scholarly journals Non-cationic RGD-containing protein carrier for tumor-targeted siRNA delivery

2021 ◽  
Author(s):  
Xiaolin Yu ◽  
Lu Xue ◽  
Jingjing Zhao ◽  
Shuhua Zhao ◽  
Daqing Wu ◽  
...  
Keyword(s):  
Targeted Delivery ◽  
Sirna Delivery ◽  
Integrin Αvβ3 ◽  
Cationic Liposome ◽  
Genetically Engineered ◽  
Endosomal Escape ◽  
Widespread Application ◽  
Rgd Peptides

Abstract Despite the recent successes in siRNA therapeutics, targeted delivery beyond the liver remains the major hurdle for the widespread application of siRNA in vivo. Current cationic liposome or polymer-based delivery agents are restricted to the liver and suffer from off-target effect, poor clearance, low serum stability, and high toxicity. In this study, we have genetically engineered a non-cationic tumor-targeted universal siRNA nanocarrier. This protein nanocarrier consists of three function domains: dsRNA binding domain (dsRBD) (from human protein kinase R) for any siRNA binding, 18-histidines for endosome escape, and two RGD peptides at N-and C-termini for targeting tumor and tumor neovasculature. We showed that cloned dual-RGD-dsRBD-18his (dual-RGD) protein protects siRNA against RNases, induces effective siRNA endosomal escape, specific targets on integrin αvβ3 expressing cells in vitro, and homes siRNA to tumor in vivo. The delivered siRNA leads target gene knockdown in the cell lines and tumor xenografts with low toxicity. This multifunctional, biomimetic, charge-neutral siRNA carrier is biodegradable, low toxic, suitable for mass production by fermentation, and serum stable, holding great potential to provide a widely applicable siRNA carrier for tumor-targeted siRNA delivery.

scholarly journals Non-Cationic RGD-Containing Protein Nanocarrier for Tumor-Targeted siRNA Delivery

Pharmaceutics ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2182
Author(s):  
Xiaolin Yu ◽  
Lu Xue ◽  
Jing Zhao ◽  
Shuhua Zhao ◽  
Daqing Wu ◽  
...  
Keyword(s):  
Targeted Delivery ◽  
Sirna Delivery ◽  
Integrin Αvβ3 ◽  
Genetically Engineered ◽  
Endosomal Escape ◽  
Widespread Application ◽  
Rgd Peptides ◽  
Low Toxicity

Despite the recent successes in siRNA therapeutics, targeted delivery beyond the liver remains the major hurdle for the widespread application of siRNA in vivo. Current cationic liposome or polymer-based delivery agents are restricted to the liver and suffer from off-target effects, poor clearance, low serum stability, and high toxicity. In this study, we genetically engineered a non-cationic non-viral tumor-targeted universal siRNA nanocarrier (MW 26 KDa). This protein nanocarrier consists of three function domains: a dsRNA binding domain (dsRBD) (from human protein kinase R) for any siRNA binding, 18-histidine for endosome escape, and two RGD peptides at the N- and C-termini for targeting tumor and tumor neovasculature. We showed that cloned dual-RGD-dsRBD-18his (dual-RGD) protein protects siRNA against RNases, induces effective siRNA endosomal escape, specifically targets integrin αvβ3 expressing cells in vitro, and homes siRNA to tumors in vivo. The delivered siRNA leads to target gene knockdown in the cell lines and tumor xenografts with low toxicity. This multifunctional and biomimetic siRNA carrier is biodegradable, has low toxicity, is suitable for mass production by fermentation, and is serum stable, holding great potential to provide a widely applicable siRNA carrier for tumor-targeted siRNA delivery.

scholarly journals A supramolecular platform for controlling and optimizing molecular architectures of siRNA targeted delivery vehicles

2020 ◽  
Vol 6 (31) ◽  
pp. eabc2148
Author(s):  
Yuting Wen ◽  
Hongzhen Bai ◽  
Jingling Zhu ◽  
Xia Song ◽  
Guping Tang ◽  
...  
Keyword(s):  
Gene Delivery ◽  
Targeted Delivery ◽  
Tumor Therapy ◽  
Sirna Delivery ◽  
Targeted Gene Delivery ◽  
Delivery Vehicles ◽  
Molecular Architectures ◽  
Host Polymer

It requires multistep synthesis and conjugation processes to incorporate multifunctionalities into a polyplex gene vehicle to overcome numerous hurdles during gene delivery. Here, we describe a supramolecular platform to precisely control, screen, and optimize molecular architectures of siRNA targeted delivery vehicles, which is based on rationally designed host-guest complexation between a β-cyclodextrin–based cationic host polymer and a library of guest polymers with various PEG shape and size, and various density of ligands. The host polymer is responsible to load/unload siRNA, while the guest polymer is responsible to shield the vehicles from nonspecific cellular uptake, to prolong their circulation time, and to target tumor cells. A series of precisely controlled molecular architectures through a simple assembly process allow for a rapid optimization of siRNA delivery vehicles in vitro and in vivo for therapeutic siRNA-Bcl2 delivery and tumor therapy, indicating the platform is a powerful screening tool for targeted gene delivery vehicles.

scholarly journals Programmably tiling rigidified DNA brick on gold nanoparticle as multi-functional shell for cancer-targeted delivery of siRNAs

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Chang Xue ◽  
Shuyao Hu ◽  
Zhi-Hua Gao ◽  
Lei Wang ◽  
Meng-Xue Luo ◽  
...  
Keyword(s):  
Gold Nanoparticle ◽  
Targeted Delivery ◽  
Target Genes ◽  
Sirna Delivery ◽  
Three Dimensional ◽  
Drug Carriers ◽  
High Serum ◽  
Exterior Surface

AbstractSmall interfering RNA (siRNA) is an effective therapeutic to regulate the expression of target genes in vitro and in vivo. Constructing a siRNA delivery system with high serum stability, especially responsive to endogenous stimuli, remains technically challenging. Herein we develop anti-degradation Y-shaped backbone-rigidified triangular DNA bricks with sticky ends (sticky-YTDBs) and tile them onto a siRNA-packaged gold nanoparticle in a programmed fashion, forming a multi-functional three-dimensional (3D) DNA shell. After aptamers are arranged on the exterior surface, a biocompatible siRNA-encapsulated core/shell nanoparticle, siRNA/Ap-CS, is achieved. SiRNAs are internally encapsulated in a 3D DNA shell and are thus protected from enzymatic degradation by the outermost layer of YTDB. The siRNAs can be released by endogenous miRNA and execute gene silencing within tumor cells, causing cell apoptosis higher than Lipo3000/siRNA formulation. In vivo treatment shows that tumor growth is completely (100%) inhibited, demonstrating unique opportunities for next-generation anticancer-drug carriers for targeted cancer therapies.

scholarly journals Targeted Delivery of siRNA through Nanocomplex using Specific Fusion Peptides for Breast Cancer Treatment

2021 ◽  
Author(s):  
Jang Hyuk Bang ◽  
Kyung Ah Kim ◽  
Yeong Chae Ryu ◽  
Byoung Choul Kim ◽  
BYEONG HEE HWANG
Keyword(s):  
Breast Cancer ◽  
Cancer Treatment ◽  
Cellular Uptake ◽  
Targeted Delivery ◽  
Small Rnas ◽  
Sirna Delivery ◽  
Fusion Peptides ◽  
Breast Cancer Cell Growth

Breast cancer is one of the serious diseases and has the second-highest mortality in women worldwide. RNA interference has been developed as a promising way of specific cancer treatment by silencing oncogenes efficiently. However, small RNAs exhibits difficulties in specific cellular uptake and instability. Therefore, we designed novel fusion peptides (RS and RT) for an efficient, stable, and specific delivery of small RNAs. Both RS and RT peptides could form self-assembled nanocomplexes via electrostatic attraction. RS nanocomplexes exhibited prolonged stability, enhanced cellular uptake, and target gene silencing by siRNAs to MDA-MB-231 breast cancer cells. Moreover, RS nanocomplexes successfully inhibited breast cancer cell growth via specific and efficient siRNA delivery. Furthermore, in vitro and in vivo safety tests showed negligible cytotoxicity and neither tissue damage nor significant inflammatory cytokine release. Therefore, the RS nanocomplexes could be expected to become a promising siRNA delivery platform for the treatment of breast cancer or other cancers.

scholarly journals Cabozantinib unlocks efficient in vivo targeted delivery of neutrophil-loaded nanoparticles into murine prostate tumors

2020 ◽  
Author(s):  
Kiranj Chaudagar ◽  
Natalie Landon-Brace ◽  
Aniruddh Solanki ◽  
Hanna M. Hieromnimon ◽  
Emma Hegermiller ◽  
...  
Keyword(s):  
Targeted Delivery ◽  
Kinase Inhibitor ◽  
Tumor Regression ◽  
Flow Cytometric Analysis ◽  
Fold Increase ◽  
Genetically Engineered ◽  
Prostate Tumors ◽  
Major Barrier

AbstractA major barrier to the successful application of nanotechnology for cancer treatment is the efficient delivery of therapeutic payloads to metastatic tumor deposits. We have previously discovered that cabozantinib, a tyrosine kinase inhibitor, triggers neutrophil-mediated anti-cancer innate immunity, resulting in tumor regression in an aggressive PTEN/p53-deficient genetically engineered murine model of advanced prostate cancer. Here, we specifically investigated the potential of cabozantinib-induced neutrophil activation and recruitment to enhance delivery of bovine serum albumin (BSA)-coated polymeric nanoparticles (NPs) into murine PTEN/p53-deficient prostate tumors. Based on the observation that BSA-coating of NPs enhanced association and internalization by activated neutrophils in vitro, relative to uncoated NPs, we systemically injected BSA-coated, dye-loaded NPs into prostate-specific PTEN/p53-deficient mice that were pre-treated with cabozantinib. Flow cytometric analysis revealed a 4-fold increase of neutrophil-associated NPs within the tumor microenvironment (TME) of mice pre-treated with cabozantinib relative to untreated controls. At steady-state, following 3 days of cabozantinib/NP administration, 1% of systemically injected dye-loaded NPs selectively accumulated within the TME of mice that were pre-treated with cabozantinib, compared to 0.11% uptake for mice that did not receive cabozantinib pre-treatment. Strikingly, neutrophil depletion with Ly6G antibody abolished NP accumulation in tumors to baseline levels, demonstrating targeted neutrophil-mediated NP delivery to the prostate TME. In summary, we have discovered a novel nano-immunotherapeutic strategy for enhanced intratumoral delivery of injected NPs, which results in significantly higher NP accumulation than reported strategies in the nanotechnology literature to-date.

scholarly journals Preparation and Characterization of Functionalized Graphene Oxide Carrier for siRNA Delivery

2018 ◽  
Vol 19 (10) ◽  
pp. 3202 ◽  
Author(s):  
Jing Li ◽  
Xu Ge ◽  
Chunying Cui ◽  
Yifan Zhang ◽  
Yifan Wang ◽  
...  
Keyword(s):  
Graphene Oxide ◽  
Gene Silencing ◽  
Targeted Delivery ◽  
Mrna Level ◽  
Sirna Delivery ◽  
Tissue Growth ◽  
Vegf Mrna ◽  
Functionalized Graphene Oxide

A successful siRNA delivery system is dependent on the development of a good siRNA carrier. Graphene oxide (GO) has gained great attention as a promising nanocarrier in recent years. It has been reported that GO could be used to deliver a series of drugs including synthetic compounds, proteins, antibodies, and genes. Our previous research indicated that functionalized GO could deliver siRNA into tumor cells and induce a gene silencing effect, to follow up the research, in this research, GO-R8/cRGDfV(GRcR) was designed and prepared for VEGF-siRNA delivery as a novel carrier. The Zeta potential and particle size of the new designed GRcR carrier was measured at (29.46 ± 5.32) mV and (135.7 ± 3.3) nm respectively, and after transfection, the VEGF mRNA level and protein expression level were down-regulated by 48.22% (p < 0.01) and 38.3% (p < 0.01) in HeLa cells, respectively. The fluorescent images of the treated BALB/c nude mice revealed that GRcR/VEGF-siRNA could conduct targeted delivery of VEGF-siRNA into tumor tissues and showed a gene silencing effect as well as a tumor growth inhibitory effect (p < 0.01) in vivo. Further studies showed that GRcR/VEGF-siRNA could effectively inhibit angiogenesis by suppressing VEGF expression. Histology and immunohistochemistry studies demonstrated that GRcR/VEGF-siRNA could inhibit tumor tissue growth effectively and have anti-angiogenesis activity, which was the result of VEGF protein downregulation. Both in vitro and in vivo results demonstrated that GRcR/VEGF-siRNA could be used as an ideal nonviral tumor-targeting vector for VEGF-siRNA delivery in gene therapy.

scholarly journals Cationic liposome–nucleic acid nanoparticle assemblies with applications in gene delivery and gene silencing

2016 ◽  
Vol 374 (2072) ◽  
pp. 20150129 ◽  
Author(s):  
Ramsey N. Majzoub ◽  
Kai K. Ewert ◽  
Cyrus R. Safinya
Keyword(s):  
Nucleic Acid ◽  
Gene Delivery ◽  
Gene Silencing ◽  
Liquid Crystalline ◽  
Cationic Liposome ◽  
Endosomal Escape ◽  
Cubic Phase ◽  
Nucleic Acid Therapeutics

Cationic liposomes (CLs) are synthetic carriers of nucleic acids in gene delivery and gene silencing therapeutics. The introduction will describe the structures of distinct liquid crystalline phases of CL–nucleic acid complexes, which were revealed in earlier synchrotron small-angle X-ray scattering experiments. When mixed with plasmid DNA, CLs containing lipids with distinct shapes spontaneously undergo topological transitions into self-assembled lamellar, inverse hexagonal, and hexagonal CL–DNA phases. CLs containing cubic phase lipids are observed to readily mix with short interfering RNA (siRNA) molecules creating double gyroid CL–siRNA phases for gene silencing. Custom synthesis of multivalent lipids and a range of novel polyethylene glycol (PEG)-lipids with attached targeting ligands and hydrolysable moieties have led to functionalized equilibrium nanoparticles (NPs) optimized for cell targeting, uptake or endosomal escape. Very recent experiments are described with surface-functionalized PEGylated CL–DNA NPs, including fluorescence microscopy colocalization with members of the Rab family of GTPases, which directly reveal interactions with cell membranes and NP pathways. In vitro optimization of CL–DNA and CL–siRNA NPs with relevant primary cancer cells is expected to impact nucleic acid therapeutics in vivo . This article is part of the themed issue ‘Soft interfacial materials: from fundamentals to formulation’.

scholarly journals Method and its Composition for encapsulation, stabilization, and delivery of siRNA in Anionic polymeric nanoplex: An In vitro- In vivo Assessment

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Nidhi Raval ◽  
Hardi Jogi ◽  
Piyush Gondaliya ◽  
Kiran Kalia ◽  
Rakesh K. Tekade
Keyword(s):  
Therapeutic Potential ◽  
Sirna Delivery ◽  
Micro Rna ◽  
Endosomal Escape ◽  
Mice Model ◽  
Escape Process ◽  
Set Up ◽  
Interfering Rna

Abstract Small interfering RNA (siRNA) are synthetic RNA duplex designed to specifically knockdown the abnormal gene to treat a disease at cellular and molecular levels. In spite of their high potency, specificity, and therapeutic potential, the full-fledged utility of siRNA is predominantly limited to in vitro set-up. Till date, Onpattro is the only USFDA approved siRNA therapeutics available in the clinic. The lack of a reliable in vivo siRNA delivery carrier remains a foremost obstacle towards the clinical translation of siRNA therapeutics. To address the obstacles associated with siRNA delivery, we tested a dendrimer-templated polymeric approach involving a USFDA approved carrier (albumin) for in vitro as well as in vivo delivery of siRNA. The developed approach is simple in application, enhances the serum stability, avoids in vivo RNase-degradation and mediates cytosolic delivery of siRNA following the endosomal escape process. The successful in vitro and in vivo delivery of siRNA, as well as targeted gene knockdown potential, was demonstrated by HDAC4 inhibition in vitro diabetic nephropathy (DN) podocyte model as well as in vivo DN C57BL/6 mice model. The developed approach has been tested using HDAC4 siRNA as a model therapeutics, while the application can also be extended to other gene therapeutics including micro RNA (miRNA), plasmids oligonucleotides, etc.

scholarly journals Genetically engineered cell membrane–coated nanoparticles for targeted delivery of dexamethasone to inflamed lungs

2021 ◽  
Vol 7 (25) ◽  
pp. eabf7820
Author(s):  
Joon Ho Park ◽  
Yao Jiang ◽  
Jiarong Zhou ◽  
Hua Gong ◽  
Animesh Mohapatra ◽  
...  
Keyword(s):  
Cell Membrane ◽  
Targeted Delivery ◽  
Biological Membrane ◽  
Genetically Engineered ◽  
Target Cells ◽  
Coated Nanoparticles ◽  
Ligand Interactions ◽  
Late Antigen

As numerous diseases are associated with increased local inflammation, directing drugs to the inflamed sites can be a powerful therapeutic strategy. One of the common characteristics of inflamed endothelial cells is the up-regulation of vascular cell adhesion molecule–1 (VCAM-1). Here, the specific affinity between very late antigen–4 (VLA-4) and VCAM-1 is exploited to produce a biomimetic nanoparticle formulation capable of targeting inflammation. The plasma membrane from cells genetically modified to constitutively express VLA-4 is coated onto polymeric nanoparticle cores, and the resulting cell membrane–coated nanoparticles exhibit enhanced affinity to target cells that overexpress VCAM-1 in vitro. A model anti-inflammatory drug, dexamethasone, is encapsulated into the nanoformulation, enabling improved delivery of the payload to inflamed lungs and significant therapeutic efficacy in vivo. Overall, this work leverages the unique advantages of biological membrane coatings to engineer additional targeting specificities using naturally occurring target-ligand interactions.

Internal and External Triggering Mechanism of “Smart” Nanoparticle-Based DDSs in Targeted Tumor Therapy

2018 ◽  
Vol 24 (15) ◽  
pp. 1639-1651 ◽  
Author(s):  
Xian-ling Qian ◽  
Jun Li ◽  
Ran Wei ◽  
Hui Lin ◽  
Li-xia Xiong
Keyword(s):  
Targeted Delivery ◽  
Tumor Therapy ◽  
Burst Release ◽  
Tumor Site ◽  
Chemotherapeutic Drugs ◽  
Triggering Mechanism ◽  
Triggering Factors ◽  
Or Genes

Background: Anticancer chemotherapeutics have a lot of problems via conventional Drug Delivery Systems (DDSs), including non-specificity, burst release, severe side-effects, and damage to normal cells. Owing to its potential to circumventing these problems, nanotechnology has gained increasing attention in targeted tumor therapy. Chemotherapeutic drugs or genes encapsulated in nanoparticles could be used to target therapies to the tumor site in three ways: “passive”, “active”, and “smart” targeting. Objective: To summarize the mechanisms of various internal and external “smart” stimulating factors on the basis of findings from in vivo and in vitro studies. Method: A thorough search of PubMed was conducted in order to identify the majority of trials, studies and novel articles related to the subject. Results: Activated by internal triggering factors (pH, redox, enzyme, hypoxia, etc.) or external triggering factors (temperature, light of different wavelengths, ultrasound, magnetic fields, etc.), “smart” DDSs exhibit targeted delivery to the tumor site, and controlled release of chemotherapeutic drugs or genes. Conclusion: In this review article, we summarize and classify the internal and external triggering mechanism of “smart” nanoparticle-based DDSs in targeted tumor therapy, and the most recent research advances are illustrated for better understanding.

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