title: A neutral lipid envelope-type nanoparticle composed of a pH-activated and vitamin E-scaffold lipid-like material as a platform for a gene carrier targeting renal cell carcinoma.
abstract: A renal cell carcinoma (RCC) is one of the refractory tumors, since it readily acquires resistance against chemotherapy. Thus, alternative therapeutic approaches such as obstructing the neovasculature are needed. We previously reported on the development of a plasmid DNA (pDNA)-encapsulating liposomal nanoparticle (LNP) as a hepatic gene delivery system that is applicable to systemic administration. The key molecular component is a SS-cleavable and pH-activated lipid-like material (ssPalm) that mounts dual sensing motifs (ternary amines and disulfide bonding) that are responsive to the intracellular environment. The main purpose of the present study was to expand its application to a tumor-targeting gene delivery system in mice bearing tumors established from a RCC (OS-RC-2). When the modification of the surface of the particle is optimized for the polyethyleneglycol (PEG), stability in the blood circulation is improved, and consequently tumor-selective gene expression can be achieved. Furthermore, gene expression in the tumor was increased slightly when the hydrophobic scaffold of the ssPalm was replaced from the conventionally used myristic acid (ssPalmM) to α-tocopherol succinate (ssPalmE). Moreover, tumor growth was significantly suppressed when the completely CpG-free pDNA encoding the solute form of VEGFR (fms-like tyrosine kinase-1: sFlt-1) was used, especially when it was delivered by the LNP formed with ssPalmE (LNP(ssPalmE)). Thus, the PEG-modified LNP(ssPalmE) is a promising gene carrier for the cancer gene therapy of RCC.
authors.affiliation: Laboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Science, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, Japan. Electronic address: akita@pharm.hokudai.ac.jp.
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Akita
authors.affiliation: Laboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Science, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, Japan.
authors.forename: Ryohei
authors.initials: R
authors.lastname: Ishiba
authors.affiliation: Laboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Science, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, Japan.
authors.forename: Ryohei
authors.initials: R
authors.lastname: Togashi
authors.affiliation: NOF CORPORATION, 3-3 Chidori-cho, Kawasaki-ku, Kawasaki, Kanagawa 210-0865, Japan.
authors.forename: Kota
authors.initials: K
authors.lastname: Tange
authors.affiliation: NOF CORPORATION, 3-3 Chidori-cho, Kawasaki-ku, Kawasaki, Kanagawa 210-0865, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Nakai
authors.affiliation: Laboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Science, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, Japan.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Hatakeyama
authors.affiliation: Laboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Science, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, Japan. Electronic address: harasima@pharm.hokudai.ac.jp.
authors.forename: Hideyoshi
authors.initials: H
authors.lastname: Harashima
mesh_terms: D000818:Animals; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D004247:DNA / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D015870:Gene Expression; D018014:Gene Transfer Techniques; D006863:Hydrogen-Ion Concentration; D007680:Kidney Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D008055:Lipids / Q000737:chemistry; D008297:Male; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D019814:Myristic Acid / Q000737:chemistry; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D012333:RNA, Messenger / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics; D014801:Vitamin A / Q000737:chemistry; D014810:Vitamin E / Q000737:chemistry
chemical_list: D008055:Lipids; D012333:RNA, Messenger; D019814:Myristic Acid; D014801:Vitamin A; D014810:Vitamin E; D011092:Polyethylene Glycols; D004247:DNA; C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1
keywords: Angiogenesis; Cancer; Gene delivery; Renal carcinoma