Name: trans-tympanic drug delivery for the treatment of ototoxicity
Uploaded: 2018-03-16T12:30:00
Description: Watch this Scientific Journal Video about Trans-Tympanic Drug Delivery for the Treatment of Ototoxicity at JoVE.com

O trabalho descrito neste artigo foi apoiado por um NCI RO1 CA166907, NIDCD RO1-DC 002396 e RO3 DC011621.

Wistar macho ratos foram tratados em conformidade com o animal National Institutes of Health use orientações e um protocolo aprovado pelo Comitê de usar e Southern Illinois University escola de medicina laboratorial Cuidado Animal. Auditivo de tronco encefálico (ABR) foi realizado em ratos, enquanto sob anestesia antes da administração de drogas e 72 h após para verificar o efeito da entrega droga trans-timpânicas.
1. auditivo de tronco encefálico (ABR)
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<ol>
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J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Comparative+adverse+effect+profiles+of+platinum+drugs.">Comparative adverse effect profiles of platinum drugs.</a> Drug Saf. 13 (4), 228-244 (1995).</li><li>Boulikas, T., Vougiouka, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Cisplatin+and+platinum+drugs+at+the+molecular+level.">Cisplatin and platinum drugs at the molecular level.</a> Oncol Rep. 10 (6), 1663-1682 (2003).</li><li>Fouladi, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Phase+II+study+of+oxaliplatin+in+children+with+recurrent+or+refractory+medulloblastoma,+supratentorial+primitive+neuroectodermal+tumors,+and+atypical+teratoid+rhabdoid+tumors:+a+pediatric+brain+tumor+consortium+study.">Phase II study of oxaliplatin in children with recurrent or refractory medulloblastoma, supratentorial primitive neuroectodermal tumors, and atypical teratoid rhabdoid tumors: a pediatric brain tumor consortium study.</a> Cancer. 107 (9), 2291-2297 (2006).</li><li>Pasetto, L. M., D'Andrea, M. R., Rossi, E., Monfardini, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Oxaliplatin-related+neurotoxicity:+how+and+why.">Oxaliplatin-related neurotoxicity: how and why.</a> Crit Rev Oncol Hematol. 59 (2), 159-168 (2006).</li><li>Ardizzoni, A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Cisplatin-+versus+carboplatin-based+chemotherapy+in+first-line+treatment+of+advanced+non-small-cell+lung+cancer:+an+individual+patient+data+meta-analysis.">Cisplatin- versus carboplatin-based chemotherapy in first-line treatment of advanced non-small-cell lung cancer: an individual patient data meta-analysis.</a> J Natl Cancer Inst. 99 (11), 847-857 (2007).</li><li>Banfi, B., Malgrange, B., Knisz, J., Steger, K., Dubois-Dauphin, M., Krause, K. 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R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Mouse+auditory+brainstem+response+testing.">Mouse auditory brainstem response testing.</a> Bio Protoc. 6 (6), 1768 (2016).</li><li>Montgomery, S. C., Cox, B. C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Whole+Mount+Dissection+and+Immunofluorescence+of+the+Adult+Mouse+Cochlea.">Whole Mount Dissection and Immunofluorescence of the Adult Mouse Cochlea.</a> J. Vis. Exp. (107), e53561 (2016).</li><li>Whitlon, D. S., Szakaly, R., Greiner, M. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Cryoembedding+and+sectioning+of+cochleas+for+immunocytochemistry+and+in+situ+hybridization.">Cryoembedding and sectioning of cochleas for immunocytochemistry and in situ hybridization.</a> Brain Res Brain Res Protoc. 6 (3), 159-166 (2001).</li><li>Londos, C., Cooper, D. M., Wolff, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Subclasses+of+external+adenosine+receptors.">Subclasses of external adenosine receptors.</a> Proc Natl Acad Sci. 77 (5), 2551-2554 (1980).</li><li>Lohse, M. J., Klotz, K. N., Lindenborn-Fotinos, J., Reddington, M., Schwabe, U., Olsson, R. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=8-Cyclopentyl-1,3-dipropylxanthine+(DPCPX)--a+selective+high+affinity+antagonist+radioligand+for+A1+adenosine+receptors.">8-Cyclopentyl-1,3-dipropylxanthine (DPCPX)--a selective high affinity antagonist radioligand for A1 adenosine receptors.</a> Naunyn Schmiedebergs Arch Pharmacol. 336 (2), 204-210 (1987).</li><li>Rybak, L. P., Whitworth, C., Scott, V., Weberg, A. D., Bhardwaj, B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Rat+as+a+potential+model+for+hearing+loss+in+biotinidase+deficiency.">Rat as a potential model for hearing loss in biotinidase deficiency.</a> Ann Otol Rhinol Laryngol. 100 (4), 294-300 (1991).</li><li>Mukherjea, D., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=NOX3+NADPH+oxidase+couples+transient+receptor+potential+vanilloid+1+to+signal+transducer+and+activator+of+transcription+1-mediated+inflammation+and+hearing+loss.">NOX3 NADPH oxidase couples transient receptor potential vanilloid 1 to signal transducer and activator of transcription 1-mediated inflammation and hearing loss.</a> Antioxid Redox Signal. 14 (6), 999-1010 (2011).</li><li>Kaur, T., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Adenosine+A1+receptor+protects+against+cisplatin+ototoxicity+by+suppressing+the+NOX3/STAT1+inflammatory+pathway+in+the+cochlea.">Adenosine A1 receptor protects against cisplatin ototoxicity by suppressing the NOX3/STAT1 inflammatory pathway in the cochlea.</a> J Neurosci. 36 (14), 3962-3977 (2016).</li><li>Kaur, T., Mukherjea, D., Sheehan, K., Jajoo, S., Rybak, L. 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A rota trans-timpânicas administração permite entrega localizada de drogas e outros agentes para a cóclea, que caso contrário poderia produzir efeitos colaterais sistêmicos significativos se administrado sistemicamente. Este método de administração de drogas permite um acesso rápido de drogas para o local de ação em doses significativamente mais elevadas do que poderia ser alcançado através da rota sistêmica. Os resultados aqui apresentados e publicados anteriormente mostraram que trans-timpânicas adminis...

O sistema auditivo periférico é requintadamente sensível às drogas como antibióticos cisplatina e aminoglicosídeos. A cisplatina é um agente quimioterapêutico amplamente utilizado para o tratamento de uma variedade de tumores sólidos, como ovário, testículo e cabeça e pescoço cancros. Ototoxicidade experimentada com o uso desta droga é dose-limitante e bastante comum, afetar 75-100% dos pacientes tratados1. Outras drogas, como a carboplatina e Oxaliplatina, têm surgido como alternativas à cisplatina2,3,4,5, mas sua utilidade é limitada a alguns cancros.
Primeiros estudos demonstraram o papel crítico de espécies reativas de oxigênio (ROS) na mediação a ototoxicidade produzida pela cisplatina e aminoglicosídeos. Estudos posteriores mostraram que o NOX3 isoforma da oxidase de NADPH é a principal fonte de ROS na cóclea e é ativada por cisplatina6,7. A geração de compromissos ROS o antioxidante capacidade das células, levando a tampão aumentou peroxidação lipídica das membranas celulares8. Além disso, a cisplatina aumenta a produção de radicais hidroxila, que geram altamente tóxico aldeído 4-hydroxynonenal (4-HNE), um iniciador de célula morte9,10. Com base nesses resultados, vários antioxidantes foram examinadas para o tratamento da ototoxicidade da Cisplatina. Estes incluem a N-acetilcisteína (NAC), tiosulfato de sódio (STS), Amifostina e D-metionina. No entanto, uma grande preocupação da terapia antioxidante é que esses antioxidantes poderiam reduzir a eficácia de quimioterápicos cisplatina quando administrado sistemicamente11 através da interação da Cisplatina com grupos tiol nas moléculas antioxidantes.
Tendo em conta estes problemas com terapia antioxidante, o objetivo deste estudo foi examinar a rota trans-timpânicas de entregar antioxidantes e outras drogas para a cóclea para reduzir a perda de audição. A rota trans-timpânicas de droga e interferência curto (si) do RNA, descrito abaixo, aparece particularmente promissor.

<table border="0" cellpadding="0" cellspacing="0" style="width:1025px;" width="1025">
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	<tbody>
		<tr height="19">
			<td height="19" style="height:19px;width:423px;">Ketathesia (100 mg/ml) 10 ml</td>
			<td style="width:192px;">Henry Schein</td>
			<td style="width:127px;">56344</td>
			<td style="width:284px;">Controlled substance&#160;</td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">AnaSed Injection/Xylazine (20 mg/ml) 20 ml</td>
			<td>Henry Schein</td>
			<td>33197</td>
			<td></td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">2.5 mm disposable ear specula</td>
			<td>Welch Allyn</td>
			<td>52432</td>
			<td></td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">Surgical Scope</td>
			<td>Zeiss</td>
			<td></td>
			<td></td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">29 G X 1/2 insulin syringe</td>
			<td>Fisher Scientific</td>
			<td>14-841-32&#160;</td>
			<td>Can be purchased through other vendors</td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">cis-Diammineplatinum(II) dichloride</td>
			<td>Sigma Aldrich</td>
			<td>P4394</td>
			<td>TOXIC - wear proper PPE</td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">Harvard 50-7103 Homeothermic Blanket Control Unit</td>
			<td>Harvard Apparatus</td>
			<td>Series 863</td>
			<td></td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">Excel International 21 G X 3/4 butterfly needle</td>
			<td>Fisher</td>
			<td>14-840-34&#160;</td>
			<td>Can be purchased through other vendors</td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">BSP Single Speed Syringe Pump</td>
			<td>Brain Tree Sci, Inc</td>
			<td>BSP-99</td>
			<td></td>
		</tr>
		<tr height="20">
			<td height="20" style="height:20px;">Pulse Sound Measurement System</td>
			<td>Bruel &#38; Kjaer</td>
			<td>Pulse 13 software</td>
			<td></td>
		</tr>
		<tr height="20">
			<td height="20" style="height:20px;">High-Frequency Module</td>
			<td>Bruel &#38; Kjaer</td>
			<td>3560C</td>
			<td></td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">1/8&#8243; Pressure-field Microphone &#8212;-Type 4138</td>
			<td>Bruel &#38; Kjaer</td>
			<td>bp2030</td>
			<td></td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">High Frequency Transducer</td>
			<td>Intelligent Hearing System</td>
			<td>M014600</td>
			<td></td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">Opti-Amp Power Transmitter</td>
			<td>Intelligent Hearing System</td>
			<td>M013010P</td>
			<td></td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">SmartEP ABR System</td>
			<td>Intelligent Hearing System</td>
			<td>M011110</td>
			<td></td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">Disposable Subdermal EEG Electrodes</td>
			<td>CareFusion</td>
			<td>019-409700</td>
			<td></td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">16% Formaldehyde, Methanol-free</td>
			<td>Fisher Scientific</td>
			<td>28908</td>
			<td>TOXIC - wear proper PPE&#160;</td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">7 mL Borosilicate Glass Scintillation Vial</td>
			<td>Fisher Scientific</td>
			<td>03-337-26</td>
			<td>Can be purchased through other vendors</td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">EDTA</td>
			<td>Fisher Scientific</td>
			<td>BP118-500</td>
			<td>Can be purchased through other vendors</td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">Sucrose</td>
			<td>Fisher Scientific</td>
			<td>S5-500</td>
			<td>Can be purchased through other vendors</td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">Tissue Plus OCT Compound</td>
			<td>Fisher Scientific</td>
			<td>4585</td>
			<td></td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">CryoMolds (15 mm x 15 mm x 5mm)</td>
			<td>Fisher Scientific</td>
			<td>22-363-553</td>
			<td>Can be purchased through other vendors</td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">Microscope Slides (25mm x 75mm)</td>
			<td>MidSci</td>
			<td>1354W</td>
			<td>Can be purchased through other vendors</td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">Coverslips (22 x 22 x 1)</td>
			<td>Fisher Scientific</td>
			<td>12-542-B</td>
			<td>Can be purchased through other vendors</td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">Poly-L-Lysine Solution (0.01%)</td>
			<td>EMD Millipore</td>
			<td>A-005-C</td>
			<td>Can be purchased through other vendors</td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">HM525 NX Cryostat</td>
			<td>Thermo Fischer Scientific</td>
			<td>956640</td>
			<td></td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">MX35 Premier Disposable Low-Profile Microtome Blades</td>
			<td>Thermo Fischer Scientific</td>
			<td>3052835</td>
			<td></td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">Wheaton&#8482;&#160;Glass 20-Slide Staining Dish with Removable Rack</td>
			<td>Fisher Scientific</td>
			<td>08-812</td>
			<td></td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">Super Pap Pen Liquid Blocker</td>
			<td>Ted Pella, Inc.</td>
			<td>22309</td>
			<td></td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">Normal Donkey Serum</td>
			<td>Jackson Immuno Research</td>
			<td>017-000-121</td>
			<td>Can be purchased through other vendors</td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">TritonX-100</td>
			<td>Acros</td>
			<td>21568</td>
			<td>Can be purchased through other vendors</td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">BSA</td>
			<td>Sigma Aldrich</td>
			<td>A7906</td>
			<td>Can be purchased through other vendors</td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">Phospho-Stat1 (Ser727) antibody</td>
			<td>Cell Signaling</td>
			<td>9177</td>
			<td></td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">VR1 Antibody (C-15)</td>
			<td>Santa Cruz</td>
			<td>sc-12503</td>
			<td></td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">DyLight 488 Donkey anti Rabbit</td>
			<td>Jackson Immuno Research</td>
			<td>711-485-152</td>
			<td>Discontinued</td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">DyLight 488 Donkey anti Goat</td>
			<td>Jackson Immuno Research</td>
			<td>705-485-003</td>
			<td>Discontinued</td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">Rhodamine (TRTIC) Donkey anti Rabbit</td>
			<td>Jackson Immuno Research</td>
			<td>711-025-152</td>
			<td>Discontinued</td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">ProLong&#174; Diamond Antifade Mountant w/ DAPI</td>
			<td>Thermo Fisher</td>
			<td>P36971</td>
			<td></td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">(&#8722;)-N6-(2-Phenylisopropyl)adenosine</td>
			<td>Sigma Aldrich</td>
			<td>P4532</td>
			<td></td>
		</tr>
		<tr height="19">
			<td height="19" style="height:19px;">8-Cyclopentyl-1,3-dipropylxanthine</td>
			<td>Sigma Aldrich</td>
			<td>C101</td>
			<td></td>
		</tr>
		<tr height="22">
			<td height="22" style="height:22px;">siRNA pSTAT1</td>
			<td>Qiagen</td>
			<td>Custome Made</td>
			<td>Kaur et al. 201120</td>
		</tr>
		<tr height="22">
			<td height="22" style="height:22px;">siRNA NOX3</td>
			<td>Qiagen</td>
			<td>Custome Made</td>
			<td>Kaur et al. 201120</td>
		</tr>
		<tr height="22">
			<td height="22" style="height:22px;">Scrambled Negative Control siRNA</td>
			<td>Qiagen</td>
			<td>1022076</td>
			<td>Kaur et al. 201120</td>
		</tr>
	</tbody>
</table>

trans-tympanic drug delivery for the treatment of ototoxicity

A administração sistémica de agentes protectores para tratar a ototoxicidade induzida por drogas é limitada pela possibilidade que estes agentes protectores poderiam interferir com a quimioterápico eficácia das drogas primárias. Isto é especialmente verdadeiro para a cisplatina de drogas, cujas ações anticâncer são atenuadas por antioxidantes que proporcionar uma protecção adequada contra perda de audição. Outros agentes otoprotective actuais ou potenciais poderiam representar um problema semelhante, se administrado sistemicamente. A aplicação de vários produtos biológicos ou agentes protectores diretamente à cóclea permitiria altos níveis desses agentes localmente com limitados efeitos secundários sistêmicos. Neste relatório, vamos demonstrar um método trans-timpânicas de entrega de várias drogas ou reagentes biológicos à cóclea, que deve melhorar a pesquisa de ciência básica na cóclea e fornecem uma maneira simples de dirigir o uso de agentes otoprotective nas clínicas. Este relatório detalha um método de entrega de droga trans-timpânicas e fornece exemplos de como essa técnica tem sido usada com sucesso em animais experimentais para tratar a ototoxicidade da Cisplatina.

Respostas ABR medido em ratos em três dias após a administração cisplatina mostrou uma elevação significativa em limiares. Elevação desses limiares foi significativamente reduzida em ratos administrados com trans-timpânicas [R] - N - phenylisopropyladenosine (R-PIA), adenosina um1 receptor agonista15, antes da Cisplatina. A especificidade da ação do R-PIA na adenosina um receptor1 demonstrou-se pela observ...

Watch this Scientific Journal Video about Trans-Tympanic Drug Delivery for the Treatment of Ototoxicity at JoVE.com

Trans-Tympanic Drug Delivery for the Treatment of Ototoxicity

Apresentamos uma técnica para administração localizada de drogas através da rota trans-timpânicas na cóclea. Entrega da droga através desta rota não iria interferir com a eficácia de anticâncer dos medicamentos quimioterápicos tais como a cisplatina.

Entrega de trans-timpânicas drogas para o tratamento da ototoxicidade

The systemic administration of protective agents to treat drug-induced ototoxicity is limited by the possibility that these protective agents could ...

Research

JoVE Journal

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