Therapeutic Gene Silencing Using Targeted Lipid Nanoparticles in Metastatic Ovarian Cancer

Singh, Manu Smriti; Ramishetti, Srinivas; Landesman-Milo, Dalit; Goldsmith, Meir; Chatterjee, Sushmita; Palakuri, Ramesh; Peer, Dan

doi:10.1002/smll.202100287

Cited by 28 publications

(30 citation statements)

References 46 publications

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“…Functionalized PEG-lipids enable bioconjugation of LNPs with ligands or biomacromolecules. For example, Singh et al used DSPE-PEG-amine to conjugate hyaluronan via NHS/EDC chemistry for tumor targeting, 41 and Parhiz et al used DSPE-PEGmaleimide to conjugate antibodies via SATA-maleimide chemistry. 42 While PEG is useful for LNP stability and bioconjugation, its desorption is also critical for cell transfection.…”

Section: Peg-anchored Lipidsmentioning

confidence: 99%

Chemistry of Lipid Nanoparticles for RNA Delivery

et al. 2021

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Metrics & MoreArticle Recommendations CONSPECTUS: Lipid nanoparticles (LNPs) are a type of lipid vesicles that possess a homogeneous lipid core. These vesicles are widely used in small-molecule drug and nucleic acid delivery and recently gained much attention because of their remarkable success as a delivery platform for COVID-19 mRNA vaccines. Nonetheless, the utility of transient protein expression induced by mRNA extends far beyond vaccines against infectious diseasesthey also hold promise as cancer vaccines, protein replacement therapies, and gene editing components for rare genetic diseases. However, naked mRNA is inherently unstable and prone to rapid degradation by nucleases and self-hydrolysis. Encapsulation of mRNA within LNPs protects mRNA from extracellular ribonucleases and assists with intracellular mRNA delivery.In this Account, we discuss the core features of LNPs for RNA delivery. We focus our attention on LNPs designed to deliver mRNA; however, we also include examples of siRNA-LNP delivery where appropriate to highlight the commonalities and the dissimilarities due to the nucleic acid structure. First, we introduce the concept of LNPs, the advantages and disadvantages of utilizing nucleic acids as therapeutic agents, and the general reasoning behind the molecular makeup of LNPs. We also briefly highlight the most recent clinical successes of LNP-based nucleic acid therapies. Second, we describe the theory and methods of LNP self-assembly. The common idea behind all of the preparation methods is inducing electrostatic interactions between the nucleic acid and charged lipids and promoting nanoparticle growth via hydrophobic interactions. Third, we break down the LNP composition with special attention to the fundamental properties and purposes of each component. This includes the identified molecular design criteria, commercial sourcing, impact on intracellular trafficking, and contribution to the properties of LNPs. One of the key components of LNPs is ionizable lipids, which initiate electrostatic binding with endosomal membranes and facilitate cytosolic release; however, the roles of other lipid components should not be disregarded, as they are associated with stability, clearance, and distribution of LNPs. Fourth, we review the attributes of LNP constructs as a whole that can heavily influence RNA delivery. These attributes are LNP size, charge, internal structure, lipid packing, lipid membrane hydration, stability, and affinity toward biomacromolecules. We also discuss the specific techniques used to examine these attributes and how they can be adjusted. Finally, we offer our perspective on the future of RNA therapies and some questions that remain in the realm of LNP formulation and optimization.

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Section: Peg-anchored Lipidsmentioning

confidence: 99%

Chemistry of Lipid Nanoparticles for RNA Delivery

et al. 2021

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“…EIF3C was one of the subunits of EIF3, playing vital roles in translation initiation [ 29 ]. Previous studies had revealed that EIF3C was inevitable for tumor progression in many cancer types, including lung cancer, glioma, and ovarian cancer [ 30 – 32 ]. However, the specific role of EIF3C in prostate cancer is still elusive.…”

Section: Resultsmentioning

confidence: 99%

“…Among the 13 subunits of EIF3 (EIF3A to EIF3M), EIF3C is the one of the functional components [ 50 ]. EIF3C was extensively reported involved in the progression of lung cancer, glioma, breast cancer, and ovarian cancer [ 30 – 32 , 34 ]. However, the role of EIF3C in prostate cancer has not been discussed.…”

Section: Discussionmentioning

confidence: 99%

circPDE5A regulates prostate cancer metastasis via controlling WTAP-dependent N6-methyladenisine methylation of EIF3C mRNA

Ding

Wang

Zheng

et al. 2022

J Exp Clin Cancer Res

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Background Circular RNA (circRNA) is a novel class noncoding RNA (ncRNA) that plays a critical role in various cancers, including prostate cancer (PCa). However, the clinical significance, biological function, and molecular mechanisms of circRNAs in prostate cancer remain to be elucidated. Methods A circRNA array was performed to identified the differentially expressed circRNAs. circPDE5A was identified as a novel circRNA which downregulated in clinical samples. Functionally, the in vitro and in vivo assays were applied to explore the role of circPDE5A in PCa metastasis. Mechanistically, the interaction between circPDE5A and WTAP was verified using RNA pulldown followed by mass spectrometry, RNA Immunoprecipitation (RIP) assays. m6A methylated RNA immunoprecipitation sequencing (MeRIP-seq) was then used to identified the downstream target of circPDE5A. Chromatin immunoprecipitation assay (ChIP) and dual-luciferase reporter assay were used to identified transcriptional factor which regulated circPDE5A expression. Results circPDE5A was identified downregulated in PCa tissues compared to adjacent normal tissue and was negatively correlated with gleason score of PCa patients. circPDE5A inhibits PCa cells migration and invasion both in vitro and in vivo. circPDE5A blocks the WTAP-dependent N6-methyladenisine (m6A) methylation of eukaryotic translation initiation factor 3c (EIF3C) mRNA by forming the circPDE5A-WTAP complex, and finally disrupts the translation of EIF3C. Moreover, the circPDE5A-dependent decrease in EIF3C expression inactivates the MAPK pathway and then restrains PCa progression. Conclusions Our findings demonstrate that FOXO4-mediated upregulation of circPDE5A controls PCa metastasis via the circPDE5A-WTAP-EIF3C-MAPK signaling pathway and could serve as a potential therapeutic targer for PCa.

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“…Aptamers are short single-stranded nucleic acid sequences with more affinity and selectivity for their designed antigen than antibodies that are heat-stable and nonimmunogenic. The main polymeric ligand is HA; it targets the CD44 receptor, which is overexpressed in many cancer cells, such as ovarian cancer cells . Finally, small molecules include sugars, such as mannose against dendritic cells or folate used for cancer targeting.…”

Section: Modification Of Nanoparticle Surface To Target-specific Cell...mentioning

confidence: 99%

Surface Modification of Lipid-Based Nanoparticles

Fourniols

Labrak

et al. 2022

ACS Nano

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There is a growing interest in the development of lipid-based nanocarriers for multiple purposes, including the recent increase of these nanocarriers as vaccine components during the COVID-19 pandemic. The number of studies that involve the surface modification of nanocarriers to improve their performance (increase the delivery of a therapeutic to its target site with less off-site accumulation) is enormous. The present review aims to provide an overview of various methods associated with lipid nanoparticle grafting, including techniques used to separate grafted nanoparticles from unbound ligands or to characterize grafted nanoparticles. We also provide a critical perspective on the usefulness and true impact of these modifications on overcoming different biological barriers, with our prediction on what to expect in the near future in this field.

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Therapeutic Gene Silencing Using Targeted Lipid Nanoparticles in Metastatic Ovarian Cancer

Cited by 28 publications

References 46 publications

Chemistry of Lipid Nanoparticles for RNA Delivery

Chemistry of Lipid Nanoparticles for RNA Delivery

circPDE5A regulates prostate cancer metastasis via controlling WTAP-dependent N6-methyladenisine methylation of EIF3C mRNA

Surface Modification of Lipid-Based Nanoparticles

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