Sustained and cancer cell targeted cytosolic delivery of Onconase results in potent antitumor effects.
The unfavorable pharmacokinetics and low tumor specificity hampered the potential clinical utility of Onconase, a promising modality in anticancer treatment with unique targets and novel mechanism of action. In this study, a modular and multi-stage drug delivery system (DDS) that can break down organ (renal accumulation), cellular (cancer cell specific uptake) and sub-cellular (endosomal escape) level barriers encountered by Onconase during its long journey from injection site to the cytoplasm of cancer cell was designed. Human serum albumin fusion extended the half-life of Onconase and significantly decreased its kidney accumulation. Epithelial cell adhesion molecular (EpCAM) specific antibody fragment appending enhanced binding and internalization of Onconase toward EpCAM positive cancer cell and increased its tumor accumulation and retention. Tethering Onconase to its carrier by cleavable disulfide linker prompted endosomal escape and restored its cytotoxicity. In vivo antitumor efficacy assay in human tumor xenograft model revealed that only when the entire organ, cellular and sub-cellular level barriers had been broken down, will Onconase turn into a potent antitumor agent.
Department of Microorganism Engineering, Beijing Institute of Biotechnology, 20 Dongdajie Street, Fengtai District, Beijing 100071, People's Republic of China.
Hong Liang
HL
Zhao
Chong
C
Xue
Ji Liang
JL
Du
Min
M
Ren
Shan
S
Xia
Yuan Guo
YG
Cheng
Zhi Min
ZM
Liu
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D003600:Cytosol / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D019073:HT29 Cells; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007677:Kidney Function Tests; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008111:Liver Function Tests; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D010843:Pichia / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics; D012260:Ribonucleases / Q000008:administration & dosage* / Q000235:genetics / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D013997:Time Factors; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D011993:Recombinant Fusion Proteins; D012260:Ribonucleases; C058703:ranpirnase