Lapatinib-loaded human serum albumin nanoparticles for the prevention and treatment of triple-negative breast cancer metastasis to the brain.

// Xu Wan 1, 2 , Xiaoyao Zheng 1 , Xiaoyin Pang 1 , Zhiqing Pang 1 , Jingjing Zhao 1 , Zheming Zhang 1 , Tao Jiang 3 , Wei Xu 3 , Qizhi Zhang 1 , Xinguo Jiang 1 1 Department of Pharmaceutics, School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, Shanghai, People's Republic of China 2 Department of Pharmacy, South Campus, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, People's Republic of China 3 Shanghai Zhangjiang Medicine Valley Public Service Platform Co., Ltd., Shanghai, People's Republic of China Correspondence to: Qizhi Zhang, email: qzzhang@fudan.edu.cn Keywords: brain metastasis, triple-negative breast cancer, lapatinib, human serum albumin nanoparticles, modified Nab technology Received: October 27, 2015      Accepted: March 18, 2016      Published: April 12, 2016 ABSTRACT Brain metastasis from triple-negative breast cancer (TNBC) has continued to lack effective clinical treatments until present. However, the feature of epidermal growth factor receptor (EGFR) frequently overexpressed in TNBC offers the opportunity to employ lapatinib, a dual-tyrosine kinase inhibitor of human epidermal growth factor receptor-2 (HER2) and EGFR, in the treatment of brain metastasis of TNBC. Unfortunately, the low oral bioavailability of lapatinib and drug efflux by blood-brain barrier have resulted in low drug delivery efficiency into the brain and limited therapeutic effects for patients with brain metastasis in clinical trials. To overcome such disadvantages, we developed lapatinib-loaded human serum albumin (HSA) nanoparticles, named LHNPs, by modified nanoparticle albumin-bound (Nab) technology. LHNPs had a core-shell structure and the new HSA/phosphatidylcholine sheath made LHNPs stable in bloodstream. Compared to free lapatinib, LHNPs could inhibit the adhesion, migration and invasion ability of high brain-metastatic 4T1 cells more effectively in vitro . Tissue distribution following intravenous administration revealed that LHNPs (i.v., 10 mg/kg) achieved increased delivery to the metastatic brain at 5.43 and 4.36 times the levels of Tykerb (p.o., 100 mg/kg) and lapatinib solution (LS, i.v., 10 mg/kg), respectively. Compared to the marketed Tykerb group, LHNPs had markedly better inhibition effects on brain micrometastasis and significantly extended the median survival time of 4T1 brain metastatic mice in consequence. The improved anti-tumor efficacy of LHNPs could be partly ascribed to down-regulating metastasis-related proteins. Therefore, these results clearly indicated that LHNPs could become a promising candidate for clinical applications against brain metastasis of TNBC.