Novel lipoproteoplex delivers Keap1 siRNA based gene therapy to accelerate diabetic wound healing

Rabbani, Piul S.; Zhou, Angela; Borab, Zachary; Frezzo, Joseph A.; Srivastava, Nikita; More, Haresh T.; Rifkin, William J.; David, Joshua A.; Berens, Samuel; Chen, Raymond; Hameedi, Sophia; Junejo, Muhammad Hyder; Kim, Camille; Sartor, Rita Abigail; Liu, Che F.; Saadeh, Pierre B.; Montclare, Jin Kim; Ceradini, Daniel J.

doi:10.1016/j.biomaterials.2017.04.001

Cited by 117 publications

(85 citation statements)

References 52 publications

(64 reference statements)

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“…Previous studies demonstrated that impaired or delayed healing was serious problem in some metabolic diseases including DM [6,8,9,10,11], because of several factors such as differentiation of the extracellular matrix dysfunction in fibroblasts and epidermal cells, and poor angiogenesis, e.g. [6,11].…”

Section: Histopathological Studymentioning

confidence: 99%

“…Most chronic wounds are associated with some illnesses including Diabetes mellitus (DM) [6][7][8] which is one of the most common disease worldwide [8,9]. In the United States, approximately 29.1 million people suffer from DM [10] and 15 % of patients with DM complain from serious complications such as chronic ulcers [8,10] which are characterized as impaired or non-healing wounds [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of the Wound Healing Properties of Luteolin Ointments on Excision and Incision Wound Models in Diabetic and Non-Diabetic Rats

Özay¹,

Güzel²,

Erdoğdu³

et al. 2018

Rec.Nat.Prod.

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Luteolin, which is structurally classified under the flavonoids, is naturally distributed abundant among medicinal plants, vegetables and fruits. The wound healing effects of Luteolin ointments were evaluated for incision and excision wound models on non-diabetic and Streptozotocin induced diabetic rats by using macroscopical, biomechanical, biochemical and histopathological methods. Two different concentrations (0.5 % and 1 % (w/w)) of the Luteolin ointment were prepared with the mixture of glycol stearate:propylene glycol:liquid paraffin (3:6:1) and 0.5 g of the ointments were applied topically on wounds once daily for 7 and 14 days. During the experiments, wounds were visually observed, photographically documented and wound areas were measured. After 7 and 14 days treatment, animals were sacrificed under anesthesia and hydroxyproline measurement and biomechanical analysis were performed. Histopathology of the wound area was evaluated considering features of re-epithelialization, thickness of the granulation tissue, angiogenesis, presence of inflammation, number of mast cells. Outcomes of this study revealed that Luteolin ointments improved wound healing process of skin tissue both in non-diabetic and diabetic wounds. The best wound healing activity was observed in incision and excision wounds (97.6 %, 96.1 %, respectively) treated with 0.5 % (w/w) Luteolin ointment on day 14 according to macroscopic results.

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Section: Histopathological Studymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Evaluation of the Wound Healing Properties of Luteolin Ointments on Excision and Incision Wound Models in Diabetic and Non-Diabetic Rats

Özay¹,

Güzel²,

Erdoğdu³

et al. 2018

Rec.Nat.Prod.

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show abstract

“…7 However, the viral carriers are prone to immunogenicity and the risk of insertional mutagenesis. 8 Therefore, nonviral carriers have great potential in the application of gene therapy due to their better safety profile. gold NP, 10 and mesoporous silica, 11 have been developed to prepare antitumor nanomedicines with passive tumor-targeting properties due to the "enhanced permeability and retention" effect.…”

Section: Introductionmentioning

confidence: 99%

siRNA-loaded selenium nanoparticle modified with hyaluronic acid for enhanced hepatocellular carcinoma therapy

Xia¹,

Guo²,

Xu³

et al. 2018

IJN

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Background Small interfering RNA (siRNA) as a new therapeutic modality holds promise for cancer treatment. However, the traditional viral carriers are prone to immunogenicity and risk of insertional mutagenesis. Methods In order to provide a tumor-targeted delivery carrier of siRNA in cancer therapy, the hyaluronic acid (HA)-selenium (Se)-polyethylenimine (PEI) nanoparticle (NP) was fabricated by decorating SeNP with HA as a tumor-targeting moiety and by linking the polycationic polymers polyethylenimine PEI onto the surface of SeNP. The siRNA was loaded to the surface of SeNP HA-Se-PEI via the electrostatic interaction between siRNA and PEI to prepare the functionalized SeNP HA-Se-PEI@siRNA. Results The HA-Se-PEI@siRNA was internalized into the HepG2 cell mainly in a clathrin-mediated endocytosis manner. Owing to the active tumor-targeted effect mediated by HA, HA-Se-PEI@siRNA achieved the obvious higher transfection efficiency, greater gene silencing ability, and stronger cytotoxicity in the HepG2 cell compared with the passive tumor-targeted NP Se-PEI@siRNA. The knockdown of hairy and enhancer of split 5 by HA-Se-PEI@siRNA induced the HepG2 cell cycle arrest at the G0/G1 phase and apoptosis. Furthermore, the treatment with HA-Se-PEI@siRNA resulted in greater antitumor efficacy compared with the Se-PEI@siRNA in vitro and in vivo. In addition, the HA-Se-PEI@siRNA was almost no toxic to the key organs of mice. Conclusion These findings provided an alternative therapeutic route for targeted cancer treatments.

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“…However, topical siRNA delivery remains challenging due to the unique structure of skin, with the stratum corneum proving difficult to penetrate, and endogenous RNAses degrading unpackaged siRNA. Cationic lipid nanoparticles have been used for both systemic as well as topical delivery, and in the present study, we utilized DOTAP and NaChol for creation of liposomes, which have shown promise in topical transdermal siRNA delivery in previous studies by our group and others . Although, liposomes are commonly used by many groups for siRNA delivery, the lipid ratios vary widely, and the optimal formulation remains unclear.…”

Section: Discussionmentioning

confidence: 98%

“…Evaluation of the release kinetics and penetration of the lipoplex/hydrogel vehicle was performed as previously described . Briefly, the dorsal skin of wild type C57 mice received a single application of lipoplex containing fluorescently tagged siGLO in hydrogel formulation, or an injection of lipoplex containing siGLO.…”

Section: Methodsmentioning

confidence: 99%

Topical inhibition of PUMA signaling mitigates radiation injury

Kowzun

Rifkin

Borab

et al. 2018

Wound Repair Regeneration

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Radiation therapy is an effective treatment strategy for many types of cancer but is limited by its side effects on normal tissues, particularly the skin, where persistent and progressive fibrotic changes occur and can impair wound healing. In this study, we attempted to mitigate the effects of irradiation on skin using a novel transcutaneous topical delivery system to locally inhibit p53 up-regulated modulator of apoptosis (PUMA) gene expression with small interfering RNA (siRNA). In an isolated skin irradiation model, the dorsal skin of C57 wild-type mice was irradiated. Prior to irradiation, PUMA and nonsense siRNA were applied via a novel hydrogel formulation to dorsal skin and reapplied weekly. Skin was harvested at multiple time points to evaluate dermal siRNA penetration, mRNA expression, protein expression, dermal thickness, subcutaneous fat, stiffness, vascular hypertrophy, SCAR index, and reactive oxygen species (ROS) generation. Murine skin treated with topical PUMA siRNA via optimized hydrogel formulation demonstrated effective PUMA inhibition in irradiated tissue at 3-4 days. Tissue stiffness, dermal thickness, vascular hypertrophy, SCAR index, ROS levels, and mRNA levels of MnSOD and TGF-β were all significantly reduced with siPUMA treatment compared to nonsense controls. Subcutaneous fat area was significantly increased, and levels of SMAD3 and Phospho-SMAD3 expression were unchanged. These results show that PUMA expression can be effectively silenced in vivo using a novel hydrogel lipoplex topical delivery system. Moreover, cutaneous PUMA inhibition mitigates radiation induced changes in tissue character, restoring a near-normal phenotype independent of SMAD3 signaling.

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Novel lipoproteoplex delivers Keap1 siRNA based gene therapy to accelerate diabetic wound healing

Cited by 117 publications

References 52 publications

Evaluation of the Wound Healing Properties of Luteolin Ointments on Excision and Incision Wound Models in Diabetic and Non-Diabetic Rats

Evaluation of the Wound Healing Properties of Luteolin Ointments on Excision and Incision Wound Models in Diabetic and Non-Diabetic Rats

siRNA-loaded selenium nanoparticle modified with hyaluronic acid for enhanced hepatocellular carcinoma therapy

Topical inhibition of PUMA signaling mitigates radiation injury

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