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qRT-PCR analysis of Notch1 mRNA expression. Notes: (A) Notch1 mRNA expression at various N/P ratios of siRNA/DMAPA-chems complexes at the same siRNA dose of 50 nM after incubated for 48 h. (B) Notch1 mRNA expression analysis when cells were treated with different siRNA dosages of siRNA/DMAPA-chems complexes at the same N/P ratio of 100 after cultured for 48 h. Values are presented as mean ± SD, n=4. Abbreviations: qRT-PCR, quantitative real-time polymerase chain reaction; RT-PCR, reverse transcription polymerase chain reaction; siRNA, small interfering RNA; n, number; SD, standard deviation; N/P, nitrogen to phosphate ratios.
Source publication
Yun-Chun Zhao,1 Li Zhang,2 Shi-Sen Feng,3 Lu Hong,3 Hai-Li Zheng,3 Li-Li Chen,4 Xiao-Ling Zheng,1 Yi-Qing Ye,1 Meng-Dan Zhao,1 Wen-Xi Wang,3 Cai-Hong Zheng1 1Pharmacy Department, Women’s Hospital, 2Pharmacy Department, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 3Department of Pharm...
Citations
... Due to the high anionic charge of siRNA, carriers based on cationic lipids are more effective [134]. The study by Zhao et al. has demonstrated that the use of siRNA to inhibit Notch1 combined with cationic cholesterol called N-(cholesterylhemisuccinoyl-amino-3-propyl)-N, N-dimethylamine (DMAPA-chems) liposomes can effectively hinder tumor growth and prompt apoptosis in SKOV-3 cell lines [113]. This approach indicates that tailored lipids can interfere with the endosome and enhance the effectiveness of drug delivery. ...
This review discusses the application of nanoliposomes containing siRNA/drug to overcome multidrug resistance for all types of cancer treatments. As drug resistance-associated factors are overexpressed in many cancer cell types, pumping chemotherapy drugs out of the cytoplasm leads to an inadequate therapeutic response. The siRNA/drug-loaded nanoliposomes are a promising approach to treating multidrug-resistant cancer, as they can effectively transmit a small-molecule drug into the target cytoplasm, ensuring that the drug binds efficiently. Moreover, nanoliposome-based therapeutics with advances in nanotechnology can effectively deliver siRNA to cancer cells. Overall, nanoliposomes have the potential to effectively deliver siRNA and small-molecule drugs in a targeted manner and are thus a promising tool for the treatment of cancer and other diseases.
... A comparative view on apoptosis modulation showed that NLC-Pip-BSA (100 µg/mL) was more effective than NLC-Pip, the first hybrid-lipid nanocarriers leading to 25% (24 h) apoptosis ( Figure 11A). with cationic cholesterol-based lipid nanoparticles for the gene therapy of ovarian cancer [54]. ...
... The coating of nanocarriers with BSA consumes the cationic charges of phosphatidylcholine and can lead to difficulty in the internalization of NLC-Pip-BSA in tumor cells. Similarly, Zhao et al., demonstrated that targeting of SKOV3 was improved with cationic cholesterol-based lipid nanoparticles for the gene therapy of ovarian cancer [54]. ...
A novel nanoscale approach was developed for the improved cellular internalization of hybrid bovine serum albumin–lipid nanocarriers loaded with piperine (NLC-Pip–BSA) in different tumor cells. The effect of the BSA-targeted–NLC-Pip and untargeted-NLC-Pip on the viability, proliferation, and levels of cell-cycle damage and apoptosis in the colon (LoVo), ovarian (SKOV3) and breast (MCF7) adenocarcinoma cell lines was comparatively discussed. NLCs were characterized concerning particle size, morphology, zeta potential, phytochemical encapsulation efficiency, ATR-FTIR, and fluorescence spectroscopy. The results showed that NLC-Pip–BSA showed a mean size below 140 nm, a zeta potential of −60 mV, and an entrapment efficiency of 81.94% for NLC-Pip and 80.45% for NLC-Pip–BSA. Fluorescence spectroscopy confirmed the coating of the NLC with the albumin. By MTS and RTCA assays, NLC-Pip–BSA showed a more pronounced response against the LoVo colon cell line and MCF-7 breast tumor cell lines than against the ovarian SKOV-3 cell line. Flow cytometry assay demonstrated that the targeted NLC-Pip had more cytotoxicity and improved apoptosis than the untargeted ones in MCF-7 tumor cells (p < 0.05). NLC-Pip caused a significant increase in MCF-7 breast tumor cell apoptosis of ~8X, while NLC-Pip–BSA has shown an 11-fold increase in apoptosis.
... Lastly, the silencing of HIF1-a, often overexpressed in ovarian cancer by means of siRNA in NPs, led to the effective inhibition of cell proliferation [76]. Regarding lipoplexes, dendrimers, and liposomes, a significant number of studies [55,56,59,[71][72][73]77,81] have reported efficient delivery in ovarian cancer cells, highlighting the significant contribution of NPs in targeted gene therapy applications. Concerning the suicide gene therapy approach, He et al. [55] used FRα-targeted folate-modified lipoplex loaded with an hTERT promoterregulated plasmid encoding VSV matrix protein (MP) (F-LP/pMP) and transfected SKOV3 ovarian cancer cells. ...
... Furthermore, the inhibition of the Wilms tumour 1 (WT1) gene, overexpressed in ovarian carcinoma but not in normal tissue, by an antisense oligodeoxynucleotide (ASODN) delivered in liposomes, led to the inhibition of ovarian cancer cell proliferation, cell cycle arrest, and increased apoptosis in vitro [71]. The delivery of shRNA against STAT3 in liposomes resulted in a reduction in the growth of intraperitoneal ovarian cancer through the inhibition of cell proliferation and apoptosis induction [72], while the delivery of siRNA against NOTCH1 in cationic cholesterol derivative-based liposomes led to the inhibition of growth and apoptosis induction in vitro [73]. As mentioned above, Xiong et al. [65] delivered WWOX in ovarian cancer cells by means of liposomes and documented decreased cancer cell growth and apoptosis induction. ...
Despite the major advances in screening and therapeutic approaches, gynaecological malignancies still present as a leading cause of death among women of reproductive age. Cervical cancer, although largely preventable through vaccination and regular screening, remains the fourth most common and most lethal cancer type in women, while the available treatment schemes still pose a fertility threat. Ovarian cancer is associated with high morbidity rates, primarily due to lack of symptoms and high relapse rates following treatment, whereas endometrial cancer, although usually curable by surgery, it still represents a therapeutic problem. On the other hand, benign abnormalities, such as fibroids, endometriosis, placental, and embryo implantation disorders, although not life-threatening, significantly affect women’s life and fertility and have high socio-economic impacts. In the last decade, targeted gene therapy approaches toward both malignant and benign gynaecological abnormalities have led to promising results, setting the ground for successful clinical trials. The above therapeutic strategies employ both viral and non-viral systems for mutation compensation, suicide gene therapy, oncolytic virotherapy, antiangiogenesis and immunopotentiation. This review discusses all the major advances in gene therapy of gynaecological disorders and highlights the novel and potentially therapeutic perspectives associated with such an approach.
... HTB-77), USA, and maintained in McCoy's 5a modified medium, supplemented with 10% fetal bovine serum, penicillin (100 U/mL), and streptomycin (100 μg/mL). Cells were cultured at 37 °C in a humidified atmosphere containing 5% CO 2 in a CO 2 incubator (Zhao et al. 2016). ...
Bartogenic acid (BA), a natural pentacyclic triterpenoid, proved to have chemomodulatory, anticancer, antidiabetic, anti-arthritic, and anti-inflammatory activity. Based on structure–activity relationship (SAR) approaches, BA has close structural resemblance to oleanolic acid and ursolic acid. These two pentacyclic triterpenoids are well accepted with respect to their therapeutic value in various ailments including anti-cancer activity. The aim of this study is to evaluate the efficacy of BA as a possible antitumor agent, along with its safety in SKOV-3 ovarian cancer. In vitro cytotoxicity of BA and paclitaxel on human ovarian cancer cells (SKOV-3) was assessed using MTT assay. Antitumor potential of BA alone, standard anticancer drug (paclitaxel) alone, and BA in combination with paclitaxel were evaluated in SKOV-3 xenografted SCID mice. Immunohistochemical analysis of NF-κB was performed and analyzed in SKOV-3 tumors. BA alone and BA in combination with paclitaxel significantly inhibited the tumor growth. IC50 of BA was found to be 15.72 μM. Similarly, paclitaxel showed significant antitumor effect with IC50 of 3.234 μM. Treatments of paclitaxel, BA, and combination of BA with paclitaxel were well tolerated during treatment period. Immunohistochemical analysis of NF-κB in SKOV-3 tumors treated with BA in combination with paclitaxel revealed antitumor effect in terms of inhibition of NF-κB. Our results suggested that BA exhibits promising antitumor effect in the restriction of SKOV-3 cells and tumors with considerable safety.
... 586 In 2016, Zhao et al. synthesized another cholesterol-based ionizable lipid, designated as DMAPA-chems, in which the head group and cholesterol moiety were connected through a 1,4-succinic acid linker with biodegradable ester and amide linkage bonds ( Figure 51). 587 DMAPA-chems LNPs encapsulating Notch1 siRNA showed high Notch1 gene knockdown efficiency in SKOV3 cells at an N/P ratio of 100. 587 In 2019, Hou et al. reported a library of vitamin-derived lipids: V B3 -Lipid, V C -Lipid, V D -Lipid, V E -Lipid, and V H -Lipid ( Figure 52). ...
... 587 DMAPA-chems LNPs encapsulating Notch1 siRNA showed high Notch1 gene knockdown efficiency in SKOV3 cells at an N/P ratio of 100. 587 In 2019, Hou et al. reported a library of vitamin-derived lipids: V B3 -Lipid, V C -Lipid, V D -Lipid, V E -Lipid, and V H -Lipid ( Figure 52). 59 These vitamin-derived lipids were prepared through the conjugation of vitamins or their derivatives with an amino lipid with a carboxylic acid group through ester or amide bond formation. ...
... Since siRNA possesses a high anionic charge, cationic lipid-based carriers are more efficient [33]. In accordance with what has been just attested, Zhao et al. have shown that inhibition of Notch1 in SKOV-3 cell lines by siRNA along with a cationic cholesterol (N-(cholesterylhemisuccinoylamino-3-propyl)-N,N-dimethylamine (DMAPA-chems) can suppress tumor growth and induces apoptosis of SKOV-3 cells [34]. ...
Ovarian cancer is one of the most common causes of mortality throughout the world. Unfortunately, chemotherapy has failed to cure advanced cancers developing multidrug resistance (MDR). Moreover, it has critical side effects because of nonspecific toxicity. Thanks to specific silencing of oncogenes and MDR-associated genes, nano-siRNA drugs can be a great help address the limitations of chemotherapy. Here, we review the current advances in nanoparticle-mediated siRNA delivery strategies such as polymeric- and lipid-based systems, rigid nanoparticles and nanoparticles coupled to specific ligand systems. Nanoparticle-based codelivery of anticancer drugs and siRNA targeting various mechanisms of MDR is a cutting-edge strategy for ovarian cancer therapy, which is completely discussed in this review.
... cells. Furthermore, small interfering RNAs (sIRNA)'s transcription and insertion into the genome, resulting in gene silencing, and knockdown of proteins after mRNA degradation, provided a positive outlook (23) . ...
... The transport of siRNA is difficult due to its hydrophilic character and its negative electric charge. The use of cationic cholesterol derivative-based liposomes is efficient as an interfering RNA (siRNA) delivery system, showing low toxicity and excellent cellular uptake and gene silencing efficiency [27]. ...
... The suppression of Notch1 activation in SKOV3 human OC cells, a protein that acts as an oncogene in OC, showed low toxicity and excellent cellular uptake and gene silencing efficiency. This study also demonstrated that this system could inhibit the growth of SKOV3 cells and promote apoptosis [27]. ...
Ovarian cancer is the most lethal gynecological malignancy in developed countries. This is due to the lack of specific symptoms that hinder early diagnosis and to the high relapse rate after treatment with radical surgery and chemotherapy. Hence, novel therapeutic modalities to improve clinical outcomes in ovarian malignancy are needed. Progress in gene therapy has allowed the development of several strategies against ovarian cancer. Most are focused on the design of improved vectors to enhance gene delivery on the one hand, and, on the other hand, on the development of new therapeutic tools based on the restoration or destruction of a deregulated gene, the use of suicide genes, genetic immunopotentiation, the inhibition of tumour angiogenesis, the alteration of pharmacological resistance, and oncolytic virotherapy. In the present manuscript, we review the recent advances made in gene therapy for ovarian cancer, highlighting the latest clinical trials experience, the current challenges and future perspectives.
... In the context of ovarian cancer, Zhao et al., studied a cationic liposome consisting of a cholesterol derivate N-(cholesterylhemisuccinoyl-amino-3propyl)-N, N-dimethylamine (DMAPA-chems) with phosphatidylcholine (S100 soybean extract) [64]. DMAPA served as a cationic head group and CHEMS as the hydrophobic moiety [64]. ...
... In the context of ovarian cancer, Zhao et al., studied a cationic liposome consisting of a cholesterol derivate N-(cholesterylhemisuccinoyl-amino-3propyl)-N, N-dimethylamine (DMAPA-chems) with phosphatidylcholine (S100 soybean extract) [64]. DMAPA served as a cationic head group and CHEMS as the hydrophobic moiety [64]. Liposome formulations containing cationic cholesterol derivatives were shown to be less toxic than other cationic liposomes [65,66]. ...
... Liposome formulations containing cationic cholesterol derivatives were shown to be less toxic than other cationic liposomes [65,66]. The transmembrane protein NOTCH1, which is a known oncogene [67], was targeted with siRNA in this study [64]. The DMAPA-cholesterol containing nanoparticles were almost nontoxic at N/P ratios up to 120, and downregulation of NOTCH1 was roughly equal in DMAPA-chems transfected cells compared to Lipofectamine control. ...
Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy, and the sixth leading cause of cancer related death in women overall. Despite improved surgical techniques and advances in chemotherapy, mortality hardly decreased over the last twenty years. The major problem is that (micro)metastases persevere in the abdominal cavity, causing incurable tumor recurrence. Therefore, there is an imminent need for new therapeutic strategies.
Oligonucleotide (ON) based therapies such as RNA interference (RNAi) provide the possibility to specifically address disease-related pathways. However, small interfering RNA (siRNA) molecules are unable to enter cells without a drug delivery system. Therefore, nanocarriers have been developed to aid intracellular delivery of siRNA. EOC is, in most cases, confined to the abdominal cavity, providing the possibility for peritoneal drug delivery. As a consequence, EOC should be an ideal candidate for ON therapies as intraperitoneal delivery reduces sequestration of drug formulations in other organs.
In this review, we will discuss delivery strategies and siRNA targets that have been tested in EOC. Delivery strategies cover the full range of delivery approaches from polymers to exotic delivery strategies like microbubble based nanoparticles. For siRNA targets, those that aim at re-sensitizing the tumor cells to chemotherapy can be discriminated from those that reduce growth and metastasis of the tumor cells.
Despite preclinical successes and the advantage that intraperitoneal delivery holds over systemic delivery, no strategy has made it into the clinic yet. We postulate that confirmatory studies that combine the most promising delivery approaches with the most promising targets are required to reach a consensus on those formulations that should be pursued for further (pre-)clinical research.
... RNA-NPCs have been used successfully as bio sensors [15][16][17]-to detect cancerous cells, as antibacterial- [18,19], and anti-cancer [20] agents. NPs have also been used extensively as vector-systems for delivery of RNA to cells and tissues [20][21][22][23][24][25][26][27][28][29][30][31], even as early as 1998 [32]. Addition of RNA substantially alters the surface properties and physical behavior of NP. ...
RNA nanotechnology is attracting a great deal of attention recently. As the multiple roles that RNA plays in molecular biology and physiological regulation become clearer, there are many opportunities for engineering RNA-Nanoparticle Complexes (RNA-NPCs). The high “engineerability” of RNA-NPCs comes from the ability to modify the RNA and NP chemistry. For example, the NP can be derived from materials with anticancer activity and the RNA delivered by it, designed to target cell signaling pathways that contribute to the molecular basis of these diseases. Despite this rapid advancement and the availability of new quantification and characterization techniques, a key challenge is to develop a better understanding of the RNA-nanobio interface; that is, the interactions of RNA with NP (RNA-nanobio interface) and how that impacts the structure, function, delivery, and activity of the RNA. Here, we attempt to summarize the state-of-the-art in this new and exciting field, and to lay out potential directions for bioengineering research on RNA-NPCs.
