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A new era of nanomedicines that involve nucleic acids/gene therapy has been opened after two decades in 21st century and new types of more efficient drug delivery systems (DDS) are ...highly expected and will include extrahepatic delivery. In this review, we summarize the possibility and expectations for the extrahepatic delivery of small interfering RNA/messenger RNA/plasmid DNA/genome editing to the spleen, lung, tumor, lymph nodes as well as the liver based on our studies as well as reported information. Passive targeting and active targeting are discussed in in vivo delivery and the importance of controlled intracellular trafficking for successful therapeutic results are also discussed. In addition, mitochondrial delivery as a novel strategy for nucleic acids/gene therapy is introduced to expand the therapeutic dimension of nucleic acids/gene therapy in the liver as well as the heart, kidney and brain.
Due to the ability of the blood–brain barrier(BBB) to prevent the entry of drugs into the brain, it is a challenge to treat central nervous system disorders pharmacologically. The development of ...nanotechnology provides potential to overcome this problem. In this review, the barriers to brain-targeted drug delivery are reviewed, including the BBB, blood–brain tumor barrier(BBTB), and nose-to-brain barrier. Delivery strategies are focused on overcoming the BBB, directly targeting diseased cells in the brain, and dual-targeted delivery. The major concerns and perspectives on constructing brain-targeted delivery systems are discussed.
SUMMARY
Precise genetic modification can be achieved via a sequence homology‐mediated process known as gene targeting (GT). Whilst established for genome engineering purposes, the application of GT ...in plants still suffers from a low efficiency for which an explanation is currently lacking. Recently reported reduced rates of GT in A. thaliana deficient in polymerase theta (Polθ), a core component of theta‐mediated end joining (TMEJ) of DNA breaks, have led to the suggestion of a direct involvement of this enzyme in the homology‐directed process. Here, by monitoring homology‐driven gene conversion in plants with CRISPR reagent and donor sequences pre‐integrated at random sites in the genome (in planta GT), we demonstrate that Polθ action is not required for GT, but instead suppresses the process, likely by promoting the repair of the DNA break by end‐joining. This finding indicates that lack of donor integration explains the previously established reduced GT rates seen upon transformation of Polθ‐deficient plants. Our study additionally provides insight into ectopic gene targeting (EGT), recombination events between donor and target that do not map to the target locus. EGT, which occurs at similar frequencies as “true” GT during transformation, was rare in our in planta GT experiments arguing that EGT predominantly results from target locus recombination with nonintegrated T‐DNA molecules. By describing mechanistic features of GT our study provides directions for the improvement of precise genetic modification of plants.
Significance Statement
Here, we resolve an outstanding question regarding the involvement of polymerase theta in gene targeting in plants: we find it to act as a suppressor instead of being a requirement. This finding, together with new insight into the requirements for ectopic gene targeting, will help guide future research for the development of precise genetic engineering methods.
Mitochondria-targeted drug delivery in cancers Cho, Hana; Cho, Yong-Yeon; Shim, Min Suk ...
Biochimica et biophysica acta. Molecular basis of disease,
08/2020, Letnik:
1866, Številka:
8
Journal Article
Recenzirano
Mitochondria are considered one of the most important subcellular organelles for targeting and delivering drugs because mitochondria are the main location for various cellular functions and energy ...(i.e., ATP) production, and mitochondrial dysfunctions and malfunctions cause diverse diseases such as neurodegenerative disorders, cardiovascular disorders, metabolic disorders, and cancers. In particular, unique mitochondrial characteristics (e.g., negatively polarized membrane potential, alkaline pH, high reactive oxygen species level, high glutathione level, high temperature, and paradoxical mitochondrial dynamics) in pathological cancers have been used as targets, signals, triggers, or driving forces for specific sensing/diagnosing/imaging of characteristic changes in mitochondria, targeted drug delivery on mitochondria, targeted drug delivery/accumulation into mitochondria, or stimuli-triggered drug release in mitochondria. In this review, we describe the distinctive structures, functions, and physiological properties of cancer mitochondria and discuss recent technologies of mitochondria-specific “key characteristic” sensing systems, mitochondria-targeted “drug delivery” systems, and mitochondrial stimuli-specific “drug release” systems as well as their strengths and weaknesses.
•Mitochondria, which regulate cellular metabolism, are a pivotal target of drugs.•Cancer mitochondria have unique properties of MMP, pH, ROS, GSH, O2, and temperature.•Lipophilic cations deliver drugs into mitochondria by a negatively polarized MMP.•Mitochondria-targeting moieties guide drugs to accumulate in mitochondria.
The past decades have witnessed great progress in nanoparticle (NP)‐based brain‐targeting drug delivery systems, while their therapeutic potentials are yet to be fully exploited given that the ...majority of them are lost during the delivery process. Rational design of brain‐targeting drug delivery systems requires a deep understanding of the entire delivery process along with the issues that they may encounter. Herein, this review first analyzes the typical delivery process of a systemically administrated NPs‐based brain‐targeting drug delivery system and proposes a six‐step CRITID delivery cascade: circulation in systemic blood, recognizing receptor on blood‐brain barrier (BBB), intracellular transport, diseased cell targeting after entering into parenchyma, internalization by diseased cells, and finally intracellular drug release. By dissecting the entire delivery process into six steps, this review seeks to provide a deep understanding of the issues that may restrict the delivery efficiency of brain‐targeting drug delivery systems as well as the specific requirements that may guarantee minimal loss at each step. Currently developed strategies used for troubleshooting these issues are reviewed and some state‐of‐the‐art design features meeting these requirements are highlighted. The CRITID delivery cascade can serve as a guideline for designing more efficient and specific brain‐targeting drug delivery systems.
This review first proposes a six‐step CRITID delivery cascade for dissecting the entire delivery process of brain‐targeting nanoparticle delivery systems. By reviewing the issues and requirements that limit delivery efficiency at each step, as well as corresponding strategies for troubleshooting, this review seeks to provide a guideline to design brain‐targeting drug delivery systems with improved delivery efficiency at each step.
Modern drug delivery system (DDS) exerts its unique superiority as to enhancing drug efficacy while reducing their toxicity, which relies heavily on an accurate route of delivery. Based on the fact ...that most drugs have their own specific target of action, increasing attention is paid to developing strategies for targeting certain tissues, cell lines, and even intracellular structures. Endoplasmic reticulum (ER) is a dynamic and versatile subcellular organelle that participates in multiple physiological and biochemical processes, supporting the survival and homeostasis-maintenance of cells. Genetic or environmental damages may induce ER stress, which is closely coupled to the occurrence and development of many human diseases and even cancers. In this review, recent progress in strategies of direct ER-targeting with specific molecules or carriers are summarized. We also discuss several advances in fields of indirect ER-targeting. This work may provide a deeper understanding over the ER biology and boost the development of precise intracellular regulation, displaying broad prospects of application.
The pitfall of all chemotherapeutics lies in drug resistance and the severe side effects experienced by patients. One way to reduce the off-target effects of chemotherapy on healthy tissues is to ...alter the biodistribution of drug. This can be achieved in two ways: Passive targeting utilizes shape, size, and surface chemistry to increase particle circulation and tumor accumulation. Active targeting employs either chemical moieties (e.g. peptides, sugars, aptamers, antibodies) to selectively bind to cell membranes or responsive elements (e.g. ultrasound, magnetism, light) to deliver its cargo within a local region. This article will focus on the systemic administration of anti-cancer agents and their ability to home to tumors and, if relevant, distant metastatic sites.
Various diseases remain untreated due to lack of suitable therapeutic moiety or a suitable drug delivery device, especially where toxicities and side effects are the primary reason for concern. ...Cancer and fungal infections are diseases where treatment schedules are not completed due to severe side effects or lengthy treatment protocols. Advanced treatment approaches such as active targeting and inhibition of angiogenesis may be preferred method for the treatment for malignancy over the conventional method. Niosomes may be a better alternative drug delivery carrier for various therapeutic moieties (either hydrophilic or hydrophobic) and also due to ease of surface modification, non-immunogenicity and economical. Active targeting approach may be done by targeting the receptors through coupling of suitable ligand on niosomal surface. Moreover, various receptors (CD44, folate, epidermal growth factor receptor (EGFR) & Vascular growth factor receptor (VGFR)) expressed by malignant cells have also been reviewed. The preparation of suitable niosomal formulation also requires considerable attention, and its formulation depends upon various factors such as selection of non-ionic surfactant, method of fabrication, and fabrication parameters. A combination therapy (dual drug and immunotherapy) has been proposed for the treatment of fungal infection with special consideration for surface modification with suitable ligand on niosomal surface to sensitize the receptors (C-type lectin receptors, Toll-like receptors & Nucleotide-binding oligomerization domain-like receptors) present on immune cells involved in fungal immunity. Certain gene silencing concept has also been discussed as an advanced alternative treatment for cancer by silencing the mRNA at molecular level using short interfering RNA (si-RNA).
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Most soluble proteins enclosed in peroxisomes encode either type-1 or type-2 peroxisomal targeting signals (PTS1 or PTS2), which act as postal codes and define the proteins' intracellular ...destination. Thus, various computational programs have been developed to evaluate the probability of specific peptide sequences for being a functional PTS or to scan the primary sequence of proteins for such signals. Among these prediction algorithms the PTS1-predictor ( https://mendel.imp.ac.at/pts1/ ) has been amply used, but the research logic of this and other PTS1 prediction tools is occasionally misjudged giving rise to characteristic pitfalls. Here, a proper utilization of the PTS1-predictor is introduced together with a framework of additional tests to increase the validity of the interpretation of results. Moreover, a list of possible causes for a mismatch between results of such predictions and experimental outcomes is provided. However, the foundational arguments apply to other prediction tools for PTS1 motifs as well.
An understanding of the interactions between nanoparticles and biological systems is of significant interest. Studies aimed at correlating the properties of nanomaterials such as size, shape, ...chemical functionality, surface charge, and composition with biomolecular signaling, biological kinetics, transportation, and toxicity in both cell culture and animal experiments are under way. These fundamental studies will provide a foundation for engineering the next generation of nanoscale devices. Here, we provide rationales for these studies, review the current progress in studies of the interactions of nanomaterials with biological systems, and provide a perspective on the long-term implications of these findings.
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