Enhanced transfection efficiency of a systemically delivered tumor-targeting immunolipoplex by inclusion of a pH-sensitive histidylated oligolysine peptide.
Successful cancer gene therapy depends on the development of non-toxic, efficient, tumor cell- specific systemic gene delivery systems. Our laboratory has developed a systemically administered, ligand-liposome complex that can effectively and preferentially deliver its therapeutic payload to both primary and metastatic tumors. To further improve the transfection efficiency of this targeting complex, a synthetic pH-sensitive histidylated oligolysine K[K(H)KKK]5-K(H)KKC (HoKC), designed to aid in endosomal escape and condensation of DNA, was included in the complex. The presence of HoKC increased the in vitro transfection efficiency over that of the original complex. Moreover, no increase in cytotoxicity was observed due to the presence of the HoKC peptide. In a DU145 human prostate cancer xenograft tumor model in athymic nude mice, inclusion of the HoKC peptide did not interfere with the tumor targeting specificity of the i.v. administered ligand/liposome/DNA complex. Most importantly, the level of transgene expression was significantly elevated in the tumors, but not in the normal tissue in those animals receiving the complex incorporating HoKC. The in vivo enhancement of transfection efficiency by this modified gene delivery vehicle could lead to a reduction in the number of administrations required for antitumor efficacy.
Yu
Wei
W
Department of Oncology, Lombardi Cancer Center, Georgetown University, The Research Building/E420, 3970 Reservoir Road NW, Washington, DC 20057-1469, USA.
Pirollo
Kathleen F
KF
Yu
Bin
B
Rait
Antonina
A
Xiang
Laiman
L
Huang
Weiqun
W
Zhou
Qi
Q
Ertem
Gözen
G
Chang
Esther H
EH
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004247:DNA / Q000378:metabolism; D015870:Gene Expression; D015316:Genetic Therapy; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007128:Immunoglobulin Fragments / Q000378:metabolism; D008024:Ligands; D008081:Liposomes / Q000378:metabolism / Q000633:toxicity; D018942:Macrolides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008942:Mitoxantrone / Q000627:therapeutic use; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D009842:Oligopeptides / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000628:therapy; D011990:Receptors, Transferrin / Q000276:immunology; D014162:Transfection / Q000379:methods*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D007128:Immunoglobulin Fragments; C483825:K(K(H)KKK)5-K(H)KKC; D008024:Ligands; D008081:Liposomes; D018942:Macrolides; D009842:Oligopeptides; D010455:Peptides; D011990:Receptors, Transferrin; C057620:bafilomycin A; D004247:DNA; D008942:Mitoxantrone