title: The potential use of lapatinib-loaded human serum albumin nanoparticles in the treatment of triple-negative breast cancer.
abstract: Triple-negative breast cancer (TNBC) is an aggressive cancer with limited treatment options. However, the shared feature of epidermal growth factor receptor (EGFR) expression in TNBC offers the opportunity for targeted molecular therapy for this breast cancer subtype. Previous studies have indicated that lapatinib, a selective small-molecular dual-tyrosine kinase inhibitor of HER2 and EGFR, is effective in reducing cancer progression and metastasis, indicating that it might be a candidate for TNBC treatment. However, its poor water solubility, low and variable oral absorption, and large daily dose all limit the clinical use of lapatinib. In this study, we developed human serum albumin (HSA) nanoparticles loaded with lapatinib for intravenous administration to overcome these disadvantages and enhance its efficacy against TNBC. 4T1 cells (a murine TNBC cells) were selected as the cell model because their growth and metastatic spread are very close to those of human breast cancer cells. Lapatinib-loaded HSA nanoparticles (LHNPs) were prepared by Nab technology. LHNPs displayed cytotoxicity similar to the free drug but exhibited superior capacity to induce early apoptosis in 4T1 monolayer cells. Importantly, LHNPs showed improved penetration and inhibition effects in tumor spheroids compared to lapatinib solution (LS). Pharmacokinetic investigations revealed that HSA nanoparticles (i.v.) effectively increased the accumulation of lapatinib in tumor tissue at 2.38 and 16.6 times the level of LS (i.v.) and Tykerb (p.o.), respectively. Consequently, it had markedly better suppression effects both on primary breast cancer and lung metastasis in tumor-bearing mice compared to the commercial drug Tykerb. The improved anti-tumor efficacy of LHNPs may be partly attributed to its close binding to SPARC, which is widely present in the extracellular matrix of tumor tissue. These results demonstrated that LHNPs might be a promising anti-tumor agent for TNBC.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, Shanghai 201203, PR 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, PR 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, PR 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, PR China.
authors.forename: Zheming
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Shanghai Zhangjiang Medicine Valley Public Service Platform Co., Ltd., Shanghai 201203, PR China.
authors.forename: Tao
authors.initials: T
authors.lastname: Jing
authors.affiliation: Shanghai Zhangjiang Medicine Valley Public Service Platform Co., Ltd., Shanghai 201203, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, Shanghai 201203, PR China. Electronic address: qzzhang@fudan.edu.cn.
authors.forename: Qizhi
authors.initials: Q
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D000077341:Lapatinib; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053758:Nanoparticles / Q000008:administration & dosage* / Q000378:metabolism; D011799:Quinazolines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D012709:Serum Albumin / Q000008:administration & dosage* / Q000378:metabolism; D016896:Treatment Outcome; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D012709:Serum Albumin; D000077341:Lapatinib
keywords: 4T1 cells; HSA nanoparticle; Lapatinib; Triple negative breast cancer