title: PE38KDEL-loaded anti-HER2 nanoparticles inhibit breast tumor progression with reduced toxicity and immunogenicity.
abstract: The clinical use of Pseudomonas exotoxin A (PE)-based immunotoxins is limited by the toxicity and immunogenicity of PE. To overcome the limitations, we have developed PE38KDEL-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles conjugated with Fab' fragments of a humanized anti-HER2 monoclonal antibody (rhuMAbHER2). The PE38KDEL-loaded nanoparticles-anti-HER2 Fab' bioconjugates (PE-NP-HER) were constructed modularly with Fab' fragments of rhuMAbHER2 covalently linked to PLGA nanoparticles containing PE38KDEL. Compared with nontargeted nanoparticles that lack anti-HER2 Fab', PE-NP-HER specifically bound to and were sequentially internalized into HER2 overexpressing breast cancer cells, which result in significant cytotoxicity in vitro. In HER2 overexpressing tumor xenograft model system, administration of PE-NP-HER showed a superior efficacy in inhibiting tumor growth compared with PE-HER referring to PE38KDEL conjugated directly to rhuMAbHER2. Moreover, PE-NP-HER was well tolerated in mice with a higher LD(50) (LD(50) of 6.86 +/- 0.47 mg/kg vs. 2.21 +/- 0.32 mg/kg for PE-NP-HER vs. PE-HER (mean +/- SD); n = 3), and had no influence on the plasma level of plasma alanine aminotransferase (ALT) of animals when injected at a dose of 1 mg/kg where PE-HER caused significant increase of serum ALT in the treated mice. Notably, PE-NP-HER was of low immunogenicity in development of anti-PE38KDEL neutralizing antibodies and was less susceptible to inactivation by anti-PE38KDEL antibodies compared with PE-HER. This novel bioconjugate, PE-NP-HER, may represent a useful strategy for cancer treatment.
authors.affiliation: Department of Pharmaceutical Science of College of Pharmacy, International Joint Cancer Institute, The Second Military Medical University, Shanghai, People's Republic of China.
authors.forename: Jie
authors.initials: J
authors.lastname: Gao
authors.forename: Geng
authors.initials: G
authors.lastname: Kou
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Huaiwen
authors.initials: H
authors.lastname: Chen
authors.forename: Bohua
authors.initials: B
authors.lastname: Li
authors.forename: Ying
authors.initials: Y
authors.lastname: Lu
authors.forename: Dapeng
authors.initials: D
authors.lastname: Zhang
authors.forename: Shuhui
authors.initials: S
authors.lastname: Wang
authors.forename: Sheng
authors.initials: S
authors.lastname: Hou
authors.forename: Weizhu
authors.initials: W
authors.lastname: Qian
authors.forename: Jianxin
authors.initials: J
authors.lastname: Dai
authors.forename: Jian
authors.initials: J
authors.lastname: Zhao
authors.forename: Yanqiang
authors.initials: Y
authors.lastname: Zhong
authors.forename: Yajun
authors.initials: Y
authors.lastname: Guo
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D045744:Cell Line, Tumor; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000737:chemistry*; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry* / Q000627:therapeutic use*; D036103:Nanotechnology / Q000379:methods; D009368:Neoplasm Transplantation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*
chemical_list: D000410:Alanine Transaminase; D000970:Antineoplastic Agents; D000922:Immunotoxins; D018719:Erb-b2 Receptor Tyrosine Kinases