N. M. Emanuel Institute of Biochemical Physics of Russian Academy of Sciences, 119334 Moscow, Russia.
Department of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia.
Int J Mol Sci. 2022 Mar 14;23(6):3119. doi: 10.3390/ijms23063119.
The conventional targeted delivery of chemotherapeutic and diagnostic agents utilizing nanocarriers is a promising approach for cancer theranostics. Unfortunately, this approach often faces hindered tumor access that decreases the therapeutic index and limits the further clinical translation of a developing drug. Here, we demonstrated a strategy of simultaneously double-targeting the drug to two distinct cites of tumor tissue: the tumor endothelium and cell surface receptors. We used fourth-generation polyamideamine dendrimers modified with a chelated Gd and functionalized with selectin ligand and alpha-fetoprotein receptor-binding peptide. According to the proposed strategy, IELLQAR peptide promotes the conjugate recruitment to the tumor inflammatory microenvironment and enhances extravasation through the interaction of nanodevice with P- and E-selectins expressed by endothelial cells. The second target moiety-alpha-fetoprotein receptor-binding peptide-enhances drug internalization into cancer cells and the intratumoral retention of the conjugate. The final conjugate contained 18 chelated Gd ions per dendrimer, characterized with a 32 nm size and a negative surface charge of around 18 mV. In vitro contrasting properties were comparable with commercially available Gd-chelate: r1 relaxivity was 3.39 for Magnevist and 3.11 for conjugate; r2 relaxivity was 5.12 for Magnevist and 4.81 for conjugate. By utilizing this dual targeting strategy, we demonstrated the increment of intratumoral accumulation, and a remarkable enhancement of antitumor effect, resulting in high-level synergy compared to monotargeted conjugates. In summary, the proposed strategy utilizing tumor tissue double-targeting may contribute to an enhancement in drug and diagnostic accumulation in aggressive tumors.
利用纳米载体对化疗药物和诊断剂进行常规靶向递送是癌症治疗学的一种有前途的方法。不幸的是，这种方法常常面临肿瘤进入受阻的问题，这降低了治疗指数，并限制了正在开发的药物的进一步临床转化。在这里，我们展示了一种将药物同时靶向肿瘤组织两个不同部位的策略：肿瘤内皮细胞和细胞表面受体。我们使用第四代聚酰胺胺树枝状聚合物进行修饰，使其螯合 Gd，并与选择素配体和甲胎蛋白受体结合肽功能化。根据提出的策略，IELLQAR 肽促进了与肿瘤炎症微环境的共轭物募集，并通过纳米器件与内皮细胞表达的 P-和 E-选择素相互作用增强了外渗。第二个靶向部分-甲胎蛋白受体结合肽增强了药物进入癌细胞和共轭物在肿瘤内的保留。最终的共轭物每个树枝状聚合物含有 18 个螯合的 Gd 离子，其大小为 32nm，表面带负电荷约为 18mV。体外对比性能与市售的 Gd-螯合物相当：r1 弛豫率为 Magnevist 的 3.39，为共轭物的 3.11；r2 弛豫率为 Magnevist 的 5.12，为共轭物的 4.81。通过利用这种双重靶向策略，我们证明了肿瘤内积累的增加，以及抗肿瘤效果的显著增强，与单靶向共轭物相比，产生了高水平的协同作用。总之，利用肿瘤组织双重靶向的这种策略可能有助于增强药物和诊断剂在侵袭性肿瘤中的积累。
