Modifying internal organization and surface morphology of siRNA lipoplexes by sodium alginate addition for efficient siRNA delivery

Arruda, Danielle Campiol; Gonzalez, Ismael José; Finet, Stéphanie; Córdova, Luis A.; Trichet, Valérie; Andrade, Gracielle Ferreira; Hoffmann, Céline; Bigey, Pascal; Macedo, W. A. A.; Silva-Cunha, Armando; Souza, Angelo Malachias de; Escriou, Virginie

doi:10.1016/j.jcis.2019.01.043

Cited by 16 publications

(19 citation statements)

References 40 publications

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“…This work aimed to obtain an efficient non-viral vector for the intravitreal delivery of siRNA, with easy preparation and high silencing efficiency. Previously, our research group developed a cationic system containing sodium alginate to increase the stability and effectiveness of lipid-based siRNA vectors [8]. However, for an intravitreal application, this positively charged system may not reach the retinal tissues due to the extended presence of negative charges in the vitreous humor [24,27,34].…”

Section: Discussionmentioning

confidence: 99%

“…Among the silencing molecules, small interfering RNAs (siRNAs) stand out, as they do not follow Dicer processing, avoiding the overload of the cellular RNAi path. The siRNA molecule is a double-stranded RNA oligonucleotide, usually with 21-27 base pairs [6][7][8]. The eye appears particularly attractive for RNAi therapies because it is easily accessible, relatively immune-privileged (due to the limited systemic exposure promoted by the blood-retina barrier (BRB)) and small, which allows small amounts of agent to achieve a therapeutic effect [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

“…The intraocular delivery of siRNA is limited by several inherent anatomical and physiological ocular structures, including the cornea and anterior segment barriers, the sclera and Bruch's choroid complex, as well as the BRB [13,14]. In addition, siRNA molecules cannot freely cross cell membranes because of their relatively large molecular weight and phosphodiester backbone [6][7][8]. Thus, the effectiveness of RNAi therapy significantly depends on the siRNA vector's ability to overcome the intrinsic ocular barriers and reach the target cells [3,15,16].…”

Section: Introductionmentioning

confidence: 99%

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Neuroprotective Effect of siRNA Entrapped in Hyaluronic Acid-Coated Lipoplexes by Intravitreal Administration

et al. 2021

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Since the possibility of silencing specific genes linked to retinal degeneration has become a reality with the use of small interfering RNAs (siRNAs), this technology has been widely studied to promote the treatment of several ocular diseases. Despite recent advances, the clinical success of gene silencing in the retina is significantly reduced by inherent anatomical and physiological ocular barriers, and new strategies are required to achieve intraocular therapeutic effectiveness. In this study, we developed lipoplexes, prepared with sodium alginate as an adjuvant and strategically coated with hyaluronic acid (HA-LIP), and investigated the potential neuroprotective effect of these systems in a retinal light damage model. Successful functionalization of the lipoplexes with hyaluronic acid was indicated in the dynamic light scattering and transmission electron microscopy results. Moreover, these HA-LIP nanoparticles were able to protect and deliver siRNA molecules targeting caspase-3 into the retina. After retinal degeneration induced by high light exposure, in vitro and in vivo quantitative reverse transcription-PCR (RT-qPCR) assays demonstrated significant inhibition of caspase-3 expression by HA-LIP. Furthermore, these systems were shown to be safe, as no evidence of retinal toxicity was observed by electroretinography, clinical evaluation or histology.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Neuroprotective Effect of siRNA Entrapped in Hyaluronic Acid-Coated Lipoplexes by Intravitreal Administration

et al. 2021

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“…found that lipoplexes formed using the FDA‐approved anionic polymer, polyglutamate, led to a more efficient lipoplex formation as well as a reduction in cellular toxicity as the dose of siRNA increased. [ 21–24 ] Other anionic polymers are definitely suitable for this application, but due to the wide usage of polyglutamate in biomedical applications, this choice made clinical sense. A similar approach was taken by Hattori et al.…”

Section: Rnai Therapeutic Delivery Systemsmentioning

confidence: 99%

Innovations in Biomaterial Design toward Successful RNA Interference Therapy for Cancer Treatment

Ward

Shodeinde

Peppas

2021

Adv Healthcare Materials

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Gene regulation using RNA interference (RNAi) therapy has been developed as one of the frontiers in cancer treatment. The ability to tailor the expression of genes by delivering synthetic oligonucleotides to tumor cells has transformed the way scientists think about treating cancer. However, its clinical application has been limited due to the need to deliver synthetic RNAi oligonucleotides efficiently and effectively to target cells. Advances in nanotechnology and biomaterials have begun to address the limitations to RNAi therapeutic delivery, increasing the likelihood of RNAi therapeutics for cancer treatment in clinical settings. Herein, innovations in the design of nanocarriers for the delivery of oligonucleotides for successful RNAi therapy are discussed.

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“…When suspended in 150 mM NaCl (Figure 3A, green curve), lipoplexes exhibited a mixture of two phases, cubic and lamellar, as we have recently shown. 29 When the saline suspension of lipoplexes was diluted in the solution of lyophilization excipients (trehalose / mannitol, 2.5 % / 1 % w/v, Figure 3A, blue curve), the cubic phase was no longer detectable and only a lamellar phase with a broad peak was detected. These results point out that the mixture of excipients had a significant influence on the supramolecular structure of the particles (see discussion section).…”

Section: Freeze-drying Of Sirna Lipoplexesmentioning

confidence: 99%

Compression of Vectors for Small Interfering RNAs Delivery: Toward Oral Administration of siRNA Lipoplexes in Tablet Forms

et al. 2020

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Currently, most non-viral nucleic acid vectors are in the form of colloidal suspensions administered primarily parenterally. This type of formulation and the mode of administration impose strong constraints such as the size of the administered vectors or the production of sterile preparations. The tablet form provides access to easy oral administration, well accepted by patients, it is also an advance for the stability of the nucleic acids vectors, since it is a dry form.Using an optimized lipid-based small interfering RNA delivery system, we studied the tabletability of a liquid suspension of these vector. We optimized the conditions of freeze-drying by choosing excipients and process, allowing for the conservation of both the gene silencing efficacy of the formulated siRNAs and the supramolecular structure of the lipid particulate system. Gene silencing efficacy was assayed on luciferase-expressing cells and the structure of the siRNA vector in freezedried and tablet forms was examined using SAXS Synchrotron radiation. The freeze-dried powders were then mixed with excipients necessary for the good progress of the compression by allowing for a regular supply of the matrix and the reduction of friction. The compression was carried out using a rotary press simulator that allow for complete monitoring of the compression conditions. After compression, formulated siRNAs retained more than 60% of their gene silencing efficacy. Within the tablets, a specific SAXS signal was detectable and the lamellar and cubic phases of the initial liquid suspension were restored after re-suspension of siRNA vectors by disintegration of the tablets. These results show that the bilayer lipid structures of the particles were preserved despite the mechanical constraints imposed by the compression. If such a result could be expected after the freeze-drying step, it was never shown, to our knowledge, that siRNA delivery systems could retain their efficacy and structure after mechanical stress such as compression. This opens promising perspectives to oral administration of siRNA as an alternative to parenteral administration.

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Modifying internal organization and surface morphology of siRNA lipoplexes by sodium alginate addition for efficient siRNA delivery

Cited by 16 publications

References 40 publications

Neuroprotective Effect of siRNA Entrapped in Hyaluronic Acid-Coated Lipoplexes by Intravitreal Administration

Neuroprotective Effect of siRNA Entrapped in Hyaluronic Acid-Coated Lipoplexes by Intravitreal Administration

Innovations in Biomaterial Design toward Successful RNA Interference Therapy for Cancer Treatment

Compression of Vectors for Small Interfering RNAs Delivery: Toward Oral Administration of siRNA Lipoplexes in Tablet Forms

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