Microparticle Depots for Controlled and Sustained Release of Endosomolytic Nanoparticles

Garland, Kyle M.; Sevimli, Sema; Kilchrist, Kameron V.; Duvall, Craig L.; Cook, Rebecca S.; Wilson, John T.

doi:10.1007/s12195-019-00571-6

Cited by 9 publications

(10 citation statements)

References 89 publications

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“…Additionally, this finding is disparate with previous data that has consistently reported a short retention profile (e.g. half-life < 1 day) for siRNA complexed to the same polymer (42,47,48,51). This discrepancy is likely attributable to the higher valency of the polymer interaction with the significantly larger dsDNA cargo and/or the extra deoxyribonuclease resistance afforded by the phosphorothioate caps of the dsDNA.…”

Section: Nanoisd Enhances Delivery and Immunostimulatory Activity Of Isd In Vivocontrasting

confidence: 88%

“…To overcome the delivery barriers that limit the activity of ISD, we employed a diblock copolymer, D-PDB, which has previously been used primarily for the cytosolic delivery of small-interfering RNA (siRNA) (35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51). Under a physiological pH of ~7.4, D-PDB self-assembles into colloidally stable, nanoparticle micelles with a cationic corona that can electrostatically load nucleic acids.…”

Section: Resultsmentioning

confidence: 99%

“…The well-established, endosomolytic polymer, poly [(DMAEMA)-block-(PAA-co-DMAEMA-co-BMA)] (D-PDB) (35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51) was used to electrostatically complex dsDNA into environmentally responsive nanoparticles capable of achieving cytosolic delivery. The DNA/polymer complexes were characterized using a library of synthetic ISD to study the effects of both N/P charge ratio (i.e.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacological Activation of cGAS for Cancer Immunotherapy

et al. 2021

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When compartmentally mislocalized within cells, nucleic acids can be exceptionally immunostimulatory and can even trigger the immune-mediated elimination of cancer. Specifically, the accumulation of double-stranded DNA in the cytosol can efficiently promote antitumor immunity by activating the cGAMP synthase (cGAS) / stimulator of interferon genes (STING) cellular signaling pathway. Targeting this cytosolic DNA sensing pathway with interferon stimulatory DNA (ISD) is therefore an attractive immunotherapeutic strategy for the treatment of cancer. However, the therapeutic activity of ISD is limited by several drug delivery barriers, including susceptibility to deoxyribonuclease degradation, poor cellular uptake, and inefficient cytosolic delivery. Here, we describe the development of a nucleic acid immunotherapeutic, NanoISD, which overcomes critical delivery barriers that limit the activity of ISD and thereby promotes antitumor immunity through the pharmacological activation of cGAS at the forefront of the STING pathway. NanoISD is a nanoparticle formulation that has been engineered to confer deoxyribonuclease resistance, enhance cellular uptake, and promote endosomal escape of ISD into the cytosol, resulting in potent activation of the STING pathway via cGAS. NanoISD mediates the local production of proinflammatory cytokines via STING signaling. Accordingly, the intratumoral administration of NanoISD induces the infiltration of natural killer cells and T lymphocytes into murine tumors. The therapeutic efficacy of NanoISD is demonstrated in preclinical tumor models by attenuated tumor growth, prolonged survival, and an improved response to immune checkpoint blockade therapy.

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Section: Nanoisd Enhances Delivery and Immunostimulatory Activity Of Isd In Vivocontrasting

confidence: 88%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pharmacological Activation of cGAS for Cancer Immunotherapy

et al. 2021

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“…Similar w/o/w approaches achieved encapsulation of siRNA against RANK of 0.67 μg of siRNA/mg of PLGA with an encapsulation efficiency of 80.8% and loading of siRNA against FcγRIII precomplexed with bPEI with an encapsulation efficiency of 85–91% . We previously achieved some of the best encapsulation results to date in a cancer application, in which we loaded endosomolytic nanoparticles by the w/o/w method and achieved approximately 1.8 μg of nucleic acid per mg of PLGA with an encapsulation efficiency of 75% . Top-down fabrication approaches provide synthesis benefits over the w/o/w strategy by enabling controlled fabrication of homogeneous microparticle populations with content defined by the polymeric slurry used during fabrication while reducing aqueous exposure in production.…”

Section: Resultsmentioning

confidence: 90%

Top-Down Fabricated microPlates for Prolonged, Intra-articular Matrix Metalloproteinase 13 siRNA Nanocarrier Delivery to Reduce Post-traumatic Osteoarthritis

et al. 2021

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Post-traumatic osteoarthritis (PTOA) associated with joint injury triggers a degenerative cycle of matrix destruction and inflammatory signaling, leading to pain and loss of function. Here, prolonged RNA interference (RNAi) of matrix metalloproteinase 13 (MMP13) is tested as a PTOA disease modifying therapy. MMP13 is upregulated in PTOA and degrades the key cartilage structural protein type II collagen. Short interfering RNA (siRNA) loaded nanoparticles (siNPs) were encapsulated in shape-defined poly(lactic-co-glycolic acid) (PLGA) based microPlates (μPLs) to formulate siNP-μPLs that maintained siNPs in the joint significantly longer than delivery of free siNPs. Treatment with siNP-μPLs against MMP13 (siMMP13-μPLs) in a mechanical load-induced mouse model of PTOA maintained potent (65−75%) MMP13 gene expression knockdown and reduced MMP13 protein production in joint tissues throughout a 28-day study. MMP13 silencing reduced PTOA articular cartilage degradation/fibrillation, meniscal deterioration, synovial hyperplasia, osteophytes, and pro-inflammatory gene expression, supporting the therapeutic potential of long-lasting siMMP13-μPL therapy for PTOA.

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“…Recently, great effort has been made to design and fabricate polymeric nanoparticles owing to their ability to encapsulate and release drugs on demand under specific conditions [13], [14].Micelles have been considered as a good drug delivery carrier due to their sustained release capacity and special characteristics [15]. Micelle which usually be achieved by the self-assembly of block co-polymers is an amphipathic nano-sized carrier with a core-shell structure.…”

Section: Introductionmentioning

confidence: 99%

Reduced administration frequency for the treatment of fungal keratitis: a sustained natamycin release from a micellar solution

Guo

Karimi

et al. 2020

Expert Opinion on Drug Delivery

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We report the synthesis and preparation of self-assembled poly(ethylene glycol)block-poly(glycidyl methacrylate) (PEG-b-PGMA) micelles harnessing the intrinsically hydrolysable characteristics of PGMA segments for the sustained delivery of a hydrophobic natamycin by topical administration on eye. Hydrolysis of the glycidyl groups could be achieved within physiologically relevant environment, resulting in increased drug release compared to conventional non-hydrolysable counterparts. It was found that the system provides an additional driving force for drug release by generation of hydrophilic hydroxyl groups to "push" the encapsulated hydrophobic drug away from the hydrophobic domains and into the surrounding environments. In vitro and in vivo results revealed that the drug carriers (PEG-b-PGMA micelles) and the encapsulated natamycin were not cytotoxic to human corneal epithelial cells and the released drug have strong antifungal ability to Candida albicans. Importantly, sustained natamycin release from micelles leads to the reduced administration frequency of natamycin from 8 times per day to 3 times per day in fungal keratitis (FK) rabbits. Corneal morphology of keratitis was improved by the release of natamycin from the micelle observed by anterior segment optical coherence tomography (AS-OCT) and histological analysis of the cornea. These results revealed that the use of micelle enhances the loading and delivery efficiency of natamycin and subsequently promotes the drug penetration in aqueous humor and cornea. The present study demonstrates a facile method that can greatly reduce dosing frequency of natamycin administration and thus improve long-term patient compliance.

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Microparticle Depots for Controlled and Sustained Release of Endosomolytic Nanoparticles

Cited by 9 publications

References 89 publications

Pharmacological Activation of cGAS for Cancer Immunotherapy

Pharmacological Activation of cGAS for Cancer Immunotherapy

Top-Down Fabricated microPlates for Prolonged, Intra-articular Matrix Metalloproteinase 13 siRNA Nanocarrier Delivery to Reduce Post-traumatic Osteoarthritis

Reduced administration frequency for the treatment of fungal keratitis: a sustained natamycin release from a micellar solution

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