Treatment of hepatocellular carcinoma in mice with PE38KDEL type I mutant-loaded poly(lactic-co-glycolic acid) nanoparticles conjugated with humanized SM5-1 F(ab') fragments.
We reported previously the development of SMFv-PE38KDEL type I mutant (PE38KDEL-I; Mut-I), a recombinant immunotoxin in which a single-chain antibody derived from mouse SM5-1 monoclonal antibody is genetically fused to PE38KDEL-I. In comparison with the SMFv-PE38KDEL wild-type, Mut-I showed improved therapeutic efficacy and reduced toxicity. To overcome the problems associated with the immune response to the Pseudomonas exotoxin A (PE) component of Mut-I, we have constructed PE38KDEL-I-loaded poly(lactic-co-glycolic acid) nanoparticles conjugated with F(ab') fragments of a humanized SM5-1 monoclonal antibody (PE-NP-S). PE-NP-S specifically bound to SM5-1 binding protein-expressing hepatocellular carcinoma cell lines and was then internalized by these cells, resulting in significant cytotoxic effect. In SM5-1 binding protein-overexpressing tumor xenograft model, administration of PE-NP-S significantly inhibited tumor development and induced tumor regression. Moreover, PE-NP-S was shown to be much weaker in inducing vascular leakage syndrome in mice than Mut-I. The LD(50) of PE-NP-S was about 4-fold higher than that of Mut-I. Remarkably, PE-NP-S was of low immunogenicity in development of anti-PE neutralizing antibodies in vivo and was less susceptible to inactivation by anti-PE neutralizing antibodies compared with Mut-I. In conclusion, the resultant PE-NP-S possessed increased cancer therapeutic efficacy and had reduced nonspecific toxicity and immunogenicity, suggesting that it is a potential candidate in cancer therapy.
Gao
Jie
J
International Joint Cancer Institute and Department of Pharmaceutical Science of College of Pharmacy, The Second Military Medical University, Shanghai, People's Republic of China.
Kou
Geng
G
Chen
Huaiwen
H
Wang
Hao
H
Li
Bohua
B
Lu
Ying
Y
Zhang
Dapeng
D
Wang
Shuhui
S
Hou
Sheng
S
Qian
Weizhu
W
Dai
Jianxin
J
Zhao
Jian
J
Zhong
Yanqiang
Y
Guo
Yajun
Y
D000818:Animals; D000906:Antibodies; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001667:Binding, Competitive / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D049109:Cell Proliferation / Q000187:drug effects; D004705:Endocytosis / Q000187:drug effects; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000627:therapeutic use* / Q000633:toxicity; D000922:Immunotoxins / Q000627:therapeutic use* / Q000633:toxicity; D019344:Lactic Acid / Q000378:metabolism*; D008113:Liver Neoplasms / Q000188:drug therapy*; D051379:Mice; D018613:Microscopy, Confocal; D053758:Nanoparticles; D011100:Polyglycolic Acid / Q000378:metabolism*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D023041:Xenograft Model Antitumor Assays
D000906:Antibodies; D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D000922:Immunotoxins; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid