Author:
Zhao Ziyu,Wang Wenhao,Wang Guanlin,Huang Zhengwei,Zhou Liping,Lin Li,Ou Yueling,Huang Wanzhen,Zhang Xuejuan,Wu Chuanbin,Tao Liang,Wang Qin
Abstract
Abstract
Background
Gene therapy for lung cancer has emerged as a novel tumor-combating strategy for its superior tumor specificity, low systematical toxicity and huge clinical translation potential. Especially, the applications of microRNA shed led on effective tumor ablation by directly interfering with the crucial gene expression, making it one of the most promising gene therapy agents. However, for lung cancer therapy, the microRNA treatment confronted three bottlenecks, the poor tumor tissue penetration effect, the insufficient lung drug accumulation and unsatisfied gene transfection efficiency. To address these issues, an inhalable RGD-TAT dual peptides-modified cationic liposomes loaded with microRNA miR-34a and gap junction (GJ) regulation agent all-trans retinoic acid (ATRA) was proposed, which was further engineered into dry powder inhalers (DPIs).
Results
Equipped with a rough particle surface and appropriate aerodynamic size, the proposed RGD-TAT-CLPs/ARTA@miR-34a DPIs were expected to deposit into the deep lung and reach lung tumor lesions guided by targeting peptide RGD. Assisted by cellular transmembrane peptides TAT, the RGD-TAT-CLPs/ARTA@miR-34a was proven to be effectively internalized by cancer cells, enhancing gene transfection efficiency. Then, the GJ between tumor cells was upregulated by ARTA, facilitating the intercellular transport of miR-34a and boosting the gene expression in the deep tumor.
Conclusion
Overall, the proposed RGD-TAT-CLPs/ARTA@miR-34a DPIs could enhance tumor tissue penetration, elevate lung drug accumulation and boost gene transfection efficiency, breaking the three bottlenecks to enhancing tumor elimination in vitro and in vivo. We believe that the proposed RGD-TAT-CLPs/ARTA@miR-34a DPIs could serve as a promising pulmonary gene delivery platform for multiple lung local disease treatments.
Funder
Guangzhou Municipal Science and Technology Project
National Natural Science Foundation of China
China Postdoctoral Science Foundation Special Funded Project
Publisher
Springer Science and Business Media LLC
Subject
Pharmaceutical Science,Applied Microbiology and Biotechnology,Biomedical Engineering,Molecular Medicine,Medicine (miscellaneous),Bioengineering
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