复合来实现体内货物递送策略。这项原理验证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。
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