Localized Delivery of Antisense Oligonucleotides by Cationic Hydrogel Suppresses TNF-α Expression and Endotoxin-Induced Osteolysis

Dong, Lei; Huang, Zhen; Cai, Xing Fu; Xiang, Jiawei; Zhu, Yi-An; Wang, Rui; Chen, Jiangning; Zhang, Junfeng

doi:10.1007/s11095-010-0334-0

Cited by 19 publications

(14 citation statements)

References 31 publications

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“…Local administration of such systems, either in non‐resectable tumors or in the tumor bed after surgical resection in combination with adjuvant regimens may be a superior alternative for providing increased survival rates of cancer patients . Several hydrogel formulations based on chitosan, fibrin, hyaluronic acid, gelatin PEG, or collagen among others have been used as scaffolds for sustained delivery of DNA and siRNA nanoparticles. Although such systems have proved the feasibility of local and sustained delivery of nucleic acids, there are still several issues that need to be addressed, such as low siRNA stability, low transfection efficiency, and material‐related toxicities.…”

Section: Introductionmentioning

confidence: 99%

Hydrogel Doped with Nanoparticles for Local Sustained Release of siRNA in Breast Cancer

Segovia

Pont

Oliva³

et al. 2014

Adv Healthcare Materials

118

101

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Of all the much hyped and pricy cancer drugs, the benefits from the promising siRNA small molecule drugs are limited. Lack of efficient delivery vehicles that would release the drug locally, protect it from degradation, and ensure high transfection efficiency, precludes it from fulfilling its full potential. This work presents a novel platform for local and sustained delivery of siRNA with high transfection efficiencies both in vitro and in vivo in a breast cancer mice model. siRNA protection and high transfection efficiency are enabled by their encapsulation in oligopeptide-terminated poly(β-aminoester) (pBAE) nanoparticles. Sustained delivery of the siRNA is achieved by the enhanced stability of the nanoparticles when embedded in a hydrogel scaffold based on polyamidoamine (PAMAM) dendrimer cross-linked with dextran aldehyde. The combination of oligopeptide-terminated pBAE polymers and biodegradable hydrogels shows improved transfection efficiency in vivo even when compared with the most potent commercially available transfection reagents. These results highlight the advantage of using composite materials for successful delivery of these highly promising small molecules to combat cancer.

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Section: Introductionmentioning

confidence: 99%

Hydrogel Doped with Nanoparticles for Local Sustained Release of siRNA in Breast Cancer

Segovia

Pont

Oliva³

et al. 2014

Adv Healthcare Materials

118

101

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“…[1] Most osteoporotic fractures require operative reduction and stabilization, but fracture healing processes in the context of ongoing osteoporosis pathology are problematic. Low bone quality and excessive bone resorption decrease the mechanical strength necessary for acceptable, durable fracture healing.…”

Section: Introductionmentioning

confidence: 99%

Selective local delivery of RANK siRNA to bone phagocytes using bone augmentation biomaterials

et al. 2012

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Fracture healing and fracture fixation in the context of osteoporosis is extremely difficult. To inhibit osteoclast-induced bone resorption and associated implant loosening in this pathology, we describe a local delivery strategy to delivery RNA interfering technology to bone sites to target and down-regulate osteoclast formation and function. Resorbable polymer, poly(lactic-co-glycolic acid) (PLGA) microparticles were exploited as a passive phagocyte-targeting carrier to deliver RANK siRNA to both osteoclast precursors and osteoclasts - the professional phagocytes in bone. These natural phagocytes internalize micron-sized particles while most other non-targeted cells in bone cannot. PLGA-siRNA microparticles were dispersed within biomedical grade calcium-based injectable bone cement clinically used in osteoporosis as a bone augmentation biomaterial for fragility fracture prevention and fixation. siRNA released from this formulation in vitro retains bioactivity against the cell target, RANK, in cultured osteoclast precursor cells, inhibiting their progression toward the osteoclastic phenotype. These data support the proof-of-concept to utilize a clinically relevant approach to locally deliver siRNA to phagocytes in bone and improve fragility fracture healing in the context of osteoporosis. This local delivery system delivers siRNA therapeutics directly to osteoporosis sites from clinically familiar injected bone augmentation materials but could be extended to other injectable biomaterials for local siRNA delivery.

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“…Direct silencing of TNF-α has also been investigated in the context of clinical indications involving bone resorption and deterioration. An antisense ODN targeting TNF-α and delivered from a gelatin/chitosan hydrogel (5 μg ODN per 500 mg hydrogel film) inhibited TNF-α by 80% in an endotoxin-induced bone resorption mouse model 151 . TNF-α gene inhibition functionally inhibited production of related inflammatory stimuli macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-κβ (RANK) by >70% and diminished bone resorption by ~95%.…”

Section: Therapeutic Applicationsmentioning

confidence: 99%

Technologies for controlled, local delivery of siRNA

Sarett

Nelson

Duvall

2015

Journal of Controlled Release

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The discovery of RNAi in the late 1990s unlocked a new realm of therapeutic possibilities by enabling potent and specific silencing of theoretically any desired genetic target. Better elucidation of the mechanism of action, the impact of chemical modifications that stabilize and reduce nonspecific effects of siRNA molecules, and the key design considerations for effective delivery systems has spurred progress toward developing clinically-successful siRNA therapies. A logical aim for initial siRNA translation is local therapies, as delivering siRNA directly to its site of action helps to ensure that a sufficient dose reaches the target tissue, lessens the potential for off-target side effects, and circumvents the substantial systemic delivery barriers. While topical siRNA delivery has progressed into numerous clinical trials, an enormous opportunity also exists to develop sustained-release, local delivery systems that enable both spatial and temporal control of gene silencing. This review focuses on material platforms that establish both localized and controlled gene silencing, with emphasis on the systems that show most promise for clinical translation.

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Localized Delivery of Antisense Oligonucleotides by Cationic Hydrogel Suppresses TNF-α Expression and Endotoxin-Induced Osteolysis

Abstract: This is a successful attempt to apply localized gene delivery method to treat inflammatory diseases in vivo.

Cited by 19 publications

References 31 publications

Hydrogel Doped with Nanoparticles for Local Sustained Release of siRNA in Breast Cancer

Hydrogel Doped with Nanoparticles for Local Sustained Release of siRNA in Breast Cancer

Selective local delivery of RANK siRNA to bone phagocytes using bone augmentation biomaterials

Technologies for controlled, local delivery of siRNA

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