title: Incorporation of lapatinib into human serum albumin nanoparticles with enhanced anti-tumor effects in HER2-positive breast cancer.
abstract: Lapatinib, a selective small-molecule dual-tyrosine kinase inhibitor of HER2 and EGFR, is effective in HER2-positive patients with advanced metastatic breast cancer. However, its low and variable oral absorption, large required daily dose and serious gastrointestinal side effects all limit its clinical use. Intravenous administration offers a good option to overcome these disadvantages. However, the poor solubility of lapatinib in water and organic solvents causes lapatinib to fail in a common injectable preparation. Considering lapatinib's high albumin binding ability (>99%), in this study, we developed human serum albumin nanoparticles loaded with lapatinib (LHNPs) by Nab technology for intravenous administration and investigated its efficacy against HER2-positive breast cancer. Raman shift, X-ray diffraction and X-ray photoelectron spectroscopy studies demonstrated that lapatinib was successfully incorporated into nanoparticles, and LHNPs exhibited good stability and sustained-release effect in vitro. LHNPs could be effectively taken up by SKBr3 cells in a concentration- and time-dependent manner, and the uptake was mediated by energy-dependent endocytosis, which involved clathrin-dependent pinocytosis. Furthermore, in vitro and in vivo data indicated that LHNPs presented the strong ability to induce apoptosis and superior anti-tumor efficacy in tumor-bearing mice to the commercial tablet Tykerb through the inhibition of HER2 phosphorylation. Subchronic toxicity assays indicated that LHNPs had no hepatic or kidney toxicity. With mature technology for industrial production and enhanced therapeutic effects, LHNPs are likely to have great potential as a safe therapeutic candidate against HER2-positive breast cancer in the clinic.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, Shanghai 201203, People's Republic of China.
authors.forename: Xu
authors.initials: X
authors.lastname: Wan
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, Shanghai 201203, People's Republic of China.
authors.forename: Xiaoyao
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, Shanghai 201203, People's Republic of China.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Pang
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, Shanghai 201203, People's Republic of China.
authors.forename: Zheming
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, Shanghai 201203, People's Republic of China. Electronic address: qzzhang@fudan.edu.cn.
authors.forename: Qizhi
authors.initials: Q
authors.lastname: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000627:therapeutic use; D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D000077341:Lapatinib; D053758:Nanoparticles; D033362:Powder Diffraction; D011799:Quinazolines / Q000737:chemistry* / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D012709:Serum Albumin / Q000737:chemistry*; D013059:Spectrum Analysis, Raman
chemical_list: D000970:Antineoplastic Agents; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D012709:Serum Albumin; C508053:ERBB2 protein, human
keywords: HER2-positive breast cancer; Human serum albumin nanoparticles; Lapatinib