title: Enhancing siRNA-based cancer therapy using a new pH-responsive activatable cell-penetrating peptide-modified liposomal system.
abstract: 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.
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences.
authors.forename: Bai
authors.initials: B
authors.lastname: Xiang
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences.
authors.forename: Xue-Li
authors.initials: XL
authors.lastname: Jia
authors.affiliation: Department of Pharmacology, Hebei Medical University, Shijiazhuang, Hebei.
authors.forename: Jin-Long
authors.initials: JL
authors.lastname: Qi
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences.
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Yang
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences.
authors.forename: Wei-Hong
authors.initials: WH
authors.lastname: Sun
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences.
authors.forename: Xiao
authors.initials: X
authors.lastname: Yan
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences.
authors.forename: Shao-Kun
authors.initials: SK
authors.lastname: Yang
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences.
authors.forename: De-Ying
authors.initials: DY
authors.lastname: Cao
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences.
authors.forename: Qing
authors.initials: Q
authors.lastname: Du
authors.affiliation: School of Pharmaceutical Sciences, Peking University, Beijing, China.
authors.forename: Xian-Rong
authors.initials: XR
authors.lastname: Qi
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D057846:Cell-Penetrating Peptides / Q000008:administration & dosage* / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods*; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism; D018698:Glutamic Acid / Q000737:chemistry; D006639:Histidine / Q000737:chemistry; D006801:Humans; D006835:Hydrazones / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D008081:Liposomes / Q000737:chemistry*; D061986:MCF-7 Cells; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000494:pharmacology; D059016:Tumor Microenvironment / Q000187:drug effects / Q000235:genetics; D000097869:Polo-Like Kinase 1
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D057846:Cell-Penetrating Peptides; D018698:Glutamic Acid; D006639:Histidine; D006835:Hydrazones; D008081:Liposomes; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D000097869:Polo-Like Kinase 1
keywords: ACPP; endosomal/lysosomal escape; hydrazone; liposome; siRNA