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

Ramot, Yuval; Rotkopf, Shay; Gabai, Rachel Malka; Khvalevsky, Elina Zorde; Muravnik, Sofia; Marzoli, Gabriela Alejandra; Domb, Abraham J.; Shemi, Amotz; Nyska, Abraham

doi:10.1177/0192623316645860

Cited by 59 publications

(46 citation statements)

References 50 publications

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“…Polymeric materials are not as clinically advanced for nucleic acid delivery as ionizable lipids, with few formulations used for the delivery of therapeutic siRNA. 47,48 Relative to lipids, polymeric materials face additional challenges related to polydispersity and clearance or biodegradation for large molecular weight polymers. Low-molecular-weight polyethyleneimine (PEI) modified with fatty chains has been used for siRNA and mRNA delivery to reduce toxicity of high-molecular weight PEI.…”

Section: Reviewmentioning

confidence: 99%

Delivering the Messenger: Advances in Technologies for Therapeutic mRNA Delivery

et al. 2019

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mRNA has broad potential as a therapeutic. Current clinical efforts are focused on vaccination, protein replacement therapies, and treatment of genetic diseases. The clinical translation of mRNA therapeutics has been made possible through advances in the design of mRNA manufacturing and intracellular delivery methods. However, broad application of mRNA is still limited by the need for improved delivery systems. In this review, we discuss the challenges for clinical translation of mRNA-based therapeutics, with an emphasis on recent advances in biomaterials and delivery strategies, and we present an overview of the applications of mRNA-based delivery for protein therapy, gene editing, and vaccination. mRNA holds the potential to revolutionize vaccination, protein replacement therapies, and the treatment of genetic diseases. Since the first pre-clinical studies in the 1990s, 1 significant progress in the clinical translation of mRNA therapeutics has been made through advances in the design of mRNA manufacturing and intracellular delivery methods. 2 The translatability and stability of mRNA as well as its immunostimulatory activity are the key factors to be optimized for specific therapeutic application. 3 Increased translation and stability can be affected by many regions of the RNA. mRNA 5 0 and 3 0 UTRs are responsible for recruiting RNA-binding proteins and microRNAs, and they can profoundly affect translational activity. 2,4 The modification of rare codons in protein-coding sequences with synonymous frequently occurring codons, so-called codon optimization, can result in order-of-magnitude changes in expression levels. 5,6 Modification of the 5 0 mRNA cap can also enhance mRNA translation by inhibiting RNA decapping and improving resistance to enzymatic degradation. 7 Chemical modification of RNA bases can be used to modify mRNA immunostimulatory activity. 8,9 The importance of immunostimulation can depend on the application, 10 and, in some cases, it may actually improve performance, as in the case of vaccines. 11Finally, methods and vehicles for intracellular delivery remain the major barrier to the broad application of mRNA therapeutics. 12 With some exceptions, the intracellular delivery of mRNA is generally more challenging than that of small oligonucleotides, and it requires encapsulation into a delivery nanoparticle, in part due to the significantly larger size of mRNA molecules (300-5,000 kDa, 1-15 kb) as compared to other types of RNAs (small interfering RNAs [siRNAs], 14 kDa; antisense oligonucleotides [ASOs], 4-10 kDa). 10,13 In this review, we discuss the challenges for clinical translation of mRNAbased therapeutics, with an emphasis on recent advances in biomaterials and delivery strategies, and we present an overview of the applications of mRNA-based delivery for protein therapy, gene editing, and vaccination. Materials for mRNA Delivery Structural Aspects of Material DesignAmong the many barriers to function, mRNA must cross the cell membrane in order to reach the cytoplasm (Figure 1). The cell me...

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Section: Reviewmentioning

confidence: 99%

Delivering the Messenger: Advances in Technologies for Therapeutic mRNA Delivery

et al. 2019

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“…LODER is a polymeric matrix of poly(lactic-co-glycolic) acid that facilitates prolonged delivery of siRNA and has been tested for the treatment of pancreatic cancer. Following preclinical safety and toxicity assessment (Ramot et al, 2016), the siG12D LODER, was evaluated in phase 1/2a clinical trial (NCT01188785) in association with chemotherapy for patients with non-operable locally advanced pancreatic cancer (Golan et al, 2015). The RNAi drug was found to be safe and well-tolerated despite some adverse reactions and importantly demonstrated anticancer effects.…”

Section: G12d Kras -Targeted Sirnamentioning

confidence: 99%

Transcription and Translation Inhibitors in Cancer Treatment

et al. 2020

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Transcription and translation are fundamental cellular processes that govern the protein production of cells. These processes are generally up regulated in cancer cells, to maintain the enhanced metabolism and proliferative state of these cells. As such cancerous cells can be susceptible to transcription and translation inhibitors. There are numerous druggable proteins involved in transcription and translation which make lucrative targets for cancer drug development. In addition to proteins, recent years have shown that the "undruggable" transcription factors and RNA molecules can also be targeted to hamper the transcription or translation in cancer. In this review, we summarize the properties and function of the transcription and translation inhibitors that have been tested and developed, focusing on the advances of the last 5 years. To complement this, we also discuss some of the recent advances in targeting oncogenes tightly controlling transcription including transcription factors and KRAS. In addition to natural and synthetic compounds, we review DNA and RNA based approaches to develop cancer drugs. Finally, we conclude with the outlook to the future of the development of transcription and translation inhibitors.

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“…siG12D LODER is a biodegradable and implantable cylindrical rod (diameter: 0.9mm; length 4mm) that is composed of a copolymer of poly (lactic-co-glyolic) acid (PLGA) (Ramot, et al 2016). This polymer matrix encapsulates anti- KRAS(12G>D) siRNA (siG12D) to enable sustained local release of siG12D for the treatment of locally advanced pancreatic cancer (Golan, et al 2015; Ramot et al 2016; Zorde Khvalevsky, et al 2013).…”

Section: Clinical Application Of Sirna Nanoparticles In Cancer Treatmentmentioning

confidence: 99%

“…This polymer matrix encapsulates anti- KRAS(12G>D) siRNA (siG12D) to enable sustained local release of siG12D for the treatment of locally advanced pancreatic cancer (Golan, et al 2015; Ramot et al 2016; Zorde Khvalevsky, et al 2013). Greater than 90% of pancreatic ductal adenocarcinomas (PDACs) harbor mutated KRAS , and the majority of these are activating mutations occur within codon 12.…”

Section: Clinical Application Of Sirna Nanoparticles In Cancer Treatmentmentioning

confidence: 99%

Silencing the roadblocks to effective triple-negative breast cancer treatments by siRNA nanoparticles

Parvani¹,

Jackson²

2017

Endocrine-Related Cancer

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Over the past decade, RNA interference (RNAi) has been ubiquitously utilized to study biological function in vitro, however limitations were associated with its utility in vivo. More recently, small interfering RNA (siRNA) nanoparticles with improved biocompatibility have gained prevalence as a potential therapeutic option for the treatment of various diseases. The adaptability of siRNA nanoparticles enables the delivery of virtually any siRNA, which is especially advantageous for therapeutic applications in heterogeneous diseases that lack unifying molecular features, such as triple negative breast cancer (TNBC). TNBC is an aggressive subtype of breast cancer that is stratified by the lack of estrogen receptor/progesterone receptor expression and HER2 amplification. There are currently no FDA-approved targeted therapies for the treatment of TNBCs, making cytotoxic chemotherapy the only treatment option available to these patients. In this review, we outline the current status of siRNA nanoparticles in clinical trials for cancer treatment, and discuss promising preclinical approaches that have utilized siRNA nanoparticles for TNBC treatment. Next, we address TNBC subtype-specific therapeutic interventions and highlight where and how siRNA nanoparticles fit into these strategies. Lastly, we point out ongoing challenges in the field of siRNA nanoparticle research that, if addressed, would significantly improve the efficacy of siRNA nanoparticles as a therapeutic option for cancer treatment.

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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

Cited by 59 publications

References 50 publications

Delivering the Messenger: Advances in Technologies for Therapeutic mRNA Delivery

Delivering the Messenger: Advances in Technologies for Therapeutic mRNA Delivery

Transcription and Translation Inhibitors in Cancer Treatment

Silencing the roadblocks to effective triple-negative breast cancer treatments by siRNA nanoparticles

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