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.

A Nanoparticle Carrier for Co-Delivery of Gemcitabine and Small Interfering RNA in Pancreatic Cancer Therapy

2016 ◽  
Vol 12 (8) ◽  
pp. 1654-1666 ◽  
Author(s):  
Jiajia Li ◽  
Yinting Chen ◽  
Linjuan Zeng ◽  
Guoda Lian ◽  
Shaojie Chen ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Therapy ◽  
Small Interfering Rna ◽  
Pancreatic Cancer Therapy ◽  
Interfering Rna

scholarly journals Preclinical Safety Evaluation in Rats of a Polymeric Matrix Containing an siRNA Drug Used as a Local and Prolonged Delivery System for Pancreatic Cancer Therapy

2016 ◽  
Vol 44 (6) ◽  
pp. 856-865 ◽  
Author(s):  
Yuval Ramot ◽  
Shay Rotkopf ◽  
Rachel Malka Gabai ◽  
Elina Zorde Khvalevsky ◽  
Sofia Muravnik ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Phase 1 ◽  
Safety Evaluation ◽  
Single Layer ◽  
Giant Cells ◽  
Recovery Phase ◽  
Polymeric Matrix ◽  
Safety Studies ◽  
Pancreatic Cancer Therapy ◽  
Interfering Rna

Conventional chemotherapy treatments for pancreatic cancer are mainly palliative. RNA interference (RNAi)-based drugs present the potential for a new targeted treatment. LOcal Drug EluteR (LODERTM) is a novel biodegradable polymeric matrix that shields drugs against enzymatic degradation and releases small interfering RNA (siRNA) against G12D-mutated KRAS (siG12D). siG12D-LODER has successfully passed a phase 1/2a clinical trial. Such a formulation necessitates biocompatibility and safety studies. We describe the safety and toxicity studies with siG12D-LODER in 192 Hsd:Sprague Dawley rats, after repeated subcutaneous administrations (days 1, 14, and 28). Animals were sacrificed on days 29 and 42 (recovery phase). In all groups, no adverse effects were noted, and all animals showed favorable local and systemic tolerability. Histopathologically, LODER implantation resulted in the expected capsule formation, composed of a thin fibrotic tissue. On the interface between the cavity and the capsule, a single layer composed of macrophages and multinucleated giant cells was observed. No difference was noted between the placebo and siG12D-LODER groups. These findings provide valuable information for future preclinical studies with siRNA-bearing biodegradable polymers and for the safety aspects of RNAi-based drugs as a targeted therapy.

scholarly journals The Landscape of Genetic Alterations Stratified Prognosis in Oriental Pancreatic Cancer Patients

2021 ◽  
Vol 11 ◽  
Author(s):  
Shiwei Guo ◽  
Xiaohan Shi ◽  
Suizhi Gao ◽  
Qunxing Hou ◽  
Lisha Jiang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Patients ◽  
Tumor Biology ◽  
Genetic Alterations ◽  
Copy Number Variations ◽  
Genomic Alteration ◽  
Solid Pseudopapillary Tumor ◽  
Specific Gene ◽  
Platinum Drug ◽  
Resistance Pathway

BackgroundPancreatic cancer is a life-threatening malignant disease with significant diversity among geographic regions and races leading to distinct carcinogenesis and prognosis. Previous studies mainly focused on Western patients, while the genomic landscape of Oriental patients, especially Chinese, remained less investigated.MethodsA total of 408 pancreatic cancer patients were enrolled. A panel containing 436 cancer-related genes was used to detect genetic alterations in tumor samples.ResultsWe profiled the genomic alteration landscape of pancreatic duct adenocarcinoma (PDAC), intraductal papillary mucinous neoplasm (IPMN), periampullary carcinoma (PVC), and solid-pseudopapillary tumor (SPT). Comparison with a public database revealed specific gene mutations in Oriental PDAC patients including higher mutation rates of DNA damage repair-related genes. Analysis of mutational signatures showed potential heterogenous carcinogenic factors caused by diabetes mellitus. KRAS mutation, especially KRAS G12D mutation, was associated with poor survival, while patients not harboring the 17 significant copy number variations (CNVs) had a better prognosis. We further identified multiple correlations between clinicopathologic variables and genetic mutations, as well as CNVs. Finally, by network-based stratification, three classes of PDAC patients were robustly clustered. Among these, class 1 (characterized by the Fanconi anemia pathway) achieved the best outcome, while class 2 (involved in the platinum drug resistance pathway) suffered from the worst prognosis.ConclusionsIn this study, we reported for the first time the genetic alteration landscape of Oriental PDAC patients identifying many Oriental-specific alterations. The relationship between genetic alterations and clinicopathological factors as well as prognosis demonstrated important genomic impact on tumor biology. This study will help to optimize clinical treatment of Oriental PDAC patients and improve their survival.

scholarly journals siRNA-Loaded Hydroxyapatite Nanoparticles for KRAS Gene Silencing in Anti-Pancreatic Cancer Therapy

Pharmaceutics ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1428
Author(s):  
Dandan Luo ◽  
Xiaochun Xu ◽  
M. Zubair Iqbal ◽  
Qingwei Zhao ◽  
Ruibo Zhao ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Therapy ◽  
Gene Silencing ◽  
Targeted Delivery ◽  
High Efficiency ◽  
Great Promise ◽  
Kras Gene ◽  
Promising Alternative ◽  
Pancreatic Cancer Therapy

Pancreatic carcinoma (PC) is greatly induced by the KRAS gene mutation, but effective targeted delivery for gene therapy has not existed. Small interfering ribonucleic acid (siRNA) serves as an advanced therapeutic modality and holds great promise for cancer treatment. However, the development of a non-toxic and high-efficiency carrier system to accurately deliver siRNA into cells for siRNA-targeted gene silencing is still a prodigious challenge. Herein, polyethylenimine (PEI)-modified hydroxyapatite (HAp) nanoparticles (HAp-PEI) were fabricated. The siRNA of the KRAS gene (siKras) was loaded onto the surface of HAp-PEI via electrostatic interaction between siRNA and PEI to design the functionalized HAp-PEI nanoparticle (HAp-PEI/siKras). The HAp-PEI/siKras was internalized into the human PC cells PANC-1 to achieve the maximum transfection efficiency for active tumor targeting. HAp-PEI/siKras effectively knocked down the expression of the KRAS gene and downregulated the expression of the Kras protein in vitro. Furthermore, the treatment with HAp-PEI/siKras resulted in greater anti-PC cells’ (PANC-1, BXPC-3, and CFPAC-1) efficacy in vitro. Additionally, the HAp-PEI exhibited no obvious in vitro cytotoxicity in normal pancreatic HPDE6-C7 cells. These findings provided a promising alternative for the therapeutic route of siRNA-targeted gene engineering for anti-pancreatic cancer therapy.

scholarly journals Polymeric Nanoparticles in Gene Therapy: New Avenues of Design and Optimization for Delivery Applications

Polymers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 745 ◽  
Author(s):  
Raj Rai ◽  
Saniya Alwani ◽  
Ildiko Badea
Keyword(s):  
Gene Therapy ◽  
Gene Delivery ◽  
Targeted Delivery ◽  
Polymeric Nanoparticles ◽  
Genetic Material ◽  
Delivery Systems ◽  
Viral Gene ◽  
Cationic Polymers ◽  
Natural Polymers ◽  
Viral Gene Delivery

The field of polymeric nanoparticles is quickly expanding and playing a pivotal role in a wide spectrum of areas ranging from electronics, photonics, conducting materials, and sensors to medicine, pollution control, and environmental technology. Among the applications of polymers in medicine, gene therapy has emerged as one of the most advanced, with the capability to tackle disorders from the modern era. However, there are several barriers associated with the delivery of genes in the living system that need to be mitigated by polymer engineering. One of the most crucial challenges is the effectiveness of the delivery vehicle or vector. In last few decades, non-viral delivery systems have gained attention because of their low toxicity, potential for targeted delivery, long-term stability, lack of immunogenicity, and relatively low production cost. In 1987, Felgner et al. used the cationic lipid based non-viral gene delivery system for the very first time. This breakthrough opened the opportunity for other non-viral vectors, such as polymers. Cationic polymers have emerged as promising candidates for non-viral gene delivery systems because of their facile synthesis and flexible properties. These polymers can be conjugated with genetic material via electrostatic attraction at physiological pH, thereby facilitating gene delivery. Many factors influence the gene transfection efficiency of cationic polymers, including their structure, molecular weight, and surface charge. Outstanding representatives of polymers that have emerged over the last decade to be used in gene therapy are synthetic polymers such as poly(l-lysine), poly(l-ornithine), linear and branched polyethyleneimine, diethylaminoethyl-dextran, poly(amidoamine) dendrimers, and poly(dimethylaminoethyl methacrylate). Natural polymers, such as chitosan, dextran, gelatin, pullulan, and synthetic analogs, with sophisticated features like guanidinylated bio-reducible polymers were also explored. This review outlines the introduction of polymers in medicine, discusses the methods of polymer synthesis, addressing top down and bottom up techniques. Evaluation of functionalization strategies for therapeutic and formulation stability are also highlighted. The overview of the properties, challenges, and functionalization approaches and, finally, the applications of the polymeric delivery systems in gene therapy marks this review as a unique one-stop summary of developments in this field.

ATB0,+-targeted delivery of triptolide prodrugs for safer and more effective pancreatic cancer therapy

2021 ◽  
Vol 33 ◽  
pp. 127728
Author(s):  
Dan Lou ◽  
Zijian Lou ◽  
Yuanzhen Lin ◽  
Hao Shangguan ◽  
Yujie Lin ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Therapy ◽  
Targeted Delivery ◽  
Pancreatic Cancer Therapy

scholarly journals Targeted Delivery System of Nanobiomaterials in Anticancer Therapy: From Cells to Clinics

2014 ◽  
Vol 2014 ◽  
pp. 1-23 ◽  
Author(s):  
Su-Eon Jin ◽  
Hyo-Eon Jin ◽  
Soon-Sun Hong
Keyword(s):  
Anticancer Drugs ◽  
Targeted Delivery ◽  
Polymeric Nanoparticles ◽  
Anticancer Therapy ◽  
Delivery Systems ◽  
Specific Receptors ◽  
Targeted Delivery System ◽  
Targeted Delivery Systems

Targeted delivery systems of nanobiomaterials are necessary to be developed for the diagnosis and treatment of cancer. Nanobiomaterials can be engineered to recognize cancer-specific receptors at the cellular levels and to deliver anticancer drugs into the diseased sites. In particular, nanobiomaterial-based nanocarriers, so-called nanoplatforms, are the design of the targeted delivery systems such as liposomes, polymeric nanoparticles/micelles, nanoconjugates, norganic materials, carbon-based nanobiomaterials, and bioinspired phage system, which are based on the nanosize of 1–100 nm in diameter. In this review, the design and the application of these nanoplatforms are discussed at the cellular levels as well as in the clinics. We believe that this review can offer recent advances in the targeted delivery systems of nanobiomaterials regardingin vitroandin vivoapplications and the translation of nanobiomaterials to nanomedicine in anticancer therapy.

scholarly journals Non‐viral siRNA delivery systems for pancreatic cancer therapy

2021 ◽  
Author(s):  
Shahin Aghamiri ◽  
Pourya Raee ◽  
Sam Talaei ◽  
Samira Mohammadi‐Yeganeh ◽  
Shiva Bayat ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Therapy ◽  
Sirna Delivery ◽  
Delivery Systems ◽  
Pancreatic Cancer Therapy

scholarly journals Cytotoxicity assessment, inflammatory properties, and cellular uptake of Neutraplex lipid-based nanoparticles in THP-1 monocyte-derived macrophages

2017 ◽  
Vol 4 ◽  
pp. 184954351774625 ◽  
Author(s):  
Eric Berger ◽  
Dalibor Breznan ◽  
Sandra Stals ◽  
Viraj J Jasinghe ◽  
David Gonçalves ◽  
...  
Keyword(s):  
Targeted Delivery ◽  
Small Interfering Rna ◽  
Human Monocyte ◽  
Antiretroviral Drugs ◽  
Small Interfering Rnas ◽  
Lactate Dehydrogenase Release ◽  
Drug Concentrations ◽  
Interfering Rna ◽  
Hiv 1

Current antiretroviral drugs used to prevent or treat human immunodeficiency virus type 1 (HIV-1) infection are not able to eliminate the virus within tissues or cells where HIV establishes reservoirs. Hence, there is an urgent need to develop targeted delivery systems to enhance drug concentrations in these viral sanctuary sites. Macrophages are key players in HIV infection and contribute significantly to the cellular reservoirs of HIV because the virus can survive for prolonged periods in these cells. In the present work, we investigated the potential of the lipid-based Neutraplex nanosystem to deliver anti-HIV therapeutics in human macrophages using the human monocyte/macrophage cell line THP-1. Neutraplex nanoparticles as well as cationic and anionic Neutraplex nanolipoplexes (Neutraplex/small interfering RNA) were prepared and characterized by dynamic light scattering. Neutraplex nanoparticles showed low cytotoxicity in CellTiter-Blue reduction and lactate dehydrogenase release assays and were not found to have pro-inflammatory effects. In addition, confocal studies showed that the Neutraplex nanoparticles and nanolipoplexes are rapidly internalized into THP-1 macrophages and that they can escape the late endosome/lysosome compartment allowing the delivery of small interfering RNAs in the cytoplasm. Furthermore, HIV replication was inhibited in the in vitro TZM-bl infectivity assay when small interfering RNAs targeting CXCR4 co-receptor was delivered by Neutraplex nanoparticles compared to a random small interfering RNA sequence. This study demonstrates that the Neutraplex nanosystem has potential for further development as a delivery strategy to efficiently and safely enhance the transport of therapeutic molecules into human monocyte-derived macrophages in the aim of targeting HIV-1 in this cellular reservoir.

Sign in / Sign up

Export Citation Format

Share Document