scholarly journals Therapeutic potential of functionalized siRNA nanoparticles on regression of liver cancer in experimental mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Azmat Ali Khan ◽  
Amer M. Alanazi ◽  
Mumtaz Jabeen ◽  
Arun Chauhan ◽  
Mohammad Azam Ansari
Keyword(s):  
Targeted Delivery ◽  
Therapeutic Potential ◽  
Survivin Expression ◽  
Significant Inhibition ◽  
Target Cells ◽  
Specific Gene ◽  
Antitumor Potential ◽  
Effective Delivery ◽  
Selective Delivery ◽  
Interfering Rna

Abstract Short interfering RNA (siRNA) possesses special ability of silencing specific gene. To increase siRNA stability, transportation and its uptake by tumor cells, effective delivery to the appropriate target cells is a major challenge of siRNA-based therapy. In the present study, an effective, safe and biocompatible survivin siRNA encapsulated, GalNAc decorated PEGylated PLGA nanoconjugates (NCs) viz., GalNAc@PEG@siRNA-PLGA were engineered and their synergistic antitumor efficacy was evaluated for targeted delivery in HCC bearing experimental mice. GalNAc@PEG@siRNA-PLGA NCs were characterized for size, bioavailability, toxicity and biocompatibility. Their antitumor potential was evaluated considering gene silencing, apoptosis, histopathology and survival of treated mice. Exceptional accumulation of hepatocytes, reduction in survivin expression and prominent regression in tumor size confirmed the ASGPR-mediated uptake of ligand-anchored NCs and silencing of survivin gene in a targeted manner. Increased DNA fragmentation and potential modulation of caspase-3, Bax and Bcl-2 factors specified the induction of apoptosis that helped in significant inhibition of HCC progression. The potential synchronous and tumor selective delivery of versatile NCs indicated the effective payloads towards the target site, increased apoptosis in cancer cells and improved survival of treated animals.

scholarly journals Engineered extracellular vesicle decoy receptor-mediated modulation of the IL6 trans-signalling pathway in muscle

2020 ◽  
Author(s):  
Mariana Conceição ◽  
Laura Forcina ◽  
Oscar P. B. Wiklander ◽  
Dhanu Gupta ◽  
Joel Z. Nordin ◽  
...  
Keyword(s):  
Targeted Delivery ◽  
Therapeutic Potential ◽  
Extracellular Vesicle ◽  
Signalling Pathway ◽  
Peptide Sequence ◽  
Target Cells ◽  
Dimerization Domain ◽  
Decoy Receptor ◽  
Stat3 Phosphorylation

AbstractThe cytokine interleukin 6 (IL6) is a key mediator of inflammation that contributes to skeletal muscle pathophysiology. IL6 activates target cells by two different mechanisms, the classical and transsignalling pathways. While classical signalling is associated with the anti-inflammatory activities of the cytokine, the IL6 trans-signalling pathway mediates chronic inflammation and is therefore a target for therapeutic intervention. Extracellular vesicles (EVs) are natural, lipid-bound nanoparticles, with potential as targeted delivery vehicles for therapeutic macromolecules. Here, we engineered EVs to express IL6 signal transducer (IL6ST) decoy receptors to selectively inhibit the IL6 trans-signalling pathway. The potency of the IL6ST decoy receptor EVs was optimized by inclusion of a GCN4 dimerization domain and a peptide sequence derived from syntenin-1 which targets the decoy receptor to EVs. The resulting engineered EVs were able to efficiently inhibit activation of the IL6 transsignalling pathway in reporter cells, while having no effect on the IL6 classical signalling. IL6ST decoy receptor EVs, were also capable of blocking the IL6 trans-signalling pathway in C2C12 myoblasts and myotubes, thereby inhibiting the phosphorylation of STAT3 and partially reversing the anti-differentiation effects observed when treating cells with IL6/IL6R complexes. Treatment of a Duchenne muscular dystrophy mouse model with IL6ST decoy receptor EVs resulted in a reduction in STAT3 phosphorylation in the quadriceps and gastrocnemius muscles of these mice, thereby demonstrating in vivo activity of the decoy receptor EVs as a potential therapy. Taken together, this study reveals the IL6 trans-signalling pathway as a promising therapeutic target in DMD, and demonstrates the therapeutic potential of IL6ST decoy receptor EVs.

scholarly journals Potential of miRNA-Based Nanotherapeutics for Uveal Melanoma

Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5192
Author(s):  
Chun Yang ◽  
Rui Wang ◽  
Pierre Hardy
Keyword(s):  
Signaling Pathways ◽  
Uveal Melanoma ◽  
Intracellular Signaling ◽  
Complex Disease ◽  
Therapeutic Potential ◽  
Cancer Therapeutics ◽  
Delivery Systems ◽  
Epigenetic Mechanism ◽  
Target Cells ◽  
Effective Delivery

Uveal melanoma (UM) is the most common adult intraocular cancer, and metastatic UM remains deadly and incurable. UM is a complex disease associated with the deregulation of numerous genes and redundant intracellular signaling pathways. As understanding of epigenetic dysregulation in the oncogenesis of UM has increased, the abnormal expression of microRNAs (miRNAs) has been found to be an epigenetic mechanism underlying UM tumorigenesis. A growing number of miRNAs are being found to be associated with aberrant signaling pathways in UM, and some have been investigated and functionally characterized in preclinical settings. This review summarizes the miRNAs with promising therapeutic potential for UM treatment, paying special attention to the therapeutic miRNAs (miRNA mimics or inhibitors) used to restore dysregulated miRNAs to their normal levels. However, several physical and physiological limitations associated with therapeutic miRNAs have prevented their translation to cancer therapeutics. With the advent of nanotechnology delivery systems, the development of effective targeted therapies for patients with UM has received great attention. Therefore, this review provides an overview of the use of nanotechnology drug delivery systems, particularly nanocarriers that can be loaded with therapeutic miRNAs for effective delivery into target cells. The development of miRNA-based therapeutics with nanotechnology-based delivery systems may overcome the barriers of therapeutic miRNAs, thereby enabling their translation to therapeutics, enabling more effective targeting of UM cells and consequently improving therapeutic outcomes.

Gene therapy vectors for targeting the heart

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Targeted Delivery ◽  
Specific Binding ◽  
Target Cells ◽  
Biological Targets ◽  
Drug Delivery Vehicles ◽  
Therapeutic Drugs ◽  
Gene Therapy Vectors ◽  
Delivery Vehicles ◽  
Selective Delivery ◽  
Targeted Medicine

The delivery of therapeutic drugs to the heart continues to be a challenge. Developing precise strategies to target the heart is equally as important as discovering new therapeutic medications. To grow this sector, a program that focuses on targeted delivery to the heart, as well as efforts to improve cardiac selectivity and retention of therapeutic medications, may be required. Targeted medicine distribution is one of the most important and unresolved issues in pharmacology. Viruses, on the other hand, have evolved unique and extremely accurate tropisms toward their biological targets through the usage of specific binding proteins. The inclusion of these viral proteins into the plasma membrane of EVs should improve the efficiency with which EVs transport drugs to target cells. Understanding the structure, content, and mechanisms of exosome–cell interactions and uptake might also help with the creation of bioengineered exosomes and other EVs that might be used as targeted drug delivery vehicles. In addition to establishing the optimal vector for each therapeutic ingredient, effective clinical translation of cardiac medicines requires minimally invasive yet highly selective delivery techniques.

DELIVERY OF THERAPEUTIC RNAs INTO TARGET CELLS IN VIVO

COSMOS ◽  
2014 ◽  
Vol 10 (01) ◽  
pp. 3-8
Author(s):  
MEI YING NG ◽  
THILO HAGEN
Keyword(s):  
Membrane Vesicles ◽  
Outer Membrane Vesicles ◽  
Target Cells ◽  
Successful Implementation ◽  
Cellular Delivery ◽  
Delivery Methods ◽  
Polymeric Nanoparticle ◽  
Effective Delivery ◽  
Interfering Rna

RNA-based therapy is one of the most promising approaches to treat human diseases. Specifically, the use of short interfering RNA (siRNA) siRNA and microRNA (miRNA) mimics for in vivo RNA interference has immense potential as it directly lowers the expression of the therapeutic target protein. However, there are a number of major roadblocks to the successful implementation of siRNA and other RNA based therapies in the clinic. These include the instability of RNAs in vivo and the difficulty to efficiently deliver the RNA into the target cells. Hence, various innovative approaches have been taken over the years to develop effective RNA delivery methods. These methods include liposome-, polymeric nanoparticle- and peptide-mediated cellular delivery. In a recent innovative study, bioengineered bacterial outer membrane vesicles were used as vehicles for effective delivery of siRNA into cells in vivo.

scholarly journals Amphiphilic peptide dendrimer-based nanovehicles for safe and effective siRNA delivery

2020 ◽  
Vol 6 (6) ◽  
pp. 278-289
Author(s):  
Chi Ma ◽  
Dandan Zhu ◽  
Yu Chen ◽  
Yiwen Dong ◽  
Wenyi Lin ◽  
...  
Keyword(s):  
Self Assembly ◽  
Sirna Delivery ◽  
Target Cells ◽  
Peptide Dendrimers ◽  
Wide Range ◽  
Effective Delivery ◽  
Amphiphilic Peptide ◽  
New Perspective ◽  
Interfering Rna ◽  
Peptide Dendrimer

AbstractSmall interfering RNA (siRNA)-based RNA interference has emerged as a promising therapeutic strategy for the treatment of a wide range of incurable diseases. However, the safe and effective delivery of siRNA therapeutics into the interior of target cells remains challenging. Here, we disclosed novel amphiphilic peptide dendrimers (AmPDs) that composed of hydrophobic two lipid-like alkyl chains and hydrophilic poly(lysine) dendrons with different generations (2C18-KK2 and 2C18-KK2K4) as nanovehicles for siRNA delivery. These AmPDs are able to self-assemble into supramolecular nanoassemblies that are capable of entrapping siRNA molecules into nanoparticles to protect siRNA from enzymatic degradation and promote efficient intracellular uptake without evident toxicity. Interestingly, by virtue of the optimal balance of hydrophobic lipid-like entity and hydrophilic poly(lysine) dendron generations, AmPD 2C18-KK2K4 bearing bigger hydrophilic dendron can package siRNA to form stable, but more ready to disassemble complexes, thereby resulting in more efficient siRNA releasing and better gene silencing effect in comparison with AmPD 2C18-KK2 bearing smaller dendron. Additional studies confirmed that 2C18-KK2K4 can capitalize on the advantages of lipid and peptide dendrimer vectors for effective siRNA delivery. Collectively, our AmPD-based nanocarriers indeed represent a safe and effective siRNA delivery system. Our findings also provide a new perspective on the modulation of self-assembly amphiphilic peptide dendrimers for the functional and adaptive delivery of siRNA therapeutics.

RNA interference and its therapeutic potential

Open Medicine ◽  
2011 ◽  
Vol 6 (2) ◽  
pp. 137-147 ◽  
Author(s):  
Anubrata Ghosal ◽  
Ahmad Kabir ◽  
Abul Mandal
Keyword(s):  
Gene Expression ◽  
Rna Interference ◽  
Small Interfering Rna ◽  
Therapeutic Potential ◽  
Specific Gene ◽  
History Of ◽  
A Cell ◽  
A New Technique ◽  
Rnai Technique ◽  
Interfering Rna

AbstractRNA interference is a technique that has become popular in the past few years. This is a biological method to detect the activity of a specific gene within a cell. RNAi is the introduction of homologous double stranded RNA to specifically target a gene’s product resulting in null or hypomorphic phenotypes. This technique involves the degradation of specific mRNA by using small interfering RNA. Both microRNA (miRNA) and small interfering RNA (siRNA) are directly related to RNA interference. RNAi mechanism is being explored as a new technique for suppressing gene expression. It is an important issue in the treatment of various diseases. This review considers different aspects of RNAi technique including its history of discovery, molecular mechanism, gene expression study, advantages of this technique against previously used techniques, barrier associated with this technique, and its therapeutic application.

scholarly journals New Engineered-Botulinum Toxins Inhibit the Release of Pain-Related Mediators

2019 ◽  
Vol 21 (1) ◽  
pp. 262 ◽  
Author(s):  
Minhong Tang ◽  
Jianghui Meng ◽  
Jiafu Wang
Keyword(s):  
Targeted Delivery ◽  
Therapeutic Potential ◽  
Unmet Need ◽  
New Approach ◽  
P Release ◽  
Effective Delivery ◽  
Ifn Γ ◽  
Cgrp Receptor Antagonist ◽  
Substance P Release ◽  
Promising Avenue

Targeted delivery of potent inhibitor of cytokine/pain-mediator into inflammatory or pain-sensing cells is a promising avenue for treating chronic pain, a world-wide major healthcare burden. An unmet need exists for a specific and effective delivery strategy. Herein, we describe a new approach using sortase to site-specifically ligate a non-toxic botulinum neurotoxin D (BoNT/D) core-therapeutic (synaptobrevin-cleaving protease and translocation domains) to cell-specific targeting ligands. An engineered core-therapeutic was efficiently ligated to IL-1β ligand within minutes. The resultant conjugate specifically entered into cultured murine primary macrophages, cleaved synaptobrevin 3 and inhibited LPS/IFN-γ evoked IL-6 release. Likewise, a CGRP receptor antagonist ligand delivered BoNT/D protease into sensory neurons and inhibited K+-evoked substance P release. As cytokines and neuropeptides are major regulators of inflammation and pain, blocking their release by novel engineered inhibitors highlights their therapeutic potential. Our report describes a new and widely-applicable strategy for the production of targeted bio-therapeutics for numerous chronic diseases.

scholarly journals Pre-Clinical and Clinical Applications of Small Interfering RNAs (siRNA) and Co-Delivery Systems for Pancreatic Cancer Therapy

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3348
Author(s):  
Sepideh Mirzaei ◽  
Mohammad Hossein Gholami ◽  
Hui Li Ang ◽  
Farid Hashemi ◽  
Ali Zarrabi ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Targeted Delivery ◽  
Polymeric Nanoparticles ◽  
Genetic Alterations ◽  
Delivery Systems ◽  
Metal Nanostructures ◽  
Specific Gene ◽  
Small Interfering Rnas ◽  
Pancreatic Cancer Therapy ◽  
Interfering Rna

Pancreatic cancer (PC) is one of the leading causes of death and is the fourth most malignant tumor in men. The epigenetic and genetic alterations appear to be responsible for development of PC. Small interfering RNA (siRNA) is a powerful genetic tool that can bind to its target and reduces expression level of a specific gene. The various critical genes involved in PC progression can be effectively targeted using diverse siRNAs. Moreover, siRNAs can enhance efficacy of chemotherapy and radiotherapy in inhibiting PC progression. However, siRNAs suffer from different off target effects and their degradation by enzymes in serum can diminish their potential in gene silencing. Loading siRNAs on nanoparticles can effectively protect them against degradation and can inhibit off target actions by facilitating targeted delivery. This leads to enhanced efficacy of siRNAs in PC therapy. Moreover, different kinds of nanoparticles such as polymeric nanoparticles, lipid nanoparticles and metal nanostructures have been applied for optimal delivery of siRNAs that are discussed in this article. This review also reveals that how naked siRNAs and their delivery systems can be exploited in treatment of PC and as siRNAs are currently being applied in clinical trials, significant progress can be made by translating the current findings into the clinical settings.

scholarly journals Recent Developments in Nanoparticle-Based siRNA Delivery for Cancer Therapy

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Jong-Min Lee ◽  
Tae-Jong Yoon ◽  
Young-Seok Cho
Keyword(s):  
Cancer Therapy ◽  
Therapeutic Potential ◽  
Sirna Delivery ◽  
Molecular Therapy ◽  
Specific Gene ◽  
Regulation Mechanism ◽  
Rna Molecules ◽  
Effective Delivery ◽  
Recent Developments

RNA interference (RNAi) is a gene regulation mechanism initiated by RNA molecules that enables sequence-specific gene silencing by promoting degradation of specific mRNAs. Molecular therapy using small interfering RNA (siRNA) has shown great therapeutic potential for diseases caused by abnormal gene overexpression or mutation. The major challenges to application of siRNA therapeutics include the stability and effective delivery of siRNAin vivo. Important progress in nanotechnology has led to the development of efficient siRNA delivery systems. In this review, the authors discuss recent advances in nanoparticle-mediated siRNA delivery and the application of siRNA in clinical trials for cancer therapy. This review will also offer perspectives on future applications of siRNA therapeutics.

Stepwise Development of Biomimetic Chimeric Peptides for Gene Delivery

2020 ◽  
Vol 27 (8) ◽  
pp. 698-710
Author(s):  
Roya Cheraghi ◽  
Mahboobeh Nazari ◽  
Mohsen Alipour ◽  
Saman Hosseinkhani
Keyword(s):  
Gene Delivery ◽  
Targeted Delivery ◽  
Viral Vectors ◽  
Large Scale ◽  
Transfection Efficiency ◽  
Cationic Lipids ◽  
Target Cells ◽  
Scale Production ◽  
Stepwise Development ◽  
Chimeric Peptides

Gene-based therapy largely relies on the vector type that allows a selective and efficient transfection into the target cells with maximum efficacy and minimal toxicity. Although, genes delivered utilizing modified viruses transfect efficiently and precisely, these vectors can cause severe immunological responses and are potentially carcinogenic. A promising method of overcoming this limitation is the use of non-viral vectors, including cationic lipids, polymers, dendrimers, and peptides, which offer potential routes for compacting DNA for targeted delivery. Although non-viral vectors exhibit reduced transfection efficiency compared to their viral counterpart, their superior biocompatibility, non-immunogenicity and potential for large-scale production make them increasingly attractive for modern therapy. There has been a great deal of interest in the development of biomimetic chimeric peptides. Biomimetic chimeric peptides contain different motifs for gene translocation into the nucleus of the desired cells. They have motifs for gene targeting into the desired cell, condense DNA into nanosize particles, translocate the gene into the nucleus and enhance the release of the particle into the cytoplasm. These carriers were developed in recent years. This review highlights the stepwise development of the biomimetic chimeric peptides currently being used in gene delivery.

Sign in / Sign up

Export Citation Format

Share Document