A novel penetratin-modified complex for noninvasive intraocular delivery of antisense oligonucleotides

Tai, Lingyu; Liu, Chang; Jiang, Kuan; Chen, Xishan; Feng, Liang; Pan, Weisan; Wei, Gang; Lu, Weiyue

doi:10.1016/j.ijpharm.2017.06.090

Cited by 35 publications

(16 citation statements)

References 40 publications

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“…In addition, Puras et al constructed DNA-loaded lipoplexes that demonstrated successful transfection of eGFP in the inner retina post-intravitreal delivery in the Sprague-Dawley rats [ 19 ]. To enhance antisense oligonucleotide permeability and retinal distribution, Tai et al used penetratin-modified hydroxyl-terminated polyamidoamine, which resulted in RPE uptake up to 8 hours post-intravitreal delivery [ 20 ]. Despite these advances, we still lack nanoparticles that can efficiently deliver nucleic acids for gene augmentation, editing and silencing to the photoreceptors and RPE post-intravitreal delivery.…”

Section: Introductionmentioning

confidence: 99%

The effects of PEGylation on LNP based mRNA delivery to the eye

et al. 2020

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Gene therapy is now an effective approach to treat many forms of retinal degeneration. Delivery agents that are cell-specific, allow for multiple dosing regimens, and have low immunogenicity are needed to expand the utility of gene therapy for the retina. We generated eight novel lipid nanoparticles (LNPs) ranging in size from 50 nm to 150 nm by changing the PEG content from 5% to 0.5%, respectively. Subretinal injections of LNP-mRNA encoding luciferase revealed that 0.5% PEG content within nanoparticles elicits the highest expression. Similar injections of LNP delivered cre mRNA into Ai9 mice revealed cell-specific protein expression in the retinal pigment epithelium (RPE), confirmed by fundus photography and immunohistochemistry of whole globe cross-sections. To investigate mechanisms of LNP delivery to the eye, we injected mCherry mRNA using the subretinal approach in apoE -/- and Mertk -/- mice. RPE transfection was observed in both mouse models suggesting that LNP intracellular delivery is not solely dependent on apolipoprotein adsorption or phagocytosis. To investigate LNP penetration, particles were delivered to the vitreous chamber via an intravitreal injection. The 0.5% PEG particles mediated the highest luciferase activity and expression was observed in the Müller glia, the optic nerve head and the trabecular meshwork, but failed to reach the RPE. Overall, particles containing less PEG (~150 nm in size) mediated the highest expression in the eye. Thus far, these particles successfully transfect RPE, Müller cells, the optic nerve head and the trabecular meshwork based on route of administration which can expand the utility of LNP-mediated gene therapies for the eye.

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Section: Introductionmentioning

confidence: 99%

The effects of PEGylation on LNP based mRNA delivery to the eye

et al. 2020

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“…Next, we studied the time-dependent cellular internalization of nanogels that were either modified or not modified with penetratin. This cell-penetrating peptide has been previously used to enhance ocular permeability and drug targeting to the retina. , Penetratin-complexed HA was shown to have a good distribution in the posterior part of the eye even when applied topically. In this study, to assess the extent of the cellular uptake of the nanogels, and for the in vitro imaging, ARPE-19 cells were used.…”

Section: Resultsmentioning

confidence: 96%

Redox-Responsive Hyaluronic Acid-Based Nanogels for the Topical Delivery of the Visual Chromophore to Retinal Photoreceptors

et al. 2021

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Delivering therapeutics to the posterior segment of the eye is challenging due to various anatomical and physical barriers. While significant improvements have been realized by introducing direct injections to diseased sites, these approaches come with potential side effects that can range from simple inflammation to severe retinal damage. The topical instillation of drugs remains a safer and preferred alternative for patients’ compliance. Here, we report the synthesis of penetratin-complexed, redox-responsive hyaluronic acid-based nanogels for the triggered release and delivery of therapeutics to the posterior part of the eye via topical application. The synthesized nanogels were shown to release their load only when exposed to a reducing environment, similar to the cytoplasm. As a model drug, visual chromophore analog, 9-cis-retinal, was loaded into nanogels and efficiently delivered to the mouse retina’s photoreceptors when applied topically. Electroretinogram measurements showed a partial recovery of photoreceptor function in all treated eyes versus untreated controls. To the best of our knowledge, this report constitutes the first attempt to use a topically applied triggered-release drug delivery system to target the pigmented layer of the retina, in addition to the first attempt to deliver the visual chromophore topically.

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“…Their results displayed an intraocular pressure reduction of 30% in normotensive adult Brown Norway male rats, after 30 min of topical application, in addition to the absence of irritation or toxicity after one week of daily administration. Tai et al [ 54 ] investigated the formation of the complex between polyamidoamine dendrimer and hyaluronic acid. This complex was functionalized with penetratin and loaded with antisense oligonucleotides for the treatment of ocular diseases by regulating the expression of target proteins and genes in cells.…”

Section: Polymeric Nanocarriers For Ocular Drug Deliverymentioning

confidence: 99%

Polymeric Nanoparticles for Drug Delivery: Recent Developments and Future Prospects

et al. 2020

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The complexity of some diseases—as well as the inherent toxicity of certain drugs—has led to an increasing interest in the development and optimization of drug-delivery systems. Polymeric nanoparticles stand out as a key tool to improve drug bioavailability or specific delivery at the site of action. The versatility of polymers makes them potentially ideal for fulfilling the requirements of each particular drug-delivery system. In this review, a summary of the state-of-the-art panorama of polymeric nanoparticles as drug-delivery systems has been conducted, focusing mainly on those applications in which the corresponding disease involves an important morbidity, a considerable reduction in the life quality of patients—or even a high mortality. A revision of the use of polymeric nanoparticles for ocular drug delivery, for cancer diagnosis and treatment, as well as nutraceutical delivery, was carried out, and a short discussion about future prospects of these systems is included.

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A novel penetratin-modified complex for noninvasive intraocular delivery of antisense oligonucleotides

Cited by 35 publications

References 40 publications

The effects of PEGylation on LNP based mRNA delivery to the eye

The effects of PEGylation on LNP based mRNA delivery to the eye

Redox-Responsive Hyaluronic Acid-Based Nanogels for the Topical Delivery of the Visual Chromophore to Retinal Photoreceptors

Polymeric Nanoparticles for Drug Delivery: Recent Developments and Future Prospects

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