Topical delivery of siRNA into skin using SPACE-peptide carriers

Chen, Ming; Zakrewsky, Michael; Gupta, Vivek; Anselmo, Aaron C.; Slee, Deborah H.; Muraski, John A.; Mitragotri, Samir

doi:10.1016/j.jconrel.2014.01.006

Cited by 98 publications

(81 citation statements)

References 63 publications

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“…SNA constructs are able to penetrate the stratum corneum of intact skin, rapidly enter epidermal and dermal cells, and knock down epidermal targets (17). In contrast to SNAs, other topical siRNAbased therapies require epidermal disruption by physical [e.g., injection, tape stripping (23), laser, or ultrasound] or chemical (e.g., conjugation to peptides or lipoplexes or incorporation into other types of nanoparticle structures, lentiviruses, or gels) means for RNAi penetration through the epidermal barrier and into KCs (24)(25)(26)(27)(28)(29)(30)(31). siRNA SNAs are unique, highly anionic constructs that do not require additional chemical modifications to facilitate transportation through the stratum corneum or entry into cells.…”

Section: Discussionmentioning

confidence: 99%

siRNA-based spherical nucleic acids reverse impaired wound healing in diabetic mice by ganglioside GM3 synthase knockdown

Randeria

Seeger²,

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

195

163

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Spherical nucleic acid (SNA) gold nanoparticle conjugates (13-nmdiameter gold cores functionalized with densely packed and highly oriented nucleic acids) dispersed in Aquaphor have been shown to penetrate the epidermal barrier of both intact mouse and human skin, enter keratinocytes, and efficiently down-regulate gene targets. ganglioside-monosialic acid 3 synthase (GM3S) is a known target that is overexpressed in diabetic mice and responsible for causing insulin resistance and impeding wound healing. GM3S SNAs increase keratinocyte migration and proliferation as well as insulin and insulin-like growth factor-1 (IGF1) receptor activation under both normo-and hyperglycemic conditions. The topical application of GM3S SNAs (50 nM) to splinted 6-mm-diameter full-thickness wounds in diet-induced obese diabetic mice decreases local GM3S expression by >80% at the wound edge through an siRNA pathway and fully heals wounds clinically and histologically within 12 d, whereas control-treated wounds are only 50% closed. Granulation tissue area, vascularity, and IGF1 and EGF receptor phosphorylation are increased in GM3S SNA-treated wounds. These data capitalize on the unique ability of SNAs to naturally penetrate the skin and enter keratinocytes without the need for transfection agents. Moreover, the data further validate GM3 as a mediator of the delayed wound healing in type 2 diabetes and support regional GM3 depletion as a promising therapeutic direction.f 27 million Americans diagnosed with type 2 diabetes (T2D), more than 6 million have chronic, nonhealing skin wounds, particularly on the plantar surface, leading to secondary bacterial infection and costing the healthcare system more than $25 billion (1, 2). In 2010 alone, more than 70,000 individuals in the United States with T2D underwent amputation (3). Improved understanding of diabetic wound pathology and new interventions for impaired wound healing are needed.Ganglioside-monosialic acid 3 (GM3), the predominant sialylated glycosphingolipid in skin, has recently been recognized to be a critical mediator of insulin resistance (4-12). Indeed, we have recently shown three-and fourfold more GM3 synthase (GM3S; also known as SAT-I or ST3Gal-V), which is required for the synthesis of GM3, in diabetic human plantar skin than in site-and age-matched control skin (4). Similarly, skin samples from the backs of diet-induced obese (DIO) and ob/ob mouse diabetic models show increased GM3S mRNA expression and GM3 levels. Knockout (KO) of GM3S improves the insulin resistance induced by a high-fat diet in mouse adipose tissue, muscle (5), and as recently shown, skin of DIO T2D mice, reversing the woundhealing impairment of T2D (4). The acceleration of wound healing by GM3S KO and GM3 depletion in mouse skin is associated with increased epidermal cell migration and proliferation as well as activation of the epidermal insulin-like growth factor-1 receptor (IGF1R) in vivo (4). Isolated cultured mouse GM3S −/− keratinocytes (KCs) migrate and proliferate more rapidly than GM3S +/+ WT l...

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Section: Discussionmentioning

confidence: 99%

siRNA-based spherical nucleic acids reverse impaired wound healing in diabetic mice by ganglioside GM3 synthase knockdown

Randeria

Seeger²,

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

195

163

View full text Add to dashboard Cite

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“…Many researchers have reported superior properties of transethosomes over classical ethosomes. [17][18][19][20][21][22][23][24][25][26][27][28][29][30] Different types of edge activators and penetration enhancers have been investigated to produce ethosomal systems with better characteristics. Transethosomes were reported to entrap drugs with molecular weights ranging from 130.077 Da to 200-325 kDa.…”

Section: Transethosomesmentioning

confidence: 99%

“…27 Highly negatively charged vesicles were produced by the incorporation of DPPG (1,2-dipalmitoyl-sn-glycero-3-phosphatidylglycerol) in the ethosomal formulation, 48 while cationic ethosomal vesicles were produced by using a cationic lipid, such as DOTAP (1,2-dioleoyl-3-trimethylammonium-propane [chloride salt]). 22 In general, the concentration range of phospholipids in an ethosomal formulation is 0.5%-5%. 24 Increasing phospholipid concentration will increase vesicular size slightly or moderately, 32,34,64 but will increase entrapment efficiency significantly.…”

Section: Phospholipidsmentioning

confidence: 99%

“…71 This penetration enhancer was incorporated in transethosomes for the delivery of hyaluronic acid and siRNAs. 21,22 The authors named these transethosomes SPACE ethosomal system. The in vitro human skin penetration of hyaluronic acid transethosomes was 7.8±1.1-fold higher than buffer solution, 5.9±2.5-fold higher than buffer-ethanol solution, and 3.2±0.6-fold higher than classical ethosomes.…”

Section: Skin-penetrating and Cell-entering Peptidementioning

confidence: 99%

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Ethosomal nanocarriers: the impact of constituents and formulation techniques on ethosomal properties, in vivo studies, and clinical trials

Abdulbaqi

Darwis

Khan

et al. 2016

IJN

313

215

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Ethosomal systems are novel lipid vesicular carriers containing a relatively high percentage of ethanol. These nanocarriers are especially designed for the efficient delivery of therapeutic agents with different physicochemical properties into deep skin layers and across the skin. Ethosomes have undergone extensive research since they were invented in 1996; new compounds were added to their initial formula, which led to the production of new types of ethosomal systems. Different preparation techniques are used in the preparation of these novel carriers. For ease of application and stability, ethosomal dispersions are incorporated into gels, patches, and creams. Highly diverse in vivo models are used to evaluate their efficacy in dermal/transdermal delivery, in addition to clinical trials. This article provides a detailed review of the ethosomal systems and categorizes them on the basis of their constituents to classical ethosomes, binary ethosomes, and transethosomes. The differences among these systems are discussed from several perspectives, including the formulation, size, ζ-potential (zeta potential), entrapment efficiency, skin-permeation properties, and stability. This paper gives a detailed review on the effects of ethosomal system constituents, preparation methods, and their significant roles in determining the final properties of these nanocarriers. Furthermore, the novel pharmaceutical dosage forms of ethosomal gels, patches, and creams are highlighted. The article also provides detailed information regarding the in vivo studies and clinical trials conducted for the evaluation of these vesicular systems.

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“…24 In addition, Chen et al, based on studies of the SPACE-siRNA conjugates, further embedded it in cationic alcohol plastids with additional free SPACE peptides to facilitate the delivery of SPACE-siRNA conjugates, which showed a dramatic increase in cellular gene-silencing activity. 25 In this study, we used a combined modification strategy for siRNA delivery. To improve the gene silencing and the targeting of siRNA, and compare the biological mechanism of different conjugates, cRGD was conjugated to siRNA at four different sites (3′-or 5′-terminus of sense strand, or …”

Section: Introductionmentioning

confidence: 99%

Reductive nanocomplex encapsulation of cRGD-siRNA conjugates for enhanced targeting to cancer cells

Zhou¹,

Liu²,

Zhang³

et al. 2017

IJN

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In this study, through covalent conjugation and lipid material entrapment, a combined modification strategy was established for effective delivery of small interfering RNA (siRNA). Single strands of siRNA targeting to BRAF V600E gene (siMB3) conjugated with cRGD peptide at 3′-terminus or 5′-terminus via cleavable disulfide bond was synthesized and then annealed with corresponding strands to obtain single and bis-cRGD-siRNA conjugates. A cationic lipid material (CLD) developed by our laboratory was mixed with the conjugates to generate nanocomplexes; their uniformity and electrical property were revealed by particle size and zeta potential measurement. Compared with CLD/siBraf, CLD/cRGD-siBraf achieved higher cell uptake and more excellent tumor-targeting ability, especially 21 (sense-5′/antisense-3″-cRGD-congjugate) nanocomplex. Moreover, they can regulate multiple pathways to varying degree and reduce acidification of endosome. Compared with the gene silencing of different conjugates, single or bis-cRGD-conjugated siRNA showed little differences except 22 (5/5) which cRGD was conjugated at 5′-terminus of antisense strand and sense strand. However bis-cRGD conjugate 21 nanocomplex exhibited better specific target gene silencing at multiple time points. Furthermore, the serum stabilities of the bis-cRGD conjugates were higher than those of the single-cRGD conjugates. In conclusion, all these data suggested that CLD/bis-conjugates, especially CLD/ 21 , can be an effective system for delivery of siRNA to target BRAF V600E gene for therapy of melanoma.

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Topical delivery of siRNA into skin using SPACE-peptide carriers

Cited by 98 publications

References 63 publications

siRNA-based spherical nucleic acids reverse impaired wound healing in diabetic mice by ganglioside GM3 synthase knockdown

siRNA-based spherical nucleic acids reverse impaired wound healing in diabetic mice by ganglioside GM3 synthase knockdown

Ethosomal nanocarriers: the impact of constituents and formulation techniques on ethosomal properties, in vivo studies, and clinical trials

Reductive nanocomplex encapsulation of cRGD-siRNA conjugates for enhanced targeting to cancer cells

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