Boyacıoğlu Özge, Varan Cem, Bilensoy Erem, Aykut Zaliha Gamze, Reçber Tuba, Nemutlu Emirhan, Kılıç Nedret, Korkusuz Petek
Hacettepe University, Graduate School of Science and Engineering, Department of Bioengineering, 06800, Beytepe, Ankara, Turkey; Atılım University, Faculty of Medicine, Department of Medical Biochemistry, 06830, Gölbaşı, Ankara, Turkey.
Hacettepe University, Graduate School of Science and Engineering, Department of Nanotechnology and Nanomedicine, 06800, Beytepe, Ankara, Turkey.
Int J Pharm. 2025 Feb 10;670:125153. doi: 10.1016/j.ijpharm.2024.125153. Epub 2024 Dec 31.
Rapid progressing non-small cell lung adenocarcinoma (NSCLC) decreases treatment success. Cannabinoids emerge as drug candidates for NSCLC due to their anti-tumoral capabilities. We previously reported the controlled release of Arachidonylcyclopropylamide (ACPA) selectively targeting cannabinoid 1 (CB1) receptor in NSCLC cells in vitro. Hydrophobic polymers like polycaprolactone (PCL) offer prolonged circulation time and slower drug clearance which is suitable for hydrophobic molecules like ACPA. Thus, the extended circulation time with enhanced bioavailability and half-life of nanoparticular ACPA is crucial for its therapeutic performance in the tumor area. We assumed that a novel high technology-controlled release system increasing the bioavailability of ACPA compared to free ACPA could be transferred to the clinic when validated in vivo. Plasma profile of ACPA and ACPA-loaded PCL-based nanomedicine by LC-MS/MS and complete blood count (CBC) was assessed in wild-type Balb/c mice. Tumor growth in nanomedicine-applied NSCLC-induced athymic nude mice was assessed using bioluminescence imaging (BLI) and caliper measurements, histomorphometry, immunohistochemistry, TUNEL assay, and Western blot on days 7-21. Injectable NanoACPA increased its systemic exposure to tissues 5.5 times and maximum plasma concentration 6 times higher than free ACPA by substantially improving bioavailability. The potent effect of NanoACPA lasted for at least two days on ectopic NSCLC model through Akt/PI3K, Ras/MEK/Erk, and JNK pathways that diminished Ki-67 proliferative and promoted TUNEL apoptotic cell scores on days 7-21. The output reveals that NanoACPA platform could be a chemotherapeutic for NSCLC in the clinic following scale-up GLP/GMP-based phase trials, owing to therapeutic efficacy at a safe low dose window.
快速进展的非小细胞肺腺癌（NSCLC）会降低治疗成功率。大麻素因其抗肿瘤能力而成为NSCLC的候选药物。我们之前报道了花生四烯酸环丙酰胺（ACPA）在体外对NSCLC细胞中大麻素1（CB1）受体的选择性靶向控释。像聚己内酯（PCL）这样的疏水性聚合物具有延长的循环时间和较慢的药物清除率，这适用于像ACPA这样的疏水性分子。因此，纳米级ACPA延长的循环时间、增强的生物利用度和半衰期对其在肿瘤区域的治疗性能至关重要。我们认为，一种与游离ACPA相比能提高ACPA生物利用度的新型高科技控释系统，在体内验证后可转化应用于临床。通过液相色谱-串联质谱法（LC-MS/MS）和全血细胞计数（CBC）评估了野生型Balb/c小鼠体内ACPA和载有ACPA的基于PCL的纳米药物的血浆谱。在第7至21天，使用生物发光成像（BLI）、卡尺测量、组织形态计量学、免疫组织化学、TUNEL检测和蛋白质印迹法评估了纳米药物应用于NSCLC诱导的无胸腺裸鼠的肿瘤生长情况。可注射的纳米ACPA通过大幅提高生物利用度，使其在组织中的全身暴露量比游离ACPA增加了5.5倍，最大血浆浓度高出6倍。纳米ACPA的强效作用通过Akt/PI3K、Ras/MEK/Erk和JNK途径在异位NSCLC模型上持续至少两天，在第7至21天降低了Ki-67增殖分数并提高了TUNEL凋亡细胞分数。结果表明，由于在安全的低剂量窗口具有治疗效果，纳米ACPA平台在基于GLP/GMP的放大阶段试验后可成为临床上治疗NSCLC的一种化疗药物。
