A novel injectable nanotherapeutic platform increasing the bioavailability and anti-tumor efficacy of Arachidonylcyclopropylamide on an ectopic non-small cell lung cancer xenograft model: A randomized controlled trial

Özge Boyacıoğlu; Cem Varan; Erem Bilensoy; Zaliha Gamze Aykut; Tuba Reçber; Emirhan Nemutlu; Nedret Kılıç; Petek Korkusuz

doi:10.1016/j.ijpharm.2024.125153

A novel injectable nanotherapeutic platform increasing the bioavailability and anti-tumor efficacy of Arachidonylcyclopropylamide on an ectopic non-small cell lung cancer xenograft model: A randomized controlled trial

Int J Pharm. 2024 Dec 31:670:125153. doi: 10.1016/j.ijpharm.2024.125153. Online ahead of print.

Authors

Özge Boyacıoğlu¹, Cem Varan², Erem Bilensoy³, Zaliha Gamze Aykut⁴, Tuba Reçber⁵, Emirhan Nemutlu⁵, Nedret Kılıç⁶, Petek Korkusuz⁷

Affiliations

¹ 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.
² Hacettepe University, Graduate School of Science and Engineering, Department of Nanotechnology and Nanomedicine, 06800, Beytepe, Ankara, Turkey.
³ Hacettepe University, Faculty of Pharmacy, Department of Pharmaceutical Technology, 06100, Sıhhiye, Ankara, Turkey.
⁴ Bilkent University, Faculty of Science, Department of Molecular Biology and Genetics, 06800, Cankaya, Ankara, Turkey.
⁵ Hacettepe University, Faculty of Pharmacy, Department of Analytical Chemistry, 06100, Sıhhiye, Ankara, Turkey.
⁶ Atılım University, Faculty of Medicine, Department of Medical Biochemistry, 06830, Gölbaşı, Ankara, Turkey.
⁷ Hacettepe University, Faculty of Medicine, Department of Histology and Embryology, 06100, Sıhhiye, Ankara, Turkey; METU MEMS Center, 06530, Ankara, Turkey. Electronic address: petek@hacettepe.edu.tr.

PMID: 39746587
DOI: 10.1016/j.ijpharm.2024.125153

Abstract

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.

Keywords: Arachidonylcyclopropylamide (ACPA); Cannabinoids; Nanomedicine; Nanoparticle-based drug delivery system; Non-small cell lung cancer; Polycaprolactone (PCL).