Kannaka Kento, Sano Kohei, Munekane Masayuki, Yamasaki Toshihide, Hagimori Masayori, Mukai Takahiro
Laboratory of Biophysical Chemistry, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe 658-8558, Japan.
Laboratory of Analytical Chemistry, School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women's University, 11-68 Koshien Kyuban-cho, Nishinomiya 663-8179, Japan.
Mol Pharm. 2022 May 2;19(5):1400-1409. doi: 10.1021/acs.molpharmaceut.1c00936. Epub 2022 Apr 11.
Liposomes are highly biocompatible drug carriers in drug delivery systems (DDSs). Preferential accumulation of liposomes and acceleration of drug release at target tumor sites are essential for effective cancer therapy using liposomal formulations; however, conventional liposomes are unsuitable for on-demand drug release. We have previously reported that drug release can be accelerated a bio-orthogonal inverse electron demand Diels-Alder (IEDDA) reaction between amphiphilic tetrazine (Tz)-containing liposomes and norbornene (NB) derivatives . In this study, we prepared HSTz-liposomes composed of hydrogenated soybean phosphatidylcholine (HSPC) and Tz compound (2-hexadecyl--(6-(6-(pyridin-2-yl)-1,2,4,5-tetrazin-3-yl)pyridin-3-yl)octadecanamide) with particle sizes of 60-80 nm and ζ-potentials of -5 to 0 mV. Similar to our previous report, the addition of 5-norbornene-2-carboxylic acid (NBCOOH) to HSTz-liposomes accelerated drug release from the liposomes . In the biodistribution study using colon26 tumor-bearing mice, the radiolabeled HSTz-liposomes were accumulated and retained in the tumor at 6-48 h post-injection, whereas the radioactivity in the blood almost disappeared at 48 h. Therefore, the timing of the injection of NBCOOH was selected to be 48 h after the injection of the HSTz-liposome to avoid the IEDDA reaction in the bloodstream. We investigated the drug release by evaluating the intratumoral localization of doxorubicin (DOX) encapsulated in HSTz-liposomes labeled with fluorescent lipids. In the tumors treated with HSTz-liposomes and NBCOOH, DOX was more widely dispersed in the tumor compared with fluorescent lipid, suggesting that the release of encapsulated drugs (DOX) from HSTz-liposomes was enhanced in the tumor tissue the bio-orthogonal IEDDA reaction. Furthermore, the combination of DOX-encapsulated HSTz-liposomes with NBCOOH significantly suppressed tumor growth compared to conventional DOX-encapsulated liposomes. In conclusion, the bio-orthogonal IEDDA reactions in the liposomal membrane enabled the acceleration of drug release from HSTz-liposomes , suggesting a promising strategy for effective cancer therapy.
脂质体是药物递送系统（DDSs）中具有高度生物相容性的药物载体。脂质体在靶肿瘤部位的优先积累和药物释放加速对于使用脂质体制剂进行有效的癌症治疗至关重要；然而，传统脂质体不适合按需药物释放。我们之前报道过，含两亲性四嗪（Tz）的脂质体与降冰片烯（NB）衍生物之间的生物正交逆电子需求狄尔斯-阿尔德（IEDDA）反应可加速药物释放。在本研究中，我们制备了由氢化大豆磷脂酰胆碱（HSPC）和Tz化合物（2-十六烷基-（6-（6-（吡啶-2-基）-1,2,4,5-四嗪-3-基）吡啶-3-基）十八烷酰胺）组成的HSTz-脂质体，其粒径为60-80nm，ζ电位为-5至0mV。与我们之前的报道相似，向HSTz-脂质体中添加5-降冰片烯-2-羧酸（NBCOOH）可加速脂质体中药物的释放。在使用荷结肠26肿瘤小鼠的生物分布研究中，放射性标记的HSTz-脂质体在注射后6-48小时在肿瘤中积累并保留，而血液中的放射性在48小时时几乎消失。因此，选择在注射HSTz-脂质体后48小时注射NBCOOH，以避免血流中的IEDDA反应。我们通过评估包裹在标记有荧光脂质的HSTz-脂质体中的阿霉素（DOX）的肿瘤内定位来研究药物释放情况。在用HSTz-脂质体和NBCOOH治疗的肿瘤中，与荧光脂质相比，DOX在肿瘤中的分布更广泛，这表明通过生物正交IEDDA反应，HSTz-脂质体中包裹药物（DOX）在肿瘤组织中的释放得到增强。此外，与传统的包裹DOX的脂质体相比，包裹DOX 的HSTz-脂质体与NBCOOH的组合显著抑制了肿瘤生长。总之，脂质体膜中的生物正交IEDDA反应能够加速HSTz-脂质体中药物的释放，这表明这是一种有效的癌症治疗的有前景的策略。
