[Activatable cell-penetrating peptides: a potential activatable modality for diseases diagnosis and therapy].

Cell-penetrating peptides are composed of positively-charged amino acids that can mediate molecules or nano-carriers across cell membranes. However, most of the known cell-penetrating peptides have no cell- or tissue-specificity, with affinity to almost all types of cells in internalization. The non-specificity of cell-penetrating peptides is a significant obstacle in the application to targeted delivery of imaging probes and therapeutic agents. Accordingly, many studies focused on selective switching of systemically-delivered inert cell-penetrating peptides into active forms in diseased tissues. Tsien groups introduced the concept of activatable cell-penetrating peptides in 2004. Subsequently, a growing number of similar delivery systems(molecular or nano-sized) have been documented, and the sensitive factors have included enzyme, lower p H, light and exogenous component. In this paper, we make an overview of the development of activatable delivery system in recent years.

Enhancing siRNA-based cancer therapy using a new pH-responsive activatable cell-penetrating peptide-modified liposomal system.

As a potent therapeutic agent, small interfering RNA (siRNA) has been exploited to silence critical genes involved in tumor initiation and progression. However, development of a desirable delivery system is required to overcome the unfavorable properties of siRNA such as its high degradability, molecular size, and negative charge to help increase its accumulation in tumor tissues and promote efficient cellular uptake and endosomal/lysosomal escape of the nucleic acids. In this study, we developed a new activatable cell-penetrating peptide (ACPP) that is responsive to an acidic tumor microenvironment, which was then used to modify the surfaces of siRNA-loaded liposomes. The ACPP is composed of a cell-penetrating peptide (CPP), an acid-labile linker (hydrazone), and a polyanionic domain, including glutamic acid and histidine. In the systemic circulation (pH 7.4), the surface polycationic moieties of the CPP (polyarginine) are "shielded" by the intramolecular electrostatic interaction of the inhibitory domain. When exposed to a lower pH, a common property of solid tumors, the ACPP undergoes acid-catalyzed breakage at the hydrazone site, and the consequent protonation of histidine residues promotes detachment of the inhibitory peptide. Subsequently, the unshielded CPP would facilitate the cellular membrane penetration and efficient endosomal/lysosomal evasion of liposomal siRNA. A series of investigations demonstrated that once exposed to an acidic pH, the ACPP-modified liposomes showed elevated cellular uptake, downregulated expression of polo-like kinase 1, and augmented cell apoptosis. In addition, favorable siRNA avoidance of the endosome/lysosome was observed in both MCF-7 and A549 cells, followed by effective cytoplasmic release. In view of its acid sensitivity and therapeutic potency, this newly developed pH-responsive and ACPP-mediated liposome system represents a potential platform for siRNA-based cancer treatment.

The complete mitochondrial genome of Yunnan black goat (Capra hircus).

Yunnan black goat (Capra hircus) is one of the famous native goat breed in China. In this study, the complete nucleotide sequence of Yunnan black goat mitochondrial genome was determined for the first time. Sequence analysis showed that the genome structure was in typical with other vertebra animals. It contained 22 tRNA genes, 2 ribosomal RNA genes, 13 protein-coding genes and 1 control region (D-loop region). The base composition was A (33.6%), G (13.1%), C (26.0%) and T (27.3%), so the percentage of A and T (60.9%) was higher than that of G and C.