Tao Chen,1– 3,* Yumeng Wei,1– 3,* Suyu Yin,1– 3,* Wen Li,1– 3 Yuxiang Wang,1– 3 Chao Pi,1– 3 Mingtang Zeng,3,4 Xiaodong Wang,5 Ligang Chen,6 Furong Liu,7 Shaozhi Fu,8 Ling Zhao2,3 

1Key Laboratory of Medical Electrophysiology, Ministry of Education, School of Pharmacy, Southwest Medical University, Luzhou, 646000, People’s Republic of China; 2Luzhou Key Laboratory of Traditional Chinese Medicine for Chronic Diseases Jointly Built by Sichuan and Chongqing, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University; Luzhou, Sichuan, 646000, People’s Republic of China; 3Central Nervous System Drug Key Laboratory of Sichuan Province, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China; 4Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China; 5Department of Hepatobiliary Diseases, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China; 6Department of neurosurgery, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China; 7Department of Oncology, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China; 8Department of Oncology, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Shaozhi Fu, Department of Oncology, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, People’s Republic of China, Tel +86 830-3165698, Fax +86 830-3165690, Email shaozhifu513@163.com Ling Zhao, Luzhou Key Laboratory of Traditional Chinese Medicine for Chronic Diseases Jointly Built by Sichuan and Chongqing, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, No. 182, Chunhui Road, Longmatan District, Luzhou, Sichuan, 646000, China, Tel +86 830 2681630, Email zhaoling@swmu.edu.cn

Purpose: The present study aimed to develop a lipid nanoplatform, denoted as “BAL-PTX-LN”, co-loaded with chiral baicalin derivatives (BAL) and paclitaxel (PTX) to promote the anti-lung cancer efficacy of paclitaxel and reduce the toxicity of chemotherapeutic drugs.
Methods: BAL-PTX-LN was optimized through central composite design based on a single-factor experiments. BAL-PTX-LN was evaluated by TEM, particle size, encapsulation efficiency, hemolysis rate, release kinetics and stability. And was evaluated by pharmacokinetics and the antitumor efficacy studied both in vitro and in vivo. The in vivo safety profile of the formulation was assessed using hematoxylin and eosin (HE) staining.
Results: BAL-PTX-LN exhibited spherical morphology with a particle size of 134.36 ± 3.18 nm, PDI of 0.24 ± 0.02, and with an encapsulation efficiency exceeding 90%, BAL-PTX-LN remained stable after 180 days storage. In vitro release studies revealed a zero-order kinetic model of PTX from the liposomal formulation. No hemolysis was observed in the preparation group. Pharmacokinetic analysis of PTX in the BAL-PTX-LN group revealed an approximately three-fold higher bioavailability and twice longer t1/2 compared to the bulk drug group. Furthermore, the IC50 of BAL-PTX-LN decreased by 2.35 times (13.48 μg/mL vs 31.722 μg/mL) and the apoptosis rate increased by 1.82 times (29.38% vs 16.13%) at 24 h compared to the PTX group. In tumor-bearing nude mice, the BAL-PTX-LN formulation exhibited a two-fold higher tumor inhibition rate compared to the PTX group (62.83% vs 29.95%), accompanied by a ten-fold decrease in Ki67 expression (4.26% vs 45.88%). Interestingly, HE staining revealed no pathological changes in tissues from the BAL-PTX-LN group, whereas tissues from the PTX group exhibited pathological changes and tumor cell infiltration.
Conclusion: BAL-PTX-LN improves the therapeutic effect of poorly soluble chemotherapeutic drugs on lung cancer, which is anticipated to emerge as a viable therapeutic agent for lung cancer in clinical applications.

Keywords: baicalin derivative, paclitaxel, chemotherapy, lung cancer, lipid nano platform, combination therapy