title: Development of nanoparticles incorporating a novel liposomal membrane destabilization peptide for efficient release of cargos into cancer cells.
abstract: In anti-cancer therapy mediated by a nanoparticle-based drug delivery system (DDS), overall efficacy depends on the release efficiency of cargos from the nanoparticles in the cancer cells as well as the specificity of delivery to tumor tissue. However, conventional liposome-based DDS have no mechanism for specifically releasing the encapsulated cargos inside the cancer cells. To overcome this barrier, we developed nanoparticles containing a novel liposomal membrane destabilization peptide (LMDP) that can destabilize membranes by cleavage with intramembranous proteases on/in cancer cells. Calcein encapsulated in liposomes modified with LMDP (LMDP-lipo) was effectively released in the presence of a membrane fraction containing an LMDP-cleavable protease. The release was inhibited by a protease inhibitor, suggesting that LMDP-lipo could effectively release its cargo into cells in response to a cancer-specific protease. Moreover, when LMDP-lipo contained fusogenic lipids, the release of cargo was accelerated, suggesting that the fusion of LMDP-lipo with cellular membranes was the initial step in the intracellular delivery. Time-lapse microscopic observations showed that the release of cargo from LMDP-lipo occurred immediately after association of LMDP-lipo with target cells. Consequently, LMDP-lipo could be a useful nanoparticle capable of effective release of cargos specifically into targeted cancer cells.
authors.affiliation: Department of Biophysical Chemistry, Kyoto Pharmaceutical University, Kyoto, Japan.
authors.forename: Shoko
authors.initials: S
authors.lastname: Itakura
authors.affiliation: Department of Biophysical Chemistry, Kyoto Pharmaceutical University, Kyoto, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Hama
authors.affiliation: Department of Biophysical Chemistry, Kyoto Pharmaceutical University, Kyoto, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ohgita
authors.affiliation: Department of Biophysical Chemistry, Kyoto Pharmaceutical University, Kyoto, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Kogure
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D016503:Drug Delivery Systems; D005452:Fluoresceins / Q000378:metabolism; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008081:Liposomes / Q000737:chemistry*; D008567:Membranes, Artificial; D053758:Nanoparticles / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry*; D059008:Time-Lapse Imaging
chemical_list: D005452:Fluoresceins; D008081:Liposomes; D008567:Membranes, Artificial; D010455:Peptides; D053829:Amyloid Precursor Protein Secretases; C007740:fluorexon