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    Chaperonin-Dendrimer Conjugates for siRNA Delivery. Nussbaumer Martin G,Duskey Jason T,Rother Martin,Renggli Kasper,Chami Mohamed,Bruns Nico Advanced science (Weinheim, Baden-Wurttemberg, Germany) The group II chaperonin thermosome (THS) is a hollow protein nanoparticle that can encapsulate macromolecular guests. Two large pores grant access to the interior of the protein cage. Poly(amidoamine) (PAMAM) is conjugated into THS to act as an anchor for small interfering RNA (siRNA), allowing to load the THS with therapeutic payload. THS-PAMAM protects siRNA from degradation by RNase A and traffics KIF11 and GAPDH siRNA into U87 cancer cells. By modification of the protein cage with the cell-penetrating peptide TAT, RNA interference is also induced in PC-3 cells. THS-PAMAM protein-polymer conjugates are therefore promising siRNA transfection reagents and greatly expand the scope of protein cages in drug delivery applications. 10.1002/advs.201600046
    A novel dendrimer-based complex co-modified with cyclic RGD hexapeptide and penetratin for noninvasive targeting and penetration of the ocular posterior segment. Yang Xiucheng,Wang Lihua,Li Lin,Han Meishan,Tang Shengnan,Wang Tengteng,Han Junping,He Xiaoyan,He Xiuting,Wang Aiping,Sun Kaoxiang Drug delivery Noninvasive drug delivery is a promising treatment strategy for ocular posterior segment diseases. Many physiological and anatomical barriers of the eye considerably restrict effective diffusion of therapeutics to the target site. To overcome this problem, a novel cyclic arginine-glycine-aspartate (RGD) hexapeptide and penetratin (PEN) co-modified PEGylation polyamidoamine (PAMAM) was designed as a nanocarriers (NCs), and its penetrating and targeting abilities were evaluated. In this study, we show that PAMAM-PEG (reaction molar ratio 1:32) has a relatively high grafting efficiency and low cytotoxicity. The particle size was within the range of 15-20 nm after modification with RGD and PEN. Cellular uptake of RGD-modified NCs involved significant affinity toward integrin αvβ3, which validated the targeting of neovasculature. An in vitro permeation study indicated that modification with PEN significantly improved penetration of the NCs (1.5 times higher). In vivo ocular distribution studies showed that, the NCs (modified with PEN or co-modified with RGD and PEN) were highly distributed in the cornea and retina ( < .001), and modification extended retinal retention time for more than 12 h. Therefore, these NCs appear to be a promising noninvasive ocular drug delivery system for ocular posterior segment diseases. 10.1080/10717544.2019.1667455
    Current state of the art in peptide-based gene delivery. Journal of controlled release : official journal of the Controlled Release Society Gene therapy involves introduction of exogenous genetic materials into the cells in order to correct a specific pathological condition. However, efficient delivery of the genetic materials to the target cells is hampered by a number of extracellular and intracellular barriers which necessitates the use of gene vectors. Despite the high transfection efficiencies of the viral vectors, their immunogenicity and complex manufacturing procedures has led to the quest for development of non-viral vectors with lower toxicity and easier fabrication from a variety of materials such as polymers and lipids. More recently, peptides have been introduced as new promising biomaterials for gene delivery owing to their desirable physicochemical properties and their biocompatibility. Various naturally derived, synthetic or hybrid peptides with varying sizes and structural features have been used for gene delivery. In this review, a summary of recent advances in the development of peptide-based gene delivery systems for delivery of different types of genetic materials to different types of cells/tissues has been provided. The focus of this review is on gene delivery systems consisting merely of peptides without incorporation of polymers or lipids. The transfection efficiencies of different groups of peptides and their abilities for targeted gene delivery have been viewed in the context of their chemical structures in order to provide an insight into the structural features required for efficient gene delivery by different classes of peptides and to serve as a guide for rational design of new types of peptide vectors for highly efficient and tissue-specific gene delivery. 10.1016/j.jconrel.2022.02.010
    Discovery of a Cyclic Cell-Penetrating Peptide with Improved Endosomal Escape and Cytosolic Delivery Efficiency. Molecular pharmaceutics Cyclic cell-penetrating peptide 12 (CPP12) is highly efficient for the cytosolic delivery of a variety of cargo molecules into mammalian cells in vitro and in vivo. However, its cytosolic entry efficiency is substantially reduced at lower concentrations or in the presence of serum proteins. In this study, CPP12 analogs were prepared by replacing its hydrophobic residues with amino acids of varying hydrophobicity and evaluated for cellular entry. Substitution of l-3-benzothienylalanine (Bta) for l-2-naphthylalanine (Nal) resulted in CPP12-2, which exhibits up to 3.8-fold higher cytosolic entry efficiency than CPP12, especially at low CPP concentrations; thanks to improved endosomal escape efficiency. CPP12-2 is well suited for the cytosolic delivery of highly potent cargos to achieve biological activity at low concentrations. 10.1021/acs.molpharmaceut.1c00924
    Cell-penetrating mechanism of intracellular targeting albumin: Contribution of macropinocytosis induction and endosomal escape. Ichimizu Shota,Watanabe Hiroshi,Maeda Hitoshi,Hamasaki Keisuke,Ikegami Komei,Chuang Victor Tuan Giam,Kinoshita Ryo,Nishida Kento,Shimizu Taro,Ishima Yu,Ishida Tatsuhiro,Seki Takahiro,Katsuki Hiroshi,Futaki Shiroh,Otagiri Masaki,Maruyama Toru Journal of controlled release : official journal of the Controlled Release Society We recently developed a cell-penetrating drug carrier composed of albumin (HSA) combined with palmitoyl-cyclic-(D-Arg). While it is possible that the palmitoyl-cyclic-(D-Arg)/HSA enters the cell mainly via macropinocytosis, the mechanism responsible for the induction of macropinocytosis and endosomal escape remain unknown. We report herein that palmitoyl-cyclic-(D-Arg)/HSA might interact with heparan sulfate proteoglycan and the chemokine receptor CXCR4 followed by multiple activations of the PKC/PI3K/JNK/mTOR signaling pathways to induce macropinocytosis. This result was further confirmed by a co-treatment with 70 kDa dextran, a macropinocytosis marker. Using liposomes that mimic endosomes, the leakage of 5,6-carboxyfluorescein from liposome was observed in the presence of palmitoyl-cyclic-(D-Arg)/HSA only in the case of the anionic late endosome-like liposomes but not the neutral early endosome-like liposomes. Heparin largely inhibited this leakage, suggesting the importance of electrostatic interactions between palmitoyl-cyclic-(D-Arg)/HSA and the late-endosomal membrane. Immunofluorescence staining and Western blotting data indicated that the intact HSA could be transferred from endosomes to the cytosol. These collective data suggest that the palmitoyl-cyclic-(D-Arg)/HSA is internalized via macropinocytosis and intact HSA is released from the late endosomes to the cytoplasm before the endosomes fuse with lysosomes. Palmitoyl-cyclic-(D-Arg)/HSA not only functions as an intracellular drug delivery carrier but also as an inducer of macropinocytosis. 10.1016/j.jconrel.2019.05.015
    Early endosomal escape of a cyclic cell-penetrating peptide allows effective cytosolic cargo delivery. Qian Ziqing,LaRochelle Jonathan R,Jiang Bisheng,Lian Wenlong,Hard Ryan L,Selner Nicholas G,Luechapanichkul Rinrada,Barrios Amy M,Pei Dehua Biochemistry Cyclic heptapeptide cyclo(FΦRRRRQ) (cFΦR4, where Φ is l-2-naphthylalanine) was recently found to be efficiently internalized by mammalian cells. In this study, its mechanism of internalization was investigated by perturbing various endocytic events through the introduction of pharmacologic agents and genetic mutations. The results show that cFΦR4 binds directly to membrane phospholipids, is internalized into human cancer cells through endocytosis, and escapes from early endosomes into the cytoplasm. Its cargo capacity was examined with a wide variety of molecules, including small-molecule dyes, linear and cyclic peptides of various charged states, and proteins. Depending on the nature of the cargos, they may be delivered by endocyclic (insertion of cargo into the cFΦR4 ring), exocyclic (attachment of cargo to the Gln side chain), or bicyclic approaches (fusion of cFΦR4 and cyclic cargo rings). The overall delivery efficiency (i.e., delivery of cargo into the cytoplasm and nucleus) of cFΦR4 was 4-12-fold higher than those of nonaarginine, HIV Tat-derived peptide, or penetratin. The higher delivery efficiency, coupled with superior serum stability, minimal toxicity, and synthetic accessibility, renders cFΦR4 a useful transporter for intracellular cargo delivery and a suitable system for investigating the mechanism of endosomal escape. 10.1021/bi5004102