title: Incorporation of lapatinib into core-shell nanoparticles improves both the solubility and anti-glioma effects of the drug.
abstract: OBJECTIVE
  Lapatinib is a dual EGFR and HER2 inhibitor that is used to treat HER2-overexpressing cancers. However, its poor water solubility hinders its clinical use. Proteobionics is a promising way to solve this problem.
  
  
  METHODS
  Lapatinib-incorporated core-shell nanoparticles (LTNPs) were prepared and characterized by cryo-transmission electron micrograph. Then, in vitro cellular uptake and in vivo glioma targeting effect were determined by both qualitative and quantitative studies. After that, anti-glioma effect of LTNPs was determined by cytotoxicity and life-span study. Finally, the mechanism was elucidated by western blot.
  
  
  RESULTS
  LTNPs elevated the water solubility of the drug from 0.007 mg/mL to over 10 mg/mL, which was better than most commercially available injection solvents. Glioma is an increasing threat to humans' health. Here, we evaluated the treatment effects of LTNPs on glioma and explored their mechanism. LTNPs were taken up by U87 cells, inhibiting their proliferation and causing a G2 phase arrest. The uptake was energy-, time- and concentration-dependent, and several pathways were involved. LTNPs inhibited the phosphorylation of the survival (phosphatidylinositol 3-kinase/Akt) pathways, which caused the anti-proliferative effect. In vivo experiments determined that LTNPs were distributed to and accumulated in glioma by the enhanced permeation and retention effect. The distribution was colocalized with SPARC expression, which may mediate endocytosis. In pharmacokinetics and glioma distribution study, LTNPs displayed a higher blood AUC, glioma concentration and glioma/brain ratio than Tykerb. A pharmacodynamics study confirmed that LTNPs could significantly expand the median survival time of glioma-bearing mice at a cumulative dose of 40 mg/kg, which was only 5% of the dose of the commercially available lapatinib tablet (Tykerb).
  
  
  CONCLUSIONS
  LTNPs effectively increased the solubility of lapatinib and improved the treatment of glioma.
authors.affiliation: School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Huile
authors.initials: H
authors.lastname: Gao
authors.affiliation: School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Yuchen
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.affiliation: School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.affiliation: School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wei
authors.affiliation: School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Shilei
authors.initials: S
authors.lastname: Cao
authors.affiliation: School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, 826 Zhangheng Road, Shanghai 201203, China. Electronic address: xgjiang@shmu.edu.cn.
authors.forename: Xinguo
authors.initials: X
authors.lastname: Jiang
mesh_terms: D000818:Animals; D019540:Area Under Curve; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004705:Endocytosis / Q000187:drug effects; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D000077341:Lapatinib; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053758:Nanoparticles; D015676:Osteonectin / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D012995:Solubility; D015996:Survival Rate; D013997:Time Factors
chemical_list: D015676:Osteonectin; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C577241:SPARC protein, human; D000077341:Lapatinib; D051057:Proto-Oncogene Proteins c-akt
keywords: Core–shell nanoparticles; Drug delivery; Glioma; Lapatinib; Small-molecule inhibitor