Liposomes are one of the most promising systems for selective cellular targeting via introduction of specific ligands for cell-surface receptors. After being taken up by the cells, these liposomes usually follow intracellular pathways of receptor-mediated endocytosis. Control of intracellular trafficking is required for optimized drug delivery. In this study, we elucidated the intracellular fate of transferrin-modified liposomes and succeeded in altering it by introducing the pH-sensitive fusogenic peptide, GALA (WEAALAEALAEALAEHLAEALAEALEALAA). Transferrins that are chemically attached to a liposomal surface (Tf-L) were internalized via receptor-mediated endocytosis more slowly than unmodified transferrins. In contrast to the recyclable nature of transferrin, liposome-attached transferrins together with encapsulated rhodamines were retained in vesicular compartments. When GALA was introduced into liposomal membranes using a cholesteryl moiety for anchoring (Chol-GALA), rhodamines were efficiently released and diffused into the cytosol. The addition of GALA to the Tf-L-containing medium or the encapsulation of GALA in Tf-L did not induce similar effects. These results clearly indicate that GALA must be present on the surface of liposomes to exert its function. In vitro energy transfer and dynamic light scattering experiments suggested that the endosomal escape of the encapsulates in Tf-L equipped with Chol-GALA can be attributed to pH-dependent membrane fusion. With GALA present on the surface, intracellular trafficking of liposomes after receptor-mediated endocytosis could be successfully controlled.
We previously reported that transferrin (Tf)-modified liposomes (Tf-L) additionally modified with a cholesterylated pH-sensitive fusogenic peptide (Chol-GALA) can release an encapsulated aqueous phase marker to cytosol via endosomal membrane fusion. However, further obstacles need to be overcome to bring the Tf-L to the level of a viral-like gene delivery system. In this study, we developed a novel packaging method to encapsulate condensed plasmid DNA into PEgylated Tf-L (Tf-PEG-L) to form a core-shell-type nanoparticle. The most difficult challenge was to provide a mechanism of escape for the condensed core from endosome to cytosol in the presence of polyethylene glycol (PEG). We hypothesized that a membrane-introduced Chol-GALA and a PEgylated GALA would interact synergistically to induce membrane fusion between liposome and endosome. By simultaneously incorporating Chol-GALA into the membrane of Tf-PEG-L and GALA at tips of PEG chains, a condensed core was released into cytosol, and transfection activity increased 100-fold. We concluded that topological control was responsible for the synergistic effect of GALA derivatives introduced on Tf-PEG-L.
Mastoparan (MP), a potent facilitator of mitochondrial permeability transition (PT), could be used as an antitumor agent, if it were encapsulated in a tumor selective delivery system. We recently developed transferrin-modified liposomes (Tf-L) with a pH-sensitive fusogenic peptide (GALA), which delivers an encapsulated fluorescent marker into cytosol efficiently. In this study, we encapsulated MP into Tf-L with GALA for the selective delivery to mitochondria of tumor cells. The MP showed potent PT activity at concentrations above 25 M in a homogenate of K 562 cells as well as in isolated mitochondria in the presence of phosphate. Tf-L equipped with cholesteryl GALA can release encapsulated sulforhodamine B, while Tf-L failed, as evidenced by confocal laser scanning microscopy. The MP, which was delivered with Tf-L with GALA, released cytochrome c (cyt c) from mitochondria to the cytosol, while free MP released cyt c not only to the cytosol but also extracellulary. These results demonstrate the utility of MP in Tf-L with GALA for cancer therapy.
The reaction of diarylalkynes with Cp2ZrBu2 and successive treatment with CrCl3 afforded linear tetramers of diarylalkynes, (1E,3E,5E,7E)-octatetraenes. On the other hand, dialkylalkynes did not give the corresponding octatetraenes but cyclized products, such as pyridines and pyridones, by the reaction with nitriles and isocyanates.
Personal Computer" TADASHI AKIMOTO, IKUO MURAl, SHIN CHAKI, YlJICm 'OGAWA, AND ISAO SHOJI Abstract--:-The design of a practical system for measuring twoparameter signals is reported. To obtain constantly changing energy spectra of nuclear reactor assemblies due to repeated insertion of pulsed neutron sources, the simultaneous acquisition of time and energy data are needed. A computer-based dual-parameter multichannel pulse-height analyzer (MCA) has been developed; it employs a personal coniputer, two analog-to-digital converters (ADC's), and a parallel interface board for handling these signals. The system showed excellent performance characteristics with a minimum data processing time of about 14 p's; a maximum conversion gain of 211 channels (for example, 512 x 512 ch); a count capacity of 232-1/ch (2 16 _lIch at 512 x 512 ch); and the time required for graphic display of approximately 3 s/2 16 dots (contour display) or about 0.1 S/(216/ 16) dots (isometric display). Large data arrays were handled dynamically with a segment register. 'The data processing speed was improved by transferring the data from the ADC to the central processing unit (CPU) in 16-bit words and simultaneously reading the statu$ flag and the data. The graphic display process was speeded up by writing the data bit corresponding to the locations directly into the graphic video random access memory (VRAM). The system is simple to oper~te, and by changing the memory size and coincidence ' resolution time by software operations, it is highly flexible.
Polyphenylalkene derivatives Q 0740Formation of Linear Tetramers of Diarylalkynes by the Zr/Cr System. -Addition of CrCl3 to a mixture of diarylalkynes (I) and zirconocene proceeds with stereoselective tetramerization to afford the linear polyaryltetraenes in all-E geometry. Additional studies of the novel Zr/Cr system reveal that transmetalation of alkyl-substituted zirconacyclopentadienes like (III) with CrCl3 provides chromacyclopentadiene intermediates which react with nitriles, isocyanates, olefins or alkynes to give the cyclization products, e.g. (V), (VII) or (IX), respectively. -(TAKAHASHI*, T.; LIU, Y.; IESATO, A.; CHAKI, S.; NAKAJIMA, K.; KANNO, K.-I.; J. Am.
Abstract-The design and feasibility of a simple and practical system for measuring two-parameter signals is reported. A dual-parameter multichannel pulse-height analyzer (MCA), which uses two central processing units (CPU's), was developed and designed. One computer (master computer) controls the other computer (slave computer), and also displays, records, and analyzes the data. The slave computer controls two analog-to-digital converters (ADC's), collects the dualparameter data, and then transfers the collected data to the master computer. Three methods of data transfer between the two CPU's are examined and discussed. The count capacity at the data collection by the slave computer was 2 16 _1 / ch (2-byte-long data), and this was expanded to 2 32 _1/ ch (4-byte-long data) at the master computer. The data are analyzed and at any time stored in the storage apparatus by the dual CPU system. The system demonstrated stable operation over long me:.surement periods and the system was effectively utilized.
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