Iontophoretic Delivery of Oligonucleotides across full Thickness Hairless Mouse Skin

Oldenburg, Kevin R.; Vo, Kham T.; Smith, G. A.; Selick, Harold E.

doi:10.1002/jps.2600840803

Cited by 53 publications

(18 citation statements)

References 29 publications

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“…In summary, for sequences targeted to the enzyme telomerase, flux is related inversely to size, supporting previous studies which report similar results for other oligomer chemistries (Nolen et al, 1994;Brand et al, 1998a;Oldenberg et al, 1995). Additionally, differential transport of equivalently sized oligomers of varying sequence suggests that oligomer permeation is sequence specific.…”

Section: Discussionsupporting

confidence: 75%

“…In a similar study (Brand et al, 1998a) using iontophoretic delivery of phosophorothioate oligomers with the TAG and CTA sequences, the general inverse trend between size and flux was seen, but the linearity was not as clear as for the PG/LA studies presented in this work. A similar relationship between size and flux was also identified for passively delivered methylphosphanate oligomers (Nolen et al, 1994) and iontophoretically delivered phosphodiester oligomers with equal portions of each base (Oldenberg et al, 1995). However, the effects of size and sequences, as well as oligomer chemistry and penetration techniques, cannot be separated in these previous studies.…”

Section: Discussionmentioning

confidence: 78%

“…Modifying the center of the molecules reduced polarity and steric-hindrance while the mass/charge ratio increased, resulting in greater penetration (unpublished results). Furthermore, comparing the iontophoretic transdermal penetration of a 15-base thrombin aptamer consisting of nine guanines and six thymidines with a globular three-dimensional (3D) structure to a scrambled aptamer without a similar 3D structure revealed that the active compound had two-fold lower penetration than the scrambled sequence, again demonstrating the influence of structure on transdermal delivery (Oldenberg et al, 1995). The effects of guanines on dermal penetration can also be seen when water is used as a solvent.…”

Section: Discussionmentioning

confidence: 95%

“…Transdermally delivered oligomers with charged backbones have been demonstrated to cross the skin in vitro (Nolen et al, 1994;Brand and Iversen, 1996;Brand et al, 1998a;Oldenberg et al, 1995). In vivo studies have shown that antisense oligomers can enter into target organs (Vlassov et al, 1993;Vlassov et al, 1994), and induce changes in target enzymes (Brand et al, 2001;Arora et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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Transdermal delivery of phosphorodiamidate Morpholino oligomers across hairless mouse skin

Pannier

Arora

Iversen

et al. 2004

International Journal of Pharmaceutics

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Transdermal delivery of phosphorodiamidate Morpholino oligomers across hairless mouse skin

Pannier

Arora

Iversen

et al. 2004

International Journal of Pharmaceutics

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“…In general, oligonucleotides are membrane-impermeable due to their high ionization, low-lipophilicity and high molecular weight. There are some reports on the improvement of transdermal delivery of antisense oligonucleotides across the stratum corneum with absorption enhancers 13) or by iontophoresis [14][15][16][17] and electroporation. 18,19) Iontophoresis is classified by the current flow pattern into constant direct current (CDC), pulse direct current (PDC), and pulse depolarization current (PDP).…”

mentioning

confidence: 99%

Intradermal Delivery of Antisense Oligonucleotides by the Pulse Depolarization Iontophoretic System

Aramaki

Arima

Takahashi

et al. 2003

Biological & Pharmaceutical Bulletin

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Antisense oligonucleotides designed to hybridize specifically to heterogeneous nuclear RNA or mature mRNA sequences have been shown to inhibit the expression of numerous genes both in vitro and in vivo.2,3) They have been considered as a promising candidate for nucleic acid drugs to realize gene-specific therapeutics for the treatment of malignant, viral, inflammatory, and autoimmune diseases. CD4ϩ helper T (Th) cells have been subdivided into at least two subsets, Th1 and Th2, on the basis of their cytokine secretion. 4,5) The balance of Th1 and Th2 cells is relevant to the outcome of immunologically mediated clinical syndromes, suggesting that Th2 is predominant in atopic dermatitis (AD).6) Interleukin-10 (IL-10) is initially characterized as a counter-regulatory cytokine for Th1 development, 4) and the overexpression of IL-10 in AD may contribute to the down-regulation of Th1 response. 7,8) Therefore, the regulation of IL-10 production may provide a potentiality for the immunotherapeutic intervention of AD. We reported that 18-mer antisense phosphorothioate oligonucleotide (S-oligo) hybridizing to the sequence of the 3Ј-untranslated region of mouse IL-10 mRNA inhibits the IL-10 production in macrophages.9) IL-10 antisense oligonucleotides may have a potentiality for AD treatment, provided that the antisense oligonucleotide can be delivered to the IL-10 producing cells such as macrophages, 7,10) dendritic cells, 10) Langerhans' cells, 11) keratinocytes, 11) and T cells 12) in the skin. In general, oligonucleotides are membrane-impermeable due to their high ionization, low-lipophilicity and high molecular weight. There are some reports on the improvement of transdermal delivery of antisense oligonucleotides across the stratum corneum with absorption enhancers 13) or by iontophoresis [14][15][16][17] and electroporation. 18,19) Iontophoresis is classified by the current flow pattern into constant direct current (CDC), pulse direct current (PDC), and pulse depolarization current (PDP). CDC iontophoresis is the most common, but its use is sometimes restricted by irritation attributed to the skin polarization. PDP iontophoresis provides a high frequency electric pulse and opens a depolarization circuit between pulses, so that the skin irritation is subsequently less in spite of the relatively high current density. 20) However, there is no paper on the iontophoretic delivery of antisense oligonucleotides using PDP iontophoresis.In the present study, we examined the permeation of phosphodiester oligonucleotide (D-oligo) having the antisense sequence to mouse IL-10 mRNA through isolated hairless mouse skin using PDP iontophoresis in vitro. To acquire basic information on the skin permeation of antisense oligonucleotides, D-oligo was used. In this paper, the advantages of PDP iontophoresis, permeation characteristics and the distribution and stability of D-oligo are discussed. It was observed that D-oligo could be delivered into the shallow layer of the skin effectively by PDP iontophoresis. Pharmacy and Life Science...

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Innovations in Oligonucleotide Drug Delivery

Lysik

Wu‐Pong

2003

Journal of Pharmaceutical Sciences

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Oligonucleotides (ONs) are a new class of therapeutic compounds under investigation for the treatment of a variety of disease states, such as cancer and HIV, and for FDA approval of an anti-CMV retinitis antisense molecule (Vitravene trade mark, Isis Pharmaceuticals). However, these molecules are limited not only by poor cellular uptake, but also by a general lack of understanding regarding the mechanism(s) of ON cellular uptake. As a result, various delivery vehicles have been developed that circumvent the proposed mechanism of uptake, endocytosis, while improving target specific delivery and/or drug stability. This review describes various traditional and novel delivery mechanisms that have been employed to improve ON cellular delivery, cost effectiveness, and therapeutic efficacy.

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Iontophoretic Delivery of Oligonucleotides across full Thickness Hairless Mouse Skin

Cited by 53 publications

References 29 publications

Transdermal delivery of phosphorodiamidate Morpholino oligomers across hairless mouse skin

Transdermal delivery of phosphorodiamidate Morpholino oligomers across hairless mouse skin

Intradermal Delivery of Antisense Oligonucleotides by the Pulse Depolarization Iontophoretic System

Innovations in Oligonucleotide Drug Delivery

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