Construction of an intranasal drug delivery system with hypothalamus‐targeting nanoparticles
Qianru Rao,
Yujie Xu,
Xiaorong Wang,
Hang Luo,
Haoqi Li,
Jingyuan Xiong,
Huile Gao,
Guo Cheng
Affiliations
Qianru Rao
Laboratory of Molecular Translational Medicine, Center for Translational Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Maternal & Child Nutrition Center, West China Second University Hospital Sichuan University Chengdu China
Yujie Xu
Laboratory of Molecular Translational Medicine, Center for Translational Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Maternal & Child Nutrition Center, West China Second University Hospital Sichuan University Chengdu China
Xiaorong Wang
Key Laboratory of Drug‐Targeting and Drug Delivery System of the Education Ministry West China School of Pharmacy Sichuan University Chengdu China
Hang Luo
Healthy Food Evaluation Research Center, West China School of Public Health and West China Fourth Hospital Sichuan University Chengdu China
Haoqi Li
Healthy Food Evaluation Research Center, West China School of Public Health and West China Fourth Hospital Sichuan University Chengdu China
Jingyuan Xiong
Healthy Food Evaluation Research Center, West China School of Public Health and West China Fourth Hospital Sichuan University Chengdu China
Huile Gao
Key Laboratory of Drug‐Targeting and Drug Delivery System of the Education Ministry West China School of Pharmacy Sichuan University Chengdu China
Guo Cheng
Laboratory of Molecular Translational Medicine, Center for Translational Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Maternal & Child Nutrition Center, West China Second University Hospital Sichuan University Chengdu China
Abstract Dysfunction of the hypothalamus is associated with endocrine imbalances, growth abnormalities, and reproductive disorders. However, there is a lack of targeted treatment strategies focused on the hypothalamus. In this study, we constructed a multifunctional nanocarrier system (S@ANP) to directly target the hypothalamic neurokinin receptor 3 (NK3R) via an intranasal delivery strategy. This system could overcome the primary obstacles in drug delivery for hypothalamus‐related diseases. Under the guidance of a modified (Trp7, β‐Ala8)‐neurokinin A (4‐10) peptide with cysteine, nanoparticles encapsulated with SB222200, an NK3R inhibitor, were found to readily penetrate hypothalamic cells with substantial loading capacity, encapsulation efficiency, and sustained release in vitro. Moreover, intranasal delivery represents an optimal delivery strategy that allows for a significant reduction in oral dosage and enables nanoparticles to bypass the blood‒brain barrier and target relevant parts of the brain. The mucolytic agent N‐acetyl‐L‐cysteine (NAC) was loaded into the nanoparticles (S@ANP + NAC) to increase mucosal solubility and intranasal delivery efficiency. In vivo evaluations showed that S@ANP + NAC could effectively target the hypothalamus and modulate NK3R‐regulated hypothalamic functions in mice. Due to its high hypothalamic targeting efficiency and low toxicity, this intranasal nanoparticle drug delivery system may serve as a potential strategy for precision therapy of hypothalamic disorders.
