Stimuli-responsive oligonucleotides in prodrug-based approaches for gene silencing

Beilstein Journal of Organic Chemistry ◽

10.3762/bjoc.14.32 ◽

2018 ◽

Vol 14 ◽

pp. 436-469 ◽

Cited By ~ 12

Author(s):

Françoise Debart ◽

Christelle Dupouy ◽

Jean-Jacques Vasseur

Keyword(s):

Gene Silencing ◽

Opposite Effect ◽

Biological Fluids ◽

General Concept ◽

Stimuli Responsive ◽

Cell Penetration ◽

A Current ◽

Target Effects ◽

Physical Heat

Oligonucleotides (ONs) have been envisaged for therapeutic applications for more than thirty years. However, their broad use requires overcoming several hurdles such as instability in biological fluids, low cell penetration, limited tissue distribution, and off-target effects. With this aim, many chemical modifications have been introduced into ONs definitively as a means of modifying and better improving their properties as gene silencing agents and some of them have been successful. Moreover, in the search for an alternative way to make efficient ON-based drugs, the general concept of prodrugs was applied to the oligonucleotide field. A prodrug is defined as a compound that undergoes transformations in vivo to yield the parent active drug under different stimuli. The interest in stimuli-responsive ONs for gene silencing functions has been notable in recent years. The ON prodrug strategies usually help to overcome limitations of natural ONs due to their low metabolic stability and poor delivery. Nevertheless, compared to permanent ON modifications, transient modifications in prodrugs offer the opportunity to regulate ON activity as a function of stimuli acting as switches. Generally, the ON prodrug is not active until it is triggered to release an unmodified ON. However, as it will be described in some examples, the opposite effect can be sought. This review examines ON modifications in response to various stimuli. These stimuli may be internal or external to the cell, chemical (glutathione), biochemical (enzymes), or physical (heat, light). For each stimulus, the discussion has been separated into sections corresponding to the site of the modification in the nucleotide: the internucleosidic phosphate, the nucleobase, the sugar or the extremities of ONs. Moreover, the review provides a current and detailed account of stimuli-responsive ONs with the main goal of gene silencing. However, for some stimuli-responsive ONs reported in this review, no application for controlling gene expression has been shown, but a certain potential in this field could be demonstrated. Additionally, other applications in different domains have been mentioned to extend the interest in such molecules.

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Stimuli-responsive release and efficient siRNA delivery in non-small cell lung cancer by a poly(l-histidine)-based multifunctional nanoplatform

Journal of Materials Chemistry B ◽

10.1039/c9tb02764e ◽

2020 ◽

Vol 8 (8) ◽

pp. 1616-1628 ◽

Cited By ~ 4

Author(s):

Menghao Shi ◽

Jiulong Zhang ◽

Ziyuan Huang ◽

Yuying Chen ◽

Shuang Pan ◽

...

Keyword(s):

Lung Cancer ◽

Gene Silencing ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Sirna Delivery ◽

Small Cell ◽

Proton Sponge ◽

Stimuli Responsive ◽

Small Cell Lung

A stimuli-responsive nanoplatform achieves successful intracellular siRNA delivery due to a proton sponge effect based on poly(l-histidine) and effective gene silencing in vivo.

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In vivo cell specific gene silencing in the liver using novel siRNA-loaded biodegradable nanohydrogel particles

Zeitschrift für Gastroenterologie ◽

10.1055/s-0036-1586951 ◽

2016 ◽

Vol 54 (08) ◽

Author(s):

D Schuppan

Keyword(s):

Gene Silencing ◽

Specific Gene

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Nitroxyl Modified Tobacco Mosaic Virus as a Metal-Free High-Relaxivity MRI and EPR Active Superoxide Sensor

10.26434/chemrxiv.6241913 ◽

2018 ◽

Author(s):

Madushani Dharmarwardana ◽

André F. Martins ◽

Zhuo Chen ◽

Philip M. Palacios ◽

Chance M. Nowak ◽

...

Keyword(s):

Tobacco Mosaic Virus ◽

Mosaic Virus ◽

Single Molecule ◽

Biological Fluids ◽

Cellular Respiration ◽

Organic Radical ◽

Paramagnetic Resonance ◽

Metal Free ◽

Disease States

Superoxide overproduction is known to occur in multiple disease states requiring critical care yet non-invasive detection of superoxide in deep tissue remains a challenge. Herein, we report a metal-free magnetic resonance imaging (MRI) and electron paramagnetic resonance (EPR) active contrast agent prepared by “click conjugating” paramagnetic organic radical contrast agents (ORCAs) to the surface of tobacco mosaic virus (TMV). While ORCAs are known to be reduced in vivo to an MRI/EPR silent state, their oxidation is facilitated specifically by reactive oxygen species—in particular superoxide—and are largely unaffected by peroxides and molecular oxygen. Unfortunately, single molecule ORCAs typically offer weak MRI contrast. In contrast, our data confirm that the macromolecular ORCA-TMV conjugates show marked enhancement for T1 contrast at low field (<3.0 T), and T2 contrast at high field (9.4 T). Additionally, we demonstrated that the unique topology of TMV allows for “quenchless fluorescent” bimodal probe for concurrent fluorescence and MRI/EPR imaging, which was made possible by exploiting the unique inner and outer surface of the TMV nanoparticle. <a>Finally, we show TMV-ORCAs do not respond to normal cellular respiration, minimizing the likelihood for background, yet still respond to enzymatically produced superoxide in complicated biological fluids like serum.</a>

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Gene Silencing using siRNA for Preventing Liver Ischaemia-Reperfusion Injury

Current Pharmaceutical Design ◽

10.2174/1381612824666180807124356 ◽

2018 ◽

Vol 24 (23) ◽

pp. 2692-2700 ◽

Cited By ~ 1

Author(s):

H. Susana Marinho ◽

Paulo Marcelino ◽

Helena Soares ◽

Maria Luísa Corvo

Keyword(s):

Gene Silencing ◽

Reperfusion Injury ◽

Therapeutic Potential ◽

Major Complication ◽

Ischaemia Reperfusion Injury ◽

Small Interference Rna ◽

Ischaemia Reperfusion ◽

Promising Therapeutic Approach ◽

Sirna Therapy

Background: Ischaemia-reperfusion injury (IRI), a major complication occurring during organ transplantation, involves an initial ischemia insult, due to loss of blood supply, followed by an inflammation-mediated reperfusion injury. A variety of molecular targets and pathways involved in liver IRI have been identified. Gene silencing through RNA interference (RNAi) by means of small interference RNA (siRNA) targeting mediators of IRI is a promising therapeutic approach. Objective: This study aims at reviewing the use of siRNAs as therapeutic agents to prevent IRI during liver transplantation. Method: We review the crucial choice of siRNA targets and the advantages and problems of the use of siRNAs. Results: We propose possible targets for siRNA therapy during liver IRI. Moreover, we discuss how drug delivery systems, namely liposomes, may improve siRNA therapy by increasing siRNA stability in vivo and avoiding siRNA off-target effects. Conclusion: siRNA therapeutic potential to preclude liver IRI can be improved by a better knowledge of what molecules to target and by using more efficient delivery strategies.

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Current Stimuli-Responsive Mesoporous Silica Nanoparticles for Cancer Therapy

Pharmaceutics ◽

10.3390/pharmaceutics13010071 ◽

2021 ◽

Vol 13 (1) ◽

pp. 71

Author(s):

Thashini Moodley ◽

Moganavelli Singh

Keyword(s):

Cancer Therapy ◽

Mesoporous Silica ◽

Silica Nanoparticles ◽

Mesoporous Silica Nanoparticles ◽

Therapeutic Agents ◽

Metal Species ◽

Stimuli Responsive ◽

Combination Drug ◽

Incidence And Mortality

With increasing incidence and mortality rates, cancer remains one of the most devastating global non-communicable diseases. Restricted dosages and decreased bioavailability, often results in lower therapeutic outcomes, triggering the development of resistance to conventionally used drug/gene therapeutics. The development of novel therapeutic strategies using multimodal nanotechnology to enhance specificity, increase bioavailability and biostability of therapeutics with favorable outcomes is critical. Gated vectors that respond to endogenous or exogenous stimuli, and promote targeted tumor delivery without prematurely cargo loss are ideal. Mesoporous silica nanoparticles (MSNs) are effective delivery systems for a variety of therapeutic agents in cancer therapy. MSNs possess a rigid framework and large surface area that can incorporate supramolecular constructs and varying metal species that allow for stimuli-responsive controlled release functions. Its high interior loading capacity can incorporate combination drug/gene therapeutic agents, conferring increased bioavailability and biostability of the therapeutic cargo. Significant advances in the engineering of MSNs structural and physiochemical characteristics have since seen the development of nanodevices with promising in vivo potential. In this review, current trends of multimodal MSNs being developed and their use in stimuli-responsive passive and active targeting in cancer therapy will be discussed, focusing on light, redox, pH, and temperature stimuli.

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Drug Delivery by Ultrasound-Responsive Nanocarriers for Cancer Treatment

Pharmaceutics ◽

10.3390/pharmaceutics13081135 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1135

Author(s):

Kristin Entzian ◽

Achim Aigner

Keyword(s):

Drug Delivery ◽

Biological Effects ◽

Invasive Technique ◽

Stimuli Responsive ◽

Comprehensive Overview ◽

Drug Concentrations ◽

Therapeutic Outcomes ◽

Cost Efficient ◽

Safety Considerations

Conventional cancer chemotherapies often exhibit insufficient therapeutic outcomes and dose-limiting toxicity. Therefore, there is a need for novel therapeutics and formulations with higher efficacy, improved safety, and more favorable toxicological profiles. This has promoted the development of nanomedicines, including systems for drug delivery, but also for imaging and diagnostics. Nanoparticles loaded with drugs can be designed to overcome several biological barriers to improving efficiency and reducing toxicity. In addition, stimuli-responsive nanocarriers are able to release their payload on demand at the tumor tissue site, preventing premature drug loss. This review focuses on ultrasound-triggered drug delivery by nanocarriers as a versatile, cost-efficient, non-invasive technique for improving tissue specificity and tissue penetration, and for achieving high drug concentrations at their intended site of action. It highlights aspects relevant for ultrasound-mediated drug delivery, including ultrasound parameters and resulting biological effects. Then, concepts in ultrasound-mediated drug delivery are introduced and a comprehensive overview of several types of nanoparticles used for this purpose is given. This includes an in-depth compilation of the literature on the various in vivo ultrasound-responsive drug delivery systems. Finally, toxicological and safety considerations regarding ultrasound-mediated drug delivery with nanocarriers are discussed.

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Gran1: A Granulysin-Derived Peptide with Potent Activity against Intracellular Mycobacterium tuberculosis

International Journal of Molecular Sciences ◽

10.3390/ijms22168392 ◽

2021 ◽

Vol 22 (16) ◽

pp. 8392

Author(s):

Reiner Noschka ◽

Fanny Wondany ◽

Gönül Kizilsavas ◽

Tanja Weil ◽

Gilbert Weidinger ◽

...

Keyword(s):

Antimicrobial Activity ◽

Mycobacterium Tuberculosis ◽

Developmental Toxicity ◽

Super Resolution ◽

In Vivo Models ◽

Large Size ◽

Acid Fragment ◽

Powerful Approach ◽

Target Effects

Granulysin is an antimicrobial peptide (AMP) expressed by human T-lymphocytes and natural killer cells. Despite a remarkably broad antimicrobial spectrum, its implementation into clinical practice has been hampered by its large size and off-target effects. To circumvent these limitations, we synthesized a 29 amino acid fragment within the putative cytolytic site of Granulysin (termed “Gran1”). We evaluated the antimicrobial activity of Gran1 against the major human pathogen Mycobacterium tuberculosis (Mtb) and a panel of clinically relevant non-tuberculous mycobacteria which are notoriously difficult to treat. Gran1 efficiently inhibited the mycobacterial proliferation in the low micro molar range. Super-resolution fluorescence microscopy and scanning electron microscopy indicated that Gran1 interacts with the surface of Mtb, causing lethal distortions of the cell wall. Importantly, Gran1 showed no off-target effects (cytokine release, chemotaxis, cell death) in primary human cells or zebrafish embryos (cytotoxicity, developmental toxicity, neurotoxicity, cardiotoxicity). Gran1 was selectively internalized by macrophages, the major host cell of Mtb, and restricted the proliferation of the pathogen. Our results demonstrate that the hypothesis-driven design of AMPs is a powerful approach for the identification of small bioactive compounds with specific antimicrobial activity. Gran1 is a promising component for the design of AMP-containing nanoparticles with selective activity and favorable pharmacokinetics to be pushed forward into experimental in vivo models of infectious diseases, most notably tuberculosis.

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Newly Developed Self-Assembling Antioxidants as Potential Therapeutics for the Cancers

Journal of Personalized Medicine ◽

10.3390/jpm11020092 ◽

2021 ◽

Vol 11 (2) ◽

pp. 92 ◽

Cited By ~ 1

Author(s):

Babita Shashni ◽

Yukio Nagasaki

Keyword(s):

Cancer Survival ◽

Self Assembling ◽

Therapeutic Regime ◽

Cancer Models ◽

Secondary Messengers ◽

Potential Therapeutics ◽

Target Effects ◽

Tempo Radical

Elevated reactive oxygen species (ROS) have been implicated as significant for cancer survival by functioning as oncogene activators and secondary messengers. Hence, the attenuation of ROS-signaling pathways in cancer by antioxidants seems a suitable therapeutic regime for targeting cancers. Low molecular weight (LMW) antioxidants such as 2,2,6,6-tetramethylpyperidine-1-oxyl (TEMPO), although they are catalytically effective in vitro, exerts off-target effects in vivo due to their size, thus, limiting their clinical use. Here, we discuss the superior impacts of our TEMPO radical-conjugated self-assembling antioxidant nanoparticle (RNP) compared to the LMW counterpart in terms of pharmacokinetics, therapeutic effect, and adverse effects in various cancer models.

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Role of Bradykinin Type 2 Receptors in Human Sweat Secretion: Translational Evidence Does Not Support a Functional Relationship

Skin Pharmacology and Physiology ◽

10.1159/000514497 ◽

2021 ◽

Vol 34 (3) ◽

pp. 162-166

Author(s):

Thad E. Wilson ◽

Seetharam Narra ◽

Kristen Metzler-Wilson ◽

Artur Schneider ◽

Kelsey A. Bullens ◽

...

Keyword(s):

Healthy Subjects ◽

Sweat Rate ◽

Sweat Glands ◽

Potential Therapeutic Target ◽

Sweat Secretion ◽

Hoe 140 ◽

A Current

Bradykinin increases skin blood flow via a cGMP mechanism but its role in sweating in vivo is unclear. There is a current need to translate cell culture and nonhuman paw pad studies into in vivo human preparations to test for therapeutic viability for disorders affecting sweat glands. Protocol 1: physiological sweating was induced in 10 healthy subjects via perfusing warm (46–48°C) water through a tube-lined suit while bradykinin type 2 receptor (B2R) antagonist (HOE-140; 40 μM) and only the vehicle (lactated Ringer’s) were perfused intradermally via microdialysis. Heat stress increased sweat rate (HOE-140 = +0.79 ± 0.12 and vehicle = +0.64 ± 0.10 mg/cm2/min), but no differences were noted with B2R antagonism. Protocol 2: pharmacological sweating was induced in 6 healthy subjects via intradermally perfusing pilocarpine (1.67 mg/mL) followed by the same B2R antagonist approach. Pilocarpine increased sweating (HOE-140 = +0.38 ± 0.16 and vehicle = +0.32 ± 0.12 mg/cm2/min); again no differences were observed with B2R antagonism. Last, 5 additional subjects were recruited for various control experiments which identified that a functional dose of HOE-140 was utilized and it was not sudorific during normothermic conditions. These data indicate B2R antagonists do not modulate physiologically or pharmacologically induced eccrine secretion volumes. Thus, B2R agonist/antagonist development as a potential therapeutic target for hypo- and hyperhidrosis appears unwarranted.

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