scholarly journals Lipid and Polymer-Based Nanoparticle siRNA Delivery Systems for Cancer Therapy

Molecules ◽  
2020 ◽  
Vol 25 (11) ◽  
pp. 2692 ◽  
Author(s):  
Francesco Mainini ◽  
Michael R. Eccles
Keyword(s):  
Cancer Therapy ◽  
Gene Silencing ◽  
Sirna Delivery ◽  
Cancer Therapeutics ◽  
Delivery Systems ◽  
Fine Tuning ◽  
Host Cells ◽  
Specific Cell ◽  
Small Interfering Rnas

RNA interference (RNAi) uses small interfering RNAs (siRNAs) to mediate gene-silencing in cells and represents an emerging strategy for cancer therapy. Successful RNAi-mediated gene silencing requires overcoming multiple physiological barriers to achieve efficient delivery of siRNAs into cells in vivo, including into tumor and/or host cells in the tumor micro-environment (TME). Consequently, lipid and polymer-based nanoparticle siRNA delivery systems have been developed to surmount these physiological barriers. In this article, we review the strategies that have been developed to facilitate siRNA survival in the circulatory system, siRNA movement from the blood into tissues and the TME, targeted siRNA delivery to the tumor or specific cell types, cellular uptake, and escape from endosomal degradation. We also discuss the use of various types of lipid and polymer-based carriers for cancer therapy, including a section on anti-tumor nanovaccines enhanced by siRNAs. Finally, we review current and recent clinical trials using NPs loaded with siRNAs for cancer therapy. The siRNA cancer therapeutics field is rapidly evolving, and it is conceivable that precision cancer therapy could, in the relatively near future, benefit from the combined use of cancer therapies, for example immune checkpoint blockade together with gene-targeting siRNAs, personalized for enhancing and fine-tuning a patient’s therapeutic response.

scholarly journals Switching the intracellular pathway and enhancing the therapeutic efficacy of small interfering RNA by auroliposome

2020 ◽  
Vol 6 (30) ◽  
pp. eaba5379 ◽  
Author(s):  
Md. Nazir Hossen ◽  
Lin Wang ◽  
Harisha R. Chinthalapally ◽  
Joe D. Robertson ◽  
Kar-Ming Fung ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Gold Nanoparticles ◽  
Gene Silencing ◽  
Small Interfering Rna ◽  
Sirna Delivery ◽  
Delivery Systems ◽  
Ovarian Cancer Cells ◽  
Interfering Rna

Gene silencing using small-interfering RNA (siRNA) is a viable therapeutic approach; however, the lack of effective delivery systems limits its clinical translation. Herein, we doped conventional siRNA-liposomal formulations with gold nanoparticles to create “auroliposomes,” which significantly enhanced gene silencing. We targeted MICU1, a novel glycolytic switch in ovarian cancer, and delivered MICU1-siRNA using three delivery systems—commercial transfection agents, conventional liposomes, and auroliposomes. Low-dose siRNA via transfection or conventional liposomes was ineffective for MICU1 silencing; however, in auroliposomes, the same dose gave >85% gene silencing. Efficacy was evident from both in vitro growth assays of ovarian cancer cells and in vivo tumor growth in human ovarian cell line—and patient-derived xenograft models. Incorporation of gold nanoparticles shifted intracellular uptake pathways such that liposomes avoided degradation within lysosomes. Auroliposomes were nontoxic to vital organs. Therefore, auroliposomes represent a novel siRNA delivery system with superior efficacy for multiple therapeutic applications.

Exploring Promises of siRNA in Cancer Therapeutics

2020 ◽  
Vol 16 (1) ◽  
pp. 29-35
Author(s):  
Mahima Kaushik ◽  
Rddhima Raghunand ◽  
Shobhit Maheshwari
Keyword(s):  
Clinical Trials ◽  
Rna Interference ◽  
Cancer Therapy ◽  
Biomedical Applications ◽  
Cancer Therapeutics ◽  
Small Interfering Rnas ◽  
Polymeric Carriers ◽  
Drug Treatments ◽  
Anticancer Treatment

Since the discovery of the RNA interference (RNAi) in 2006, several attempts have been made to use it for designing and developing drug treatments for a variety of diseases, including cancer. In this mini-review, we focus on the potential of small interfering RNAs (siRNA) in anticancer treatment. We first describe the significant barriers that exist on the path to clinical application of siRNA drugs. Then the current delivery approaches of siRNAs using lipids, polymers, and, in particular, polymeric carriers that overcome the aforementioned obstacles have been reviewed. Also, few siRNA mediated drugs currently in clinical trials for cancer therapy, and a collated list of siRNA databases having a qualitative and/ or quantitative summary of the data in each database have been briefly mentioned. This mini review aims to facilitate our understanding about the siRNA, their delivery systems and the possible barriers in their in vivo usage for biomedical applications.

Chemo-drug controlled-release strategies of nanocarrier in the development of cancer therapeutics.

2020 ◽  
Vol 27 ◽  
Author(s):  
Yunyi Liu ◽  
Hailong Ou ◽  
Xiaming Pei ◽  
Bin Jiang ◽  
Yihan Ma ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Cancer Therapy ◽  
Drug Delivery Systems ◽  
High Surface ◽  
Cancer Therapeutics ◽  
Delivery Systems ◽  
Magnetic Nanomaterials ◽  
Future Application ◽  
Stimulus Responsive

: Nanoparticles have been widely used in cancer therapy because of its nanoscale, high surface ratio, multifuntions and so on. With specific construction of nanoparticles, such as choosing magnetic nanomaterials or citric acid coated nanoparticle, scientists can kill tumor cells effectively and accurately，importantly， reducing the side effect of conventional chemotherapy. Currently, they have been continually applied in cancer therapeutics research. Scientists not only designed nanoparticles loading with therapeutic drugs, but also equipped with targeted molecules. These works make nanoparticles become a multifuntional nanocarrier. In the construction of multifunctional nanocarriers, nanoparticles play the important work of drug delivery. Normally, enabling drugs delivery to tumor tissues is a difficult task. During the period of internal circulation, it is hard to keep the nanocarriers stability. As well as not attach to normal cells or serum. With the application of stimulus-responsive nanomaterials, scientists develop many nanocarriers with controllable drug release. These controllable drug delivery systems can quickly respond to microenvironmental changes (PH, enzyme, etc.) or external stimuli (photo, heat, magnetic or electric fields). Thus, it is to overcome the side effects by controllable drug delivery systems in vivo. In this article, we summarize the various kinds of stimulus-responsive nanocarriers for cancer therapy and discuss its possibilities and challenges in future application.

scholarly journals Delivery Systems for the Direct Application of siRNAs to Induce RNA Interference (RNAi) In Vivo

2006 ◽  
Vol 2006 ◽  
pp. 1-15 ◽  
Author(s):  
Achim Aigner
Keyword(s):  
Rna Interference ◽  
Sirna Delivery ◽  
Critical Factor ◽  
Delivery Systems ◽  
Tumor Xenograft ◽  
Target Cells ◽  
Specific Gene ◽  
Mouse Tumor ◽  
Small Interfering Rnas

RNA interference (RNAi) is a powerful method for specific gene silencing which may also lead to promising novel therapeutic strategies. It is mediated through small interfering RNAs (siRNAs) which sequence-specifically trigger the cleavage and subsequent degradation of their target mRNA. One critical factor is the ability to deliver intact siRNAs into target cells/organs in vivo. This review highlights the mechanism of RNAi and the guidelines for the design of optimal siRNAs. It gives an overview of studies based on the systemic or local application of naked siRNAs or the use of various nonviral siRNA delivery systems. One promising avenue is the the complexation of siRNAs with the polyethylenimine (PEI), which efficiently stabilizes siRNAs and, upon systemic administration, leads to the delivery of the intact siRNAs into different organs. The antitumorigenic effects of PEI/siRNA-mediated in vivo gene-targeting of tumor-relevant proteins like in mouse tumor xenograft models are described.

scholarly journals The chemical structure and phosphorothioate content of hydrophobically modified siRNAs impact extrahepatic distribution and efficacy

2020 ◽  
Vol 48 (14) ◽  
pp. 7665-7680
Author(s):  
Annabelle Biscans ◽  
Jillian Caiazzi ◽  
Sarah Davis ◽  
Nicholas McHugh ◽  
Jacquelyn Sousa ◽  
...  
Keyword(s):  
Chemical Structure ◽  
Clinical Stage ◽  
Sirna Delivery ◽  
Fine Tuning ◽  
Endosomal Escape ◽  
Systematic Evaluation ◽  
Small Interfering Rnas ◽  
Tissue Accumulation ◽  
The Impact

Abstract Small interfering RNAs (siRNAs) have revolutionized the treatment of liver diseases. However, robust siRNA delivery to other tissues represents a major technological need. Conjugating lipids (e.g. docosanoic acid, DCA) to siRNA supports extrahepatic delivery, but tissue accumulation and gene silencing efficacy are lower than that achieved in liver by clinical-stage compounds. The chemical structure of conjugated siRNA may significantly impact invivo efficacy, particularly in tissues with lower compound accumulation. Here, we report the first systematic evaluation of the impact of siRNA scaffold—i.e. structure, phosphorothioate (PS) content, linker composition—on DCA-conjugated siRNA delivery and efficacy in vivo. We found that structural asymmetry (e.g. 5- or 2-nt overhang) has no impact on accumulation, but is a principal factor for enhancing activity in extrahepatic tissues. Similarly, linker chemistry (cleavable versus stable) altered activity, but not accumulation. In contrast, increasing PS content enhanced accumulation of asymmetric compounds, but negatively impacted efficacy. Our findings suggest that siRNA tissue accumulation does not fully define efficacy, and that the impact of siRNA chemical structure on activity is driven by intracellular re-distribution and endosomal escape. Fine-tuning siRNA chemical structure for optimal extrahepatic efficacy is a critical next step for the progression of therapeutic RNAi applications beyond liver.

scholarly journals siRNA Delivery Technology for Cancer Therapy: Promise and Challenges

2019 ◽  
Author(s):  
Fateme Karimi Dermani ◽  
Farid Azizi Jalilian ◽  
Hossein Hossienkhani ◽  
Razieh Ezati ◽  
Razieh Amini
Keyword(s):  
Cancer Therapy ◽  
Sirna Delivery ◽  
Delivery Systems ◽  
Therapeutic Interventions ◽  
Great Promise ◽  
Specific Gene ◽  
Small Interfering Rnas ◽  
Systemic Delivery ◽  
New Class ◽  
Delivery Technology

Abstract- Small interfering RNAs (siRNA) technology has shown great promise as a new class of therapeutic interventions for the treatment of cancer and other diseases. It is a remarkable endogenous pathway that can regulate sequence-specific gene silencing. Despite the excitement about possible applications of this biological process for sequence-specific gene regulation, the major limitations against the use of siRNA-based therapeutics are their rapid degradation by serum nuclease, poor cellular uptake, and rapid renal clearance following systemic delivery, off-target effects and the induction of immune responses. Many researchers have tried to overcome these limitations by developing nuclease-resistant chemically-modified siRNAs and a variety of synthetic and natural biodegradable lipids and polymers to enhance the efficacy and safety profiles of siRNA delivery. Ideal siRNA-based delivery systems for cancer therapy must be clinically suitable, safe and effective. In this review, we introduce the greatest challenges in achieving efficient RNAi delivery and discuss design criteria and various delivery strategies for cancer therapy, including chemical modifications, lipid-based nano-vectors, polymer-mediated delivery systems, conjugate delivery systems, and others.

scholarly journals DDB2 regulates DNA replication through PCNA-independent degradation of CDT2

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Xiaojun Wu ◽  
Min Yu ◽  
Zhuxia Zhang ◽  
Feng Leng ◽  
Yue Ma ◽  
...  
Keyword(s):  
Dna Replication ◽  
Cancer Therapy ◽  
Target Genes ◽  
Ubiquitin Ligases ◽  
Ovarian Teratoma ◽  
Control Group ◽  
E3 Ubiquitin Ligases ◽  
Small Interfering Rnas ◽  
Interacting Protein

Abstract Background Targeting ubiquitin-dependent proteolysis is one of the strategies in cancer therapy. CRLCDT2 and CRLDDB2 are two key E3 ubiquitin ligases involved in DNA replication and DNA damage repair. But CDT2 and DDB2 are opposite prognostic factors in kinds of cancers, and the underlining mechanism needs to be elucidated. Methods Small interfering RNAs were used to determine the function of target genes. Co-immunoprecipitation (Co-IP) was performed to detect the interaction between DDB2 and CDT2. Immunofluorescence assays and fluorescence activating cell sorting (FACS) were used to measure the change of DNA content. In vivo ubiquitination assay was carried out to clarify the ubiquitination of CDT2 mediated by DDB2. Cell synchronization was performed to arrest cells at G1/S and S phase. The mechanism involved in DDB2-mediated CDT2 degradation was investigated by constructing plasmids with mutant variants and measured by Western blot. Immunohistochemistry was performed to determine the relationship between DDB2 and CDT2. Paired two-side Student’s t-test was used to measure the significance of the difference between control group and experimental group. Results Knockdown of DDB2 stabilized CDT2, while over-expression of DDB2 enhanced ubiquitination of CDT2, and subsequentially degradation of CDT2. Although both DDB2 and CDT2 contain PIP (PCNA-interacting protein) box, PIP box is dispensable for DDB2-mediated CDT2 degradation. Knockdown of PCNA had negligible effects on the stability of CDT2, but promoted accumulation of CDT1, p21 and SET8. Silencing of DDB2 arrested cell cycle in G1 phase, destabilized CDT1 and reduced the chromatin loading of MCMs, thereby blocked the formation of polyploidy induced by ablation of CDT2. In breast cancer and ovarian teratoma tissues, high level of DDB2 was along with lower level of CDT2. Conclusions We found that CRL4DDB2 is the novel E3 ubiquitin ligases of CDT2, and DDB2 regulates DNA replication through indirectly regulates CDT1 protein stability by degrading CDT2 and promotes the assembly of pre-replication complex. Our results broaden the horizon for understanding the opposite function of CDT2 and DDB2 in tumorigenesis, and may provide clues for drug discovery in cancer therapy.

scholarly journals In vivo gene silencing following non-invasive siRNA delivery into the skin using a novel topical formulation

2014 ◽  
Vol 196 ◽  
pp. 355-362 ◽  
Author(s):  
Vikas Hegde ◽  
Robyn P. Hickerson ◽  
Sitheswaran Nainamalai ◽  
Paul A. Campbell ◽  
Frances J.D. Smith ◽  
...  
Keyword(s):  
Gene Silencing ◽  
Sirna Delivery ◽  
Topical Formulation ◽  
Non Invasive

scholarly journals Hydrophobicity drives the systemic distribution of lipid-conjugated siRNAs via lipid transport pathways

2018 ◽  
Author(s):  
Maire F. Osborn ◽  
Andrew H. Coles ◽  
Annabelle Biscans ◽  
Reka A. Haraszti ◽  
Loic Roux ◽  
...  
Keyword(s):  
Sirna Delivery ◽  
Lipid Transport ◽  
Small Interfering Rnas ◽  
Transport Pathways ◽  
Efficient Delivery ◽  
Systemic Distribution ◽  
Lipoprotein Binding ◽  
The Impact ◽  
Plasma Half Life

AbstractEfficient delivery of therapeutic RNA is the fundamental obstacle preventing its clinical utility. Lipid conjugation improves plasma half-life, tissue accumulation, and cellular uptake of small interfering RNAs (siRNAs). However, the impact of conjugate structure and hydrophobicity on siRNA pharmacokinetics is unclear, impeding the design of clinically relevant lipid-siRNAs. Using a panel of biologically-occurring lipids, we show that lipid conjugation modulates siRNA hydrophobicity and governs spontaneous partitioning into distinct plasma lipoprotein classes in vivo. Lipoprotein binding influences siRNA distribution by delaying renal excretion and promoting uptake into lipoprotein receptor-enriched tissues. Lipid-siRNAs elicit mRNA silencing without causing toxicity in a tissue-specific manner. Lipid-siRNA internalization occurs independently of lipoprotein endocytosis, and is mediated by siRNA phosphorothioate modifications. Although biomimetic lipoprotein nanoparticles have been considered for the enhancement of siRNA delivery, our findings suggest that hydrophobic modifications can be leveraged to incorporate therapeutic siRNA into endogenous lipid transport pathways without the requirement for synthetic formulation.

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