Small molecules convey big messages: Boosting non-viral nucleic acid delivery with low molecular weight drugs

Joris, Freya; Smedt, Stefaan C. De; Raemdonck, Koen

doi:10.1016/j.nantod.2017.06.012

Cited by 16 publications

(14 citation statements)

References 123 publications

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“…Thus, we anticipate that sufficiently high adjuvant concentrations may be reached in tissues given the extremely high distribution volumes of CADs and, based on the data presented here, non-lethal LMP at lower CAD doses being sufficient to substantially promote siRNA delivery [43]. On the other hand, co-encapsulation of the delivery enhancing compound into the nanoparticle could further contribute to successful in vivo translation by conferring improved control over extra-and intracellular distribution, lowering the required dose or dosing frequency to observe an adjuvant effect and reducing systemic toxicity [44].…”

Section: Desloratadine Improves Therapeutic Sirna Deliverymentioning

confidence: 80%

Repurposing cationic amphiphilic drugs as adjuvants to induce lysosomal siRNA escape in nanogel transfected cells

Joris

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Vyver

et al. 2018

Journal of Controlled Release

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Cytosolic delivery remains a major bottleneck for siRNA therapeutics. To facilitate delivery, siRNAs are often enclosed in nanoparticles (NPs). However, upon endocytosis such NPs are mainly trafficked towards lysosomes. To avoid degradation, cytosolic release of siRNA should occur prior to fusion of endosomes with lysosomes, but current endosomal escape strategies remain inefficient. In contrast to this paradigm, we aim to exploit lysosomal accumulation by treating NP-transfected cells with low molecular weight drugs that release the siRNA from the lysosomes into the cytosol. We show that FDA-approved cationic amphiphilic drugs (CADs) significantly improved gene silencing by siRNA-loaded nanogels in cancer cells through simple sequential incubation. CADs induced lysosomal phospholipidosis, leading to transient lysosomal membrane permeabilization and improved siRNA release without cytotoxicity. Of note, the lysosomes could be applied as an intracellular depot for triggered siRNA release by multiple CAD treatments.

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Section: Desloratadine Improves Therapeutic Sirna Deliverymentioning

confidence: 80%

Repurposing cationic amphiphilic drugs as adjuvants to induce lysosomal siRNA escape in nanogel transfected cells

Joris

Backer

Vyver

et al. 2018

Journal of Controlled Release

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“…Nonetheless, as CADs and NPs need to be present in the same intracellular compartment to enable the adjuvant effect, coencapsulation of the CAD and the small NA in the same NP and/or local application (e.g., topical, pulmonary) should improve control over extra-and intracellular distribution, thus contributing to a successful in vivo translation. 14,101…”

Section: Resultsmentioning

confidence: 99%

“…Small molecular drugs have proven successful in facilitating (one or more steps) of the intracellular NA delivery process. ,,,− Since the discovery of chloroquine as a small molecule endosomal escape enhancer in 1981, it was only in recent years that other NA delivery enhancers were identified. ,− Recently, our group demonstrated that lysosomal sequestered siRNA can be released into the cytosol by exposing dextran nanogel-transfected non-small cell lung cancer (NSCLC) cells to selected cationic amphiphilic drugs (CADs) . Due to their physicochemical properties, these drugs tend to accumulate inside the acidified lysosomal compartment where they functionally inhibit the acid sphingomyelinase (ASM) enzyme.…”

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confidence: 99%

Cationic Amphiphilic Drugs Boost the Lysosomal Escape of Small Nucleic Acid Therapeutics in a Nanocarrier-Dependent Manner

et al. 2020

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Small nucleic acid (NA) therapeutics, such as small interfering RNA (siRNA), are generally formulated in nanoparticles (NPs) to overcome the multiple extra- and intracellular barriers upon in vivo administration. Interaction with target cells typically triggers endocytosis and sequesters the NPs in endosomes, thus hampering the pharmacological activity of the encapsulated siRNAs that occurs in the cytosol. Unfortunately, for most state-of-the-art NPs, endosomal escape is largely inefficient. As a result, the bulk of the endocytosed NA drug is rapidly trafficked toward the degradative lysosomes that are considered as a dead end for siRNA nanomedicines. In contrast to this paradigm, we recently reported that cationic amphiphilic drugs (CADs) could strongly promote functional siRNA delivery from the endolysosomal compartment via transient induction of lysosomal membrane permeabilization. However, many questions still remain regarding the broader applicability of such a CAD adjuvant effect on NA delivery. Here, we report a drug repurposing screen (National Institutes of Health Clinical Collection) that allowed identification of 56 CAD adjuvants. We furthermore demonstrate that the CAD adjuvant effect is dependent on the type of nanocarrier, with NPs that generate an appropriate pool of decomplexed siRNA in the endolysosomal compartment being most susceptible to CAD-promoted gene silencing. Finally, the CAD adjuvant effect was verified on human ovarian cancer cells and for antisense oligonucleotides. In conclusion, this study strongly expands our current knowledge on how CADs increase the cytosolic release of small NAs, providing relevant insights to more rationally combine CAD adjuvants with NA-loaded NPs for future therapeutic applications.

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“…Two main pH-sensitive strategies have emerged: (1) masking of lytic agents with acid-degradable protecting groups and (2) encapsulation of lytic agents in polymeric micelles that dissociate upon protonation. A few interesting strategies utilizing small molecule drugs to enhance endosomal escape have been recently reviewed; 123 thus, for the purposes of brevity we will limit our discussion in this section to peptideenabled endosomal escape. Many researchers have enhanced polyplex uptake and endosomal escape through the incorporation of unmodified membrane lytic peptides such as melittin, 124,125 KALA, 126 gp41, 127 or diphtheria toxin.…”

Section: Methods For Balancing Potentmentioning

confidence: 99%

pH-Sensitive Polymers as Dynamic Mediators of Barriers to Nucleic Acid Delivery

2018

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The nonviral delivery of exogenous nucleic acids (NA) into cells for therapeutic purposes has rapidly matured into tangible clinical impact. Synthetic polymers are particularly attractive vectors for NA delivery due to their relatively inexpensive production compared to viral alternatives and their highly tailorable chemical properties; indeed, many preclinical investigations have revealed the primary biological barriers to nonviral NA delivery by systematically varying polymeric material properties. This review focuses on applications of pH-sensitive chemistries that enable polymeric vectors to serially address multiple biological barriers to NA delivery. In particular, we focus on recent innovations with in vivo evaluation that dynamically enable colloidal stability, cellular uptake, endosomal escape, and nucleic acid release. We conclude with a summary of successes to date and projected areas for impactful future research.

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Small molecules convey big messages: Boosting non-viral nucleic acid delivery with low molecular weight drugs

Cited by 16 publications

References 123 publications

Repurposing cationic amphiphilic drugs as adjuvants to induce lysosomal siRNA escape in nanogel transfected cells

Repurposing cationic amphiphilic drugs as adjuvants to induce lysosomal siRNA escape in nanogel transfected cells

Cationic Amphiphilic Drugs Boost the Lysosomal Escape of Small Nucleic Acid Therapeutics in a Nanocarrier-Dependent Manner

pH-Sensitive Polymers as Dynamic Mediators of Barriers to Nucleic Acid Delivery

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