Immuno-LipoTRAIL: Targeted delivery of TRAIL-functionalized liposomal nanoparticles.
The TNF-related apoptosis-inducing ligand (TRAIL) is a powerful inducer of apoptosis in tumor cells; however, clinical studies with recombinant soluble TRAIL were rather disappointing. Here, we developed TRAIL-functionalized liposomes (LipoTRAIL, LT) to mimic membrane-displayed TRAIL for efficient activation of death receptors DR4 and DR5 and enhanced induction of apoptosis, which were combined with an anti-EGFR single-chain Fv fragment (scFv) for targeted delivery to EGFR-positive tumor cells. These immuno-LipoTRAILs (ILTs) bound specifically to EGFR-expressing cells (Colo205) and exhibited increased cytotoxicity compared with that of nontargeted LTs. Compared to that of the soluble TRAIL, the plasma half-life of the functionalized liposomes was strongly extended, and increased antitumor activity of LT and ILT was demonstrated in a xenograft tumor model. Thus, we established a multifunctional liposomal TRAIL formulation (ILT) with improved pharmacokinetic and pharmacodynamic behavior, characterized by targeted delivery and increased induction of apoptosis due to multivalent TRAIL presentation.
Institut für Zellbiologie und Immunologie, Universität Stuttgart , Allmandring 31, 70569 Stuttgart, Germany.
Oliver
O
Seifert
Nadine
N
Pollak
Anja
A
Nusser
Frank
F
Steiniger
Ronny
R
Rüger
Klaus
K
Pfizenmaier
Roland E
RE
Kontermann
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008081:Liposomes / Q000737:chemistry / Q000276:immunology*; D051379:Mice; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D008958:Models, Molecular; D053758:Nanoparticles / Q000737:chemistry*; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D010316:Particle Size; D013329:Structure-Activity Relationship; D013499:Surface Properties; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000737:chemistry / Q000276:immunology*
D000970:Antineoplastic Agents; D008081:Liposomes; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human