title: Prostate cancer cell death produced by the co-delivery of Bcl-xL shRNA and doxorubicin using an aptamer-conjugated polyplex.
abstract: We investigated the synergism between shRNAs against Bcl-xL and doxorubicin (DOX) using aptamer-conjugated polyplexes (APs) in combination cancer therapy. Synergistic and selective cancer cell death was achieved by AP-mediated co-delivery of very small amounts of DOX and Bcl-xL-specific shRNA, which simultaneously activated an intrinsic apoptotic pathway. A branched polyethyleneimine (PEI) was grafted to polyethylene glycol (PEI-PEG) to serve as a vehicle for shRNA delivery, and its surface was further conjugated with an anti-PSMA aptamer (APT) for the selective delivery of APs to prostate cancer cells that express prostate-specific membrane antigens (PSMA) on their cell surface. The APs were finally obtained after intercalation of DOX to form shRNA/PEI-PEG-APT/DOX conjugates. Cell viability assays and FACS analysis of GFP expression against PC3 (PSMA deficient) and LNCaP (PSMA overexpressed) cells demonstrated that the synthesized APs inhibited the growth of PSMA-abundant prostate cancer cells with strong cell selectivity. Consequently, IC(50) values of APs loaded with both DOX and shRNA were approximately 17-fold less than those for the simple mixture of shRNA plus drug (shRNA/Lipofectamine + DOX). These results suggest that AP-mediated co-delivery of an anti-cancer drug and shRNA against Bcl-xL may widen the therapeutic window and allow for the selective destruction of cancer cells.
authors.affiliation: Department of Chemical and Biomolecular Engineering, College of Engineering, Yonsei University, Seoul, Republic of Korea.
authors.forename: Eunjung
authors.initials: E
authors.lastname: Kim
authors.forename: Yukyung
authors.initials: Y
authors.lastname: Jung
authors.forename: Hyangtae
authors.initials: H
authors.lastname: Choi
authors.forename: Jaemoon
authors.initials: J
authors.lastname: Yang
authors.forename: Jin-Suck
authors.initials: JS
authors.lastname: Suh
authors.forename: Yong-Min
authors.initials: YM
authors.lastname: Huh
authors.forename: Kunhong
authors.initials: K
authors.lastname: Kim
authors.forename: Seungjoo
authors.initials: S
authors.lastname: Haam
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D052157:Aptamers, Nucleotide / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D004337:Drug Carriers / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008297:Male; D008422:Materials Testing; D011092:Polyethylene Glycols / Q000737:chemistry / Q000378:metabolism; D011094:Polyethyleneimine / Q000737:chemistry / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics / Q000627:therapeutic use
chemical_list: D000903:Antibiotics, Antineoplastic; D052157:Aptamers, Nucleotide; C494811:BCL2L1 protein, human; D004337:Drug Carriers; D034741:RNA, Small Interfering; D051020:bcl-X Protein; D011092:Polyethylene Glycols; D004317:Doxorubicin; D011094:Polyethyleneimine