In vitro and in vivo intracellular liposomal delivery of antisense oligonucleotides and anticancer drug.
The specific aims of this investigation were (1) to show that conventional and PEGylated liposomes can penetrate cancer cells in vitro and in vivo; (2) to demonstrate that liposomes can be successfully used both for cytoplasmic and nuclear delivery of therapeutics, including anticancer drugs and antisense oligonucleotides; (3) to examine the specific activity of anticancer drugs and nucleotides delivered inside tumor cells by PEGylated liposomes; and (4) to confirm that simultaneous inhibition of pump and nonpump cellular resistance by liposomal ASO can substantially enhance the antitumor activity of traditional well established anticancer drugs in mice bearing xenografts of human multidrug resistant ovarian carcinoma. Experimental results show that PEGylated liposomes are capable of penetrating directly into tumor cells after systemic administration in vivo and do successfully provide cytoplasmic and nuclear delivery of encapsulated anticancer drug (doxorubicin, DOX) and antisense oligonucleotides (ASO). Encapsulation of DOX and ASO into liposomes substantially increased their specific activity. Simultaneous suppression of pump and nonpump resistance dramatically enhanced the ability of DOX for inducing apoptosis leading to higher in vitro cytotoxicity and in vivo antitumor activity.
Pakunlu
Refika I
RI
Department of Pharmaceutics, Rutgers, The State University of New Jersey, Piscataway, NJ 08854-8020, USA.
Wang
Yang
Y
Saad
Maha
M
Khandare
Jayant J
JJ
Starovoytov
Valentin
V
Minko
Tamara
T
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology; D004337:Drug Carriers; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019450:Genes, MDR; D019254:Genes, bcl-2; D006801:Humans; D008081:Liposomes; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011092:Polyethylene Glycols / Q000737:chemistry; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013778:Tetrazolium Salts; D013844:Thiazoles
D000970:Antineoplastic Agents; D004337:Drug Carriers; D008081:Liposomes; D009363:Neoplasm Proteins; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D013778:Tetrazolium Salts; D013844:Thiazoles; D011092:Polyethylene Glycols; D004317:Doxorubicin; C022616:thiazolyl blue