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.
Reaching
the corneal endothelium through the topical administration
of therapeutic drugs remains a challenge in ophthalmology. Besides,
endothelial cells are not able to regenerate, and diseases at this
site can lead to corneal blindness. Targeting the corneal endothelium
implies efficient penetration through the three corneal layers, which
still remains difficult for small molecules. Carbon quantum dots (CQDs)
have demonstrated great potential for ocular nanomedicine. This study
focuses on the corneal penetration abilities of differently charged
CQDs and their use as permeation enhancers for drugs. Excised whole
bovine eyes were used as an ex vivo model to investigate
corneal penetration of CQDs derived from glucosamine using β-alanine,
ethylenediamine, or spermidine as a passivation agent. It was found
that negatively charged CQDs have limited corneal penetration ability,
while positively charged CQDs derived from glucosamine hydrochloride
and spermidine (CQD-S) penetrate the entire corneal epithelium all
the way down to the endothelium. CQD-S were shown to enhance the penetration
of FITC-dextran 150 kDa, suggesting that they could be used as efficient
penetration enhancers for therapeutic delivery to the corneal endothelium.
Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Due to a lack of effective treatments, patients with metastatic disease have a median survival time of 6-12 months. We recently demonstrated that the SAMMSON long non-coding RNA (lncRNA) is essential for uveal melanoma cell survival and that antisense oligonucleotide (ASO)-mediated silencing of SAMMSON impaired cell viability and tumor growth in vitro and in vivo. By screening a library of 2911 clinical stage compounds, we identified the mTOR inhibitor GDC-0349 to synergize with SAMMSON inhibition in UM. Mechanistic studies revealed that mTOR inhibition enhanced uptake and reduced lysosomal accumulation of lipid complexed SAMMSON ASOs, improving SAMMSON knockdown and further decreasing UM cell viability. We found mTOR inhibition to also enhance target knockdown in other cancer cell lines as well as normal cells when combined with lipid nanoparticle complexed or encapsulated ASOs or small interfering RNAs (siRNAs). Our results are relevant to nucleic acid treatment in general and highlight the potential of mTOR inhibition to enhance ASO and siRNA mediated target knockdown.
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