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 Novel fusion peptide‐mediated siRNA delivery using self‐assembled nanocomplex

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Yeong Chae Ryu ◽  
Kyung Ah Kim ◽  
Byoung Choul Kim ◽  
Hui-Min David Wang ◽  
Byeong Hee Hwang
Keyword(s):  
Gene Silencing ◽  
Cellular Uptake ◽  
Viral Infections ◽  
Immune Cell ◽  
Sirna Delivery ◽  
Cellular Membrane ◽  
Fusion Peptides ◽  
Self Assembled

Abstract Background Gene silencing using siRNA can be a new potent strategy to treat many incurable diseases at the genetic level, including cancer and viral infections. Treatments using siRNA essentially requires an efficient and safe method of delivering siRNA into cells while maintaining its stability. Thus, we designed novel synergistic fusion peptides, i.e., SPACE and oligoarginine. Results Among the novel fusion peptides and siRNAs, nanocomplexes have enhanced cellular uptake and gene silencing effect in vitro and improved retention and gene silencing effects of siRNAs in vivo. Oligoarginine could attract siRNAs electrostatically to form stable and self-assembled nanocomplexes, and the SPACE peptide could interact with the cellular membrane via hydrogen bonding. Therefore, nanocomplexes using fusion peptides showed improved and evident cellular uptake and gene silencing of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) via the lipid raft-mediated endocytosis pathway, especially to the HDFn cells of the skin, and all of the fusion peptides were biocompatible. Also, intratumorally injected nanocomplexes had increased retention time of siRNAs at the site of the tumor. Finally, nanocomplexes demonstrated significant in vivo gene silencing effect without overt tissue damage and immune cell infiltration. Conclusions The new nanocomplex strategy could become a safe and efficient platform for the delivery of siRNAs into cells and tissues to treat various target diseases through gene silencing.

scholarly journals Novel Fusion Peptide-Mediated siRNA Delivery Using Self-Assembled Nanocomplex

2020 ◽  
Author(s):  
Yeong Chae Ryu ◽  
Kyungah Kim ◽  
Byoung Choul Kim ◽  
Hui-Min David Wang ◽  
Byeong Hee Hwang
Keyword(s):  
Gene Therapy ◽  
Gene Silencing ◽  
Cellular Uptake ◽  
Viral Infections ◽  
Sirna Delivery ◽  
Cellular Membrane ◽  
Fusion Peptides ◽  
Self Assembled

Abstract Background: Gene therapy using siRNA can be a new potent strategy to treat many incurable diseases at the genetic level, including cancer and viral infections. Treatments using siRNA essentially requires an efficient and safe method of delivering siRNA into cells while maintaining its stability. Thus, we designed novel synergistic fusion peptides, i.e., SPACE and oligoarginine.Results: Among the novel fusion peptides and siRNAs, nanocomplexes have outstanding cellular uptake and gene silencing effect in vitro and high stability and retention effect of siRNAs in vivo. Oligo arginine could attract siRNAs electrostatically to form stable and self-assembled nanocomplexes, and the SPACE peptide could interact with the cellular membrane via hydrogen bonding. Therefore, nanocomplexes using fusion peptides showed improved and evident cellular uptake and gene silencing of Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) via the lipid raft-mediated endocytosis pathway, especially to the HDFn cells of the skin, and all of the fusion peptides were biocompatible. Also, intratumorally injected nanocomplexes had increased stability and retention of siRNAs at the site of the tumor. Conclusions: The new nanocomplex strategy could become a safe and efficient platform for the delivery of siRNAs into cells and tissues to treat various target diseases through gene therapy.

scholarly journals Novel fusion peptide-mediated siRNA delivery using self-assembled nanocomplex

2021 ◽  
Author(s):  
Yeong Chae Ryu ◽  
Kyungah Kim ◽  
Byoung Choul Kim ◽  
Hui-Min David Wang ◽  
BYEONG HEE HWANG
Keyword(s):  
Gene Silencing ◽  
Cellular Uptake ◽  
Viral Infections ◽  
Sirna Delivery ◽  
Cellular Membrane ◽  
Fusion Peptides ◽  
Genetic Level ◽  
Self Assembled

Abstract Background: Gene silencing using siRNA can be a new potent strategy to treat many incurable diseases at the genetic level, including cancer and viral infections. Treatments using siRNA essentially requires an efficient and safe method of delivering siRNA into cells while maintaining its stability. Thus, we designed novel synergistic fusion peptides, i.e., SPACE and oligoarginine.Results: Among the novel fusion peptides and siRNAs, nanocomplexes have enhanced cellular uptake and gene silencing effect in vitro and improved retention and gene silencing effects of siRNAs in vivo. Oligoarginine could attract siRNAs electrostatically to form stable and self-assembled nanocomplexes, and the SPACE peptide could interact with the cellular membrane via hydrogen bonding. Therefore, nanocomplexes using fusion peptides showed improved and evident cellular uptake and gene silencing of Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) via the lipid raft-mediated endocytosis pathway, especially to the HDFn cells of the skin, and all of the fusion peptides were biocompatible. Also, intratumorally injected nanocomplexes had increased retention time of siRNAs at the site of the tumor. Finally, nanocomplexes demonstrated significant in vivo gene silencing effect without immunogenicity.Conclusions: The new nanocomplex strategy could become a safe and efficient platform for the delivery of siRNAs into cells and tissues to treat various target diseases through gene silencing.

scholarly journals Delivery of melittin-loaded niosomes for breast cancer treatment: an in vitro and in vivo evaluation of anti-cancer effect

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Farnaz Dabbagh Moghaddam ◽  
Iman Akbarzadeh ◽  
Ehsan Marzbankia ◽  
Mahsa Farid ◽  
Leila khaledi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Treatment ◽  
Cell Lines ◽  
Encapsulation Efficiency ◽  
Inbred Mice ◽  
Breast Cancer Treatment ◽  
Anticancer Effect ◽  
Anti Cancer

Abstract Background Melittin, a peptide component of honey bee venom, is an appealing candidate for cancer therapy. In the current study, melittin, melittin-loaded niosome, and empty niosome had been optimized and the anticancer effect assessed in vitro on 4T1 and SKBR3 breast cell lines and in vivo on BALB/C inbred mice. "Thin-layer hydration method" was used for preparing the niosomes; different niosomal formulations of melittin were prepared and characterized in terms of morphology, size, polydispersity index, encapsulation efficiency, release kinetics, and stability. A niosome was formulated and loaded with melittin as a promising drug carrier system for chemotherapy of the breast cancer cells. Hemolysis, apoptosis, cell cytotoxicity, invasion and migration of selected concentrations of melittin, and melittin-loaded niosome were evaluated on 4T1 and SKBR3 cells using hemolytic activity assay, flow cytometry, MTT assay, soft agar colony assay, and wound healing assay. Real-time PCR was used to determine the gene expression. 40 BALB/c inbred mice were used; then, the histopathology, P53 immunohistochemical assay and estimate of renal and liver enzyme activity for all groups had been done. Results This study showed melittin-loaded niosome is an excellent substitute in breast cancer treatment due to enhanced targeting, encapsulation efficiency, PDI, and release rate and shows a high anticancer effect on cell lines. The melittin-loaded niosome affects the genes expression by studied cells were higher than other samples; down-regulates the expression of Bcl2, MMP2, and MMP9 genes while they up-regulate the expression of Bax, Caspase3 and Caspase9 genes. They have also enhanced the apoptosis rate and inhibited cell migration, invasion in both cell lines compared to the melittin samples. Results of histopathology showed reduce mitosis index, invasion and pleomorphism in melittin-loaded niosome. Renal and hepatic biomarker activity did not significantly differ in melittin-loaded niosome and melittin compared to healthy control. In immunohistochemistry, P53 expression did not show a significant change in all groups. Conclusions Our study successfully declares that melittin-loaded niosome had more anti-cancer effects than free melittin. This project has demonstrated that niosomes are suitable vesicle carriers for melittin, compare to the free form.

scholarly journals In-Vitro Application of Magnetic Hybrid Niosomes: Targeted siRNA-Delivery for Enhanced Breast Cancer Therapy

Pharmaceutics ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 394 ◽  
Author(s):  
Viktor Maurer ◽  
Selin Altin ◽  
Didem Ag Seleci ◽  
Ajmal Zarinwall ◽  
Bilal Temel ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cellular Uptake ◽  
Sirna Delivery ◽  
Superparamagnetic Iron Oxide ◽  
Cost Effective ◽  
Chemotherapeutic Agents ◽  
Therapy Outcome ◽  
Ionic Surfactant ◽  
Combinational Therapy

Even though the administration of chemotherapeutic agents such as erlotinib is clinically established for the treatment of breast cancer, its efficiency and the therapy outcome can be greatly improved using RNA interference (RNAi) mechanisms for a combinational therapy. However, the cellular uptake of bare small interfering RNA (siRNA) is insufficient and its fast degradation in the bloodstream leads to a lacking delivery and no suitable accumulation of siRNA inside the target tissues. To address these problems, non-ionic surfactant vesicles (niosomes) were used as a nanocarrier platform to encapsulate Lifeguard (LFG)-specific siRNA inside the hydrophilic core. A preceding entrapment of superparamagnetic iron-oxide nanoparticles (FexOy-NPs) inside the niosomal bilayer structure was achieved in order to enhance the cellular uptake via an external magnetic manipulation. After verifying a highly effective entrapment of the siRNA, the resulting hybrid niosomes were administered to BT-474 cells in a combinational therapy with either erlotinib or trastuzumab and monitored regarding the induced apoptosis. The obtained results demonstrated that the nanocarrier successfully caused a downregulation of the LFG gene in BT-474 cells, which led to an increased efficacy of the chemotherapeutics compared to plainly added siRNA. Especially the application of an external magnetic field enhanced the internalization of siRNA, therefore increasing the activation of apoptotic signaling pathways. Considering the improved therapy outcome as well as the high encapsulation efficiency, the formulated hybrid niosomes meet the requirements for a cost-effective commercialization and can be considered as a promising candidate for future siRNA delivery agents.

Antineoplastic Activity of Products Derived From Cellulose-containing Materials: Study of Levoglucosenone and Structurally-related Analogous as New Alternatives for Breast Cancer Treatment

2021 ◽  
Author(s):  
Damian Ignacio Delbart ◽  
German Francisco Giri ◽  
Agostina Cammarata ◽  
Lizeth Ariza Bareño ◽  
Natalia Loreley Amigo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Treatment ◽  
Breast Cancer Treatment ◽  
Soybean Hulls ◽  
Mitochondrial Potential ◽  
Cell Content ◽  
Lung Colonization ◽  
Ethidium Bromide Staining

Abstract Purpose: Breast cancer is the leading cause of cancer death among women worldwide. For this reason, the development of new therapies is still essential. In this work we have analyzed the antitumor potential of levoglucosenone, a chiral building block derived from glucose, and three structurally related analogues obtained from soybean hulls pyrolysis.Methods: Employing human and murine mammary cancer models, we have evaluated the effect of our compounds on cell viability through MTS assay, apoptosis induction by acridine orange / ethidium bromide staining and/or flow cytometry and the loss of mitochondrial potential by tetramethylrhodamine methyl ester staining. Autophagy and senescence induction were also evaluated by Western blot and β-galactosidase activity respectively. Secreted metalloproteases activity was determined by quantitative zymography. Migratory capacity was assessed by wound healing assays while invasive potential was analyzed using Matrigel-coated transwell chambers. In vivo studies were also performed to evaluate subcutaneous tumor growth and experimental lung colonization.Results: Apoptosis was identified as the main mechanism responsible for the reduction of monolayer cell content induced by the compounds without detecting modulations of autophagy or senescence processes. Two of the four compounds were able to modulate in vitro events associated with tumor progression, such as migratory potential, invasiveness, and proteases secretion. Furthermore, tumor volume and metastatic spread were significantly reduced in vivo after treatment with the compounds.Conclusion: We could obtain from soybean hulls, a material with almost no commercial value, a variety of chemical compounds useful for breast cancer treatment.

Novel Mitochondrial Targeting Multifunctional Surface Charge-Reversal Polymeric Nanoparticles for Cancer Treatment

2019 ◽  
Vol 15 (11) ◽  
pp. 2151-2163 ◽  
Author(s):  
Lei Fang ◽  
Huaying Fan ◽  
Chunjing Guo ◽  
Linhan Cui ◽  
Peng Zhang ◽  
...  
Keyword(s):  
Cancer Treatment ◽  
Targeted Delivery ◽  
Polymeric Nanoparticles ◽  
In Vitro Cytotoxicity ◽  
Hydrodynamic Diameter ◽  
Mitochondrial Targeting ◽  
Anticancer Activities ◽  
Charge Reversal

Polymeric nanoparticles were widely used as delivery vehicles for targeted delivery of anticancer drugs, because of their targeting property and versatility. Mitochondria are one of the important organelles that regulate the apoptosis of cancer cells and can be considered as a pivotal target for cancer treatment. A pH-responsive charge-reversal and mitochondrial targeting nanoparticles, Vitamin B6-oligomeric hyaluronic acid-dithiodipropionic acid-berberine (B6-oHA-SS-Ber), were prepared in this study. Ber is a lipophilic cation that was conjugated with oHA through disulfide bonds to produce mitochondria-targeted conjugates (oHA-SS-Ber). B6 was conjugated to oHA to obtain B6-oHA-SS-Ber and the two types of Cur-loaded nanoparticles (Cur-NPs) were formulated by the dialysis method. Due to pKa of B6, the charge they carried in the tumor tissue acidic microenvironment can be transferred from negative charge to positive charge, further targeting mitochondria. In our study, we successfully synthesized B6-HA-SS-Ber and characterized the structure by 1H-NMR. According to the results of transmission electron microscopy (TEM), we found that the B6-oHA-SS-Ber/Cur micelles could self-assembled in water to form spherical nanoparticles, with a hydrodynamic diameter of 172.9±13 nm. Moreover, in vitro cytotoxicity, cellular uptake, lysosome escape and mitochondrial distribution researches revealed the better effect of B6-oHA-SS-Ber/Cur micelles in comparison to oHA-SS-Ber/Cur. In vivo anticancer activities indicated that the B6-oHA-SS-Ber/Cur micelles exhibited effective inhibition of tumor growth.

scholarly journals Novel nanomedicine with a chemical-exchange saturation transfer effect for breast cancer treatment in vivo

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Yanlong Jia ◽  
Chaochao Wang ◽  
Jiehua Zheng ◽  
Guisen Lin ◽  
Dalong Ni ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Treatment ◽  
Chemical Exchange ◽  
Raft Polymerization ◽  
Animal Experiments ◽  
Chemical Exchange Saturation Transfer ◽  
Saturation Transfer ◽  
Cest Imaging

Abstract Background Nanomedicine is a promising new approach to cancer treatment that avoids the disadvantages of traditional chemotherapy and improves therapeutic indices. However, the lack of a real-time visualization imaging technology to monitor drug distribution greatly limits its clinical application. Image-tracked drug delivery is of great clinical interest; it is useful for identifying those patients for whom the therapy is more likely to be beneficial. This paper discusses a novel nanomedicine that displays features of nanoparticles and facilitates functional magnetic resonance imaging but is challenging to prepare. Results To achieve this goal, we synthesized an acylamino-containing amphiphilic block copolymer (polyethylene glycol-polyacrylamide-polyacetonitrile, PEG-b-P(AM-co-AN)) by reversible addition-fragmentation chain transfer (RAFT) polymerization. The PEG-b-P(AM-co-AN) has chemical exchange saturation transfer (CEST) effects, which enable the use of CEST imaging for monitoring nanocarrier accumulation and providing molecular information of pathological tissues. Based on PEG-b-P(AM-co-AN), a new nanomedicine PEG-PAM-PAN@DOX was constructed by nano-precipitation. The self-assembling nature of PEG-PAM-PAN@DOX made the synthesis effective, straightforward, and biocompatible. In vitro studies demonstrate decreased cytotoxicity of PEG-PAM-PAN@DOX compared to free doxorubicin (half-maximal inhibitory concentration (IC50), mean ~ 0.62 μg/mL vs. ~ 5 μg/mL), and the nanomedicine more efficiently entered the cytoplasm and nucleus of cancer cells to kill them. Further, in vivo animal experiments showed that the nanomedicine developed was not only effective against breast cancer, but also displayed an excellent sensitive CEST effect for monitoring drug accumulation (at about 0.5 ppm) in tumor areas. The CEST signal of post-injection 2 h was significantly higher than that of pre-injection (2.17 ± 0.88% vs. 0. 09 ± 0.75%, p < 0.01). Conclusions The nanomedicine with CEST imaging reflects the characterization of tumors and therapeutic functions has great potential medical applications.

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.

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