Tumor-targeted PE38KDEL delivery via PEGylated anti-HER2 immunoliposomes.
We previously reported the development of PE38KDEL-loaded anti-HER2 poly(lactic-co-glycolic acid) (PLGA) nanoparticles that bind and internalize in HER2-overexpressing breast cancer cells, enabling potent anti-tumor activity. To overcome the problems associated with the short half-lives of this drug delivery system, we have constructed PE38KDEL-loaded anti-HER2 PEGylated liposomes (PE-HER-liposomes). PE-HER-liposomes were constructed with Fab' of recombinant humanized anti-HER2 monoclonal antibody (anti-HER2 Fab') covalently linked to PEGylated liposomes containing PE38KDEL (PE-liposomes). We attached anti-HER2 Fab' to the terminus of PEG (polyethylene glycol) on PEGylated liposomes. Incorporation of pyridylthiopropionoylamino-PEG-distearoylphosphatidylethanolamine (PDP-PEG-DSPE) into PEGylated liposomes followed by mild thiolysis of the PDP groups resulted in the formation of reactive thiol groups at the periphery of the liposomes. Efficient attachment of maleimide-derivatized anti-HER2 Fab' took place under mild conditions. The characterization of PE-HER-liposomes, such as particle size, was evaluated by dynamic light-scattering detector. The Micro BCA method was used to determine the encapsulation efficiency of PE38KDEL and the quantity of conjugated Fab'. Flow cytometry and confocal microscopy showed that PE-HER-liposomes possessed receptor-specific binding and internalization for HER2-overexpressing SK-BR3 cells. Remarkably, PE-HER-liposomes were more cytotoxic than non-targeted PE-liposomes in HER2-overexpressing breast cancer cells. In conclusion, PE-HER-liposomes could serve as a promising therapeutic candidate for the treatment of HER2-overexpressing breast cancers.
Gao
Jie
J
International Joint Cancer Institute & Department of Pharmaceutical Science, School of Pharmacy, the Second Military Medical University, 800 Xiang Yin Road, Shanghai, People's Republic of China.
Zhong
Wei
W
He
Jinqiu
J
Li
Huimei
H
Zhang
He
H
Zhou
Guichen
G
Li
Bohua
B
Lu
Ying
Y
Zou
Hao
H
Kou
Geng
G
Zhang
Dapeng
D
Wang
Hao
H
Guo
Yajun
Y
Zhong
Yanqiang
Y
D036002:ADP Ribose Transferases / Q000276:immunology / Q000493:pharmacokinetics* / Q000494:pharmacology; D001427:Bacterial Toxins / Q000276:immunology / Q000493:pharmacokinetics* / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000276:immunology; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D005098:Exotoxins / Q000276:immunology / Q000493:pharmacokinetics* / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D006207:Half-Life; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D008081:Liposomes; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology; D013438:Sulfhydryl Compounds / Q000737:chemistry; D037521:Virulence Factors / Q000276:immunology / Q000493:pharmacokinetics* / Q000494:pharmacology; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D001427:Bacterial Toxins; D005098:Exotoxins; D007140:Immunoglobulin Fab Fragments; D008081:Liposomes; D011092:Polyethylene Glycols; D018719:Erb-b2 Receptor Tyrosine Kinases; D013438:Sulfhydryl Compounds; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C508053:ERBB2 protein, human