title: Improved antitumor activity of TRAIL fusion protein via formation of self-assembling nanoparticle.
abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been known as a promising agent for cancer therapy due to its specific apoptosis-inducing effect on tumor cells rather than most normal cells. However, systemically delivered TRAIL suffers from a rapid clearance from the body with an extremely short half-life. Thermally responsive elastin-like polypeptides (ELPs) are a promising class of temperature sensitive biopolymers based on the structural motif found in mammalian tropoelastin and retain the advantages of polymeric drug delivery systems. We therefore expressed RGD-TRAIL fused with ELP (RGD-TRAIL-ELP) in E. coli. Purification of RGD-TRAIL-ELP was achieved by the conveniently inverse transition cycling (ITC). The purified RGD-TRAIL-ELP without any chemical conjugation was able to self-assemble into nanoparticle under physiological condition. Non-reducing SDS-PAGE results showed that trimer content of RGD-TRAIL-ELP increased 3.4-fold than RGD-TRAIL. Flow cytometry confirmed that RGD-TRAIL-ELP 3-fold enhanced apoptosis-inducing capacity than RGD-TRAIL. Single intraperitoneal injection of the RGD-TRAIL-ELP nanoparticle induced nearly complete tumor regression in the COLO-205 tumor xenograft model. Histological observation confirmed that RGD-TRAIL-ELP induced significant tumor cell apoptosis without apparent liver toxicity. These findings suggested that a great potential application of the RGD-TRAIL-ELP nanoparticle system as a safe and efficient delivery strategy for cancer therapy.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences and Affiliated Stomatological Hospital, Nanjing University, Nanjing, Jiangsu 210046, P.R. China.|State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu 210009, P.R. China.
authors.forename: Kaizong
authors.initials: K
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences and Affiliated Stomatological Hospital, Nanjing University, Nanjing, Jiangsu 210046, P.R. China.
authors.forename: Ningjun
authors.initials: N
authors.lastname: Duan
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences and Affiliated Stomatological Hospital, Nanjing University, Nanjing, Jiangsu 210046, P.R. China.
authors.forename: Chunmei
authors.initials: C
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu 210009, P.R. China.
authors.forename: Ran
authors.initials: R
authors.lastname: Mo
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences and Affiliated Stomatological Hospital, Nanjing University, Nanjing, Jiangsu 210046, P.R. China.|State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu 210009, P.R. China.|Nanjing Industrial Innovation Center for Pharmaceutical Biotechnology, Nanjing, Jiangsu 210019, P.R. China.|Changzhou High-Tech Research Institute of Nanjing University, Changzhou, Jiangsu 213164, P.R. China.
authors.forename: Zichun
authors.initials: Z
authors.lastname: Hua
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D017209:Apoptosis; D045744:Cell Line, Tumor; D004549:Elastin / Q000235:genetics; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry*; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D009842:Oligopeptides / Q000235:genetics; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D009842:Oligopeptides; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C047981:arginyl-glycyl-aspartic acid; D004549:Elastin