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: Hidetaka Akita, Ryohei Ishiba, Ryohei Togashi, Kota Tange, Yuta Nakai, Hiroto Hatakeyama, Hideyoshi Harashima
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 200 Pg. 97-105 (Feb 28 2015) ISSN: 1873-4995 [Electronic] Netherlands
• PMID: 25543000 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier B.V. All rights reserved.

Chemical References

• Lipids
• RNA, Messenger
• Myristic Acid
• Vitamin A
• Vitamin E
• Polyethylene Glycols
• DNA
• Flt1 protein, mouse
• Vascular Endothelial Growth Factor Receptor-1

Topics

• Animals
• Carcinoma, Renal Cell (genetics, pathology, therapy)
• Cell Line, Tumor
• DNA (administration & dosage, chemistry, pharmacokinetics)
• Gene Expression
• Gene Transfer Techniques
• Hydrogen-Ion Concentration
• Kidney Neoplasms (genetics, pathology, therapy)
• Lipids (chemistry)
• Male
• Mice, Inbred ICR
• Mice, Nude
• Myristic Acid (chemistry)
• Nanoparticles (administration & dosage, chemistry)
• Polyethylene Glycols (chemistry)
• RNA, Messenger (metabolism)
• Tumor Burden (drug effects)
• Vascular Endothelial Growth Factor Receptor-1 (genetics)
• Vitamin A (chemistry)
• Vitamin E (chemistry)