title: A novel combined micellar system of lapatinib and Paclitaxel with enhanced antineoplastic effect against human epidermal growth factor receptor-2 positive breast tumor in vitro.
abstract: Lapatinib (LPT) could sensitize human epidermal growth factor receptor-2 (HER-2) positive breast cancer to paclitaxel (PTX) and induce synergetic action with PTX in preclinical test and phase II/III trial. In this study, LPT-conjugated poly (ethylene glycol) (PEG) and poly (lactic acid) (PLA) (LPT-PEG-PLA) was first synthesized and confirmed with ¹H Nuclear Magnetic Resonance and Matrix-Assisted Laser Desorption/ Ionization Time of Flight Mass Spectrometry, which was used for the preparation of a novel PEG-PLA combined micelles of LPT and PTX (PPM-LP). The obtained PPM-LP exhibited uniform, spherical shape with a size of 25.80 ± 0.47 nm and zeta potential of -3.17 ± 0.15 mv. PTX existed in molecular or amorphous forms in the micelles and superficial LPT could better delay PTX release. The cytotoxicity of PPM-LP with LPT conjugation against SKBr-3 cells (HER-2 positive) was found to be significantly increasing as compared with PPM-PTX, whereas there was no significant difference against MDA-MB-231 cells (HER-2 negative). PPM-LP could escape from endosomes and be distributed into cytoplasm and led to cell arrest in G2/M and G1/S phases simultaneously. Results of nucleus staining and flow cytometry confirmed that LPT could remarkably increase antineoplastic effect of PTX against SKBr-3 cells. All these results demonstrated that PPM-LP may be a promising drug delivery system for HER-2 positive breast cancer.
authors.affiliation: School of Pharmacy and Key Laboratory of Smart Drug Delivery, Ministry of Education and PLA, Fudan University, Shanghai, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wei
authors.forename: Shuai
authors.initials: S
authors.lastname: Xu
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.forename: Aifeng
authors.initials: A
authors.lastname: Zou
authors.forename: Shuang
authors.initials: S
authors.lastname: Zhang
authors.forename: Yan
authors.initials: Y
authors.lastname: Xiong
authors.forename: Shilei
authors.initials: S
authors.lastname: Cao
authors.forename: Qizhi
authors.initials: Q
authors.lastname: Zhang
authors.forename: Yajie
authors.initials: Y
authors.lastname: Wang
authors.forename: Xinguo
authors.initials: X
authors.lastname: Jiang
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004338:Drug Combinations; D004339:Drug Compounding; D004705:Endocytosis / Q000187:drug effects; D005260:Female; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry*; D000077341:Lapatinib; D008823:Micelles; D017239:Paclitaxel / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010316:Particle Size; D011091:Polyesters; D011092:Polyethylene Glycols / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry*; D011799:Quinazolines / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D012995:Solubility; D013499:Surface Properties
chemical_list: D004337:Drug Carriers; D004338:Drug Combinations; D019344:Lactic Acid; D000077341:Lapatinib; D008823:Micelles; D017239:Paclitaxel; D011091:Polyesters; D011092:Polyethylene Glycols; D011108:Polymers; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C033616:poly(lactide); C508053:ERBB2 protein, human
keywords: cancer chemotherapy; conjugation; human epidermal growth factor receptor-2; lapatinib; micelle; paclitaxel; polymeric drug delivery systems; poorly water-soluble drugs; sensitize; solubility