PT1664722E - Polielectrólito imobilizado à superfície com grupos funcionais múltiplos capazes de se ligarem covalentemente às biomoléculas - Google Patents
Polielectrólito imobilizado à superfície com grupos funcionais múltiplos capazes de se ligarem covalentemente às biomoléculas Download PDFInfo
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Description
1
Descrição "Polielectrólito imobilizado à superfície com grupos funcionais múltiplos capazes de se ligarem covalentemente às biomoléculas"
Campo da Invenção
Esta invenção situa-se no campo da química dos polielectrólitos.
Antecedentes da invenção
Como alternativa para solucionar muitos dos problemas associados com a utilização para diagnóstico de ''microarranjos manchados" expressão anglo-saxónica "spotted arrays"- de oligonucleótidos (os problemas são descritos em "Multianalyte Molecular Analyis Using Application-Specific Random Particle Arrays", pedido de patente de invenção US N° 10/204, 799 registado em 8/23/2002; WO 01/98765) são formados arranjos ligando preferencialmente sondas oligonucleótidicas a microesferas de partículas codificadas incluindo partículas codificadas feitas de resina polimérica. Ver pedido de patente de invenção US N° 10/271,602 "Multiplexed Analysis of Polymorphic Loci by Concurrent Interrogation and Enzyme-Mediated Detection", registada em 10/15/2002, e com o número 10/204,799 supra. Os conjugados partículas codificadas-sondas são então reunidos num formato de arranjo 2D e colocados em contacto com amostras em que se antecipa conterem polinucleótidos alvo com subsequências complementares a sondas, em que os polinucleótidos alvo nas amostras foram previamente marcados com fluorescência. A ligação entre as sondas e os alvos é determinada pela presença de um sinal de ensaio de fluorescência. Partículas de sondas que geram um sinal de 2 ensaio positivo podem ser determinadas descodificando o arranj o.
Em Hirota et ai. (US2002/0155481) são produzidos biochips planares em que as sondas de ácido nucleico encontram-se imobilizadas sobre uma superfície funcional. Albumina de soro de bovino pode ser adicionada como solução de reforço para guiar as sondas para os locais de ligação do chip antes da ligação covalente da sonda, através de técnicas padrão utilizando ácidos nucleicos modificados e superfícies funcionalizadas.
Em Trau et al. (WO02/12888) são descritas micropartícuias que possuem um polielectrólito ligado covalentemente sobre uma superfície funcionalizada e ligadas a elas um ácido nucleico.
Existem vários processos conhecidos e comercialmente disponíveis para a ligação de sondas oligonucleótidicas a microesferas. Um grande número de esquemas para imobilização covalente para sondas oligonucleótidas a micropartícuias foram concebidos e encontram-se disponíveis na literatura ou comercialmente. Tradicionalmente técnicas de imobilização utilizam esferas funcionalizadas (i.e. esferas funcionalizadas com grupos reactivos, tais como amino, carbóxilo, tosilo, aldeído, epóxido, hidrazida e outros) para ligar a grupos funcionais complementares na extremidade das sondas oligonucleótidas (Maire K. Walsh, Xinwen Wang e Bart C. Weimer, "Optimizing the immobilization of single-stranded DNA onto glass beads, J. Biochem. Biophys. Methods 2001; 47:221-231). Frequentemente tais protocolos de ligação conduzem a orientação imprópria e problema de impedimento estereoquímico. O comportamento de hibridização de tais sondas covalentemente imobilizadas pode ser melhorado introduzindo moléculas de espaçamento 3 (Edwin Southern, Kalim Mir e Mikhail Shchepinov; Molecular Interactions on Microarrays. Nature Genetics Supplement, 21, 1999, p.5-9), contudo a implementação é frequentemente difícil e não praticável.
Uma química de ligação de sondas prática e robusta é por isso importante para um desempenho óptimo de um ensaio baseado em arranjos de microesferas. A química tem de permitir às sondas ligarem-se às partículas com elevada eficiência de modo a manter uma concentração consistente de sondas à superfície da esfera e também a reacção não pode alterar a eficiência da ligação sonda alvo. Além disso, a reacção tem de possuir variabilidade mínima de lote para lote. Num método habitualmente utilizado as micropartículas funcionalizadas são revestidas com Neutravidina (Pierce, Rockford, IL), estreptavidina ou avidina que são proteínas que se ligam à biotina para mediar a imobilização de sondas biotiniladas. A interacção avidina-biotina é altamente específica e uma das mais fortes conhecidas (com uma constante de associação (KA) da ordem de 1015M_1 em soluções aquosas) e disponibiliza quase uma ligação irreversível entre a proteína imobilizada à superfície da proteína e a molécula da sonda biotinilada. Ver pedido de patente de invenção US N°10/271,602, supra. O processo descrito abaixo para ligar sondas a polielectrólitos é preferido em relação a estes processos conhecidos, porque foi demonstrado ser capaz de induzir a ligação de um maior número de oligonucleótidos a esferas.
Sumário A invenção disponibiliza um processo de ligar moléculas de ácido nucleico a uma micropartícula 4 compreendendo: ligar covalentemente a uma temperatura de 65°C albumina de soro de bovino à superfície funcionalizada de uma micropartícula feita de polímero de uma resina polimérica, vidro ou látex e de ligar covalentemente as moléculas de ácido nucleicos possuindo extremidades 3' ou 5' funcionalizadas a albumina de soro de bovino nas extremidades 3' ou 5' das moléculas de ácido nucleico.
Um polielectrólito que possui grupos funcionais múltiplos expostos sendo cada grupo capaz de se ligar covalentemente a uma molécula é imobilizado sobre uma superfície tendo como objectivo a ligação a uma biomolécula. A biomolécula é um ácido nucleico, por ex. um oligonucleótido funcionalizado com uma amina. A BSA (Albumina do soro de bovino) encontra-se ligada a uma superfície funcionalizada utilizando uma estratégia de imobilização covalente, por ex. uma reacção com a superfície de uma micropartícula activada por tosilo. Após uma tal reacção, grupos funcionais reactivos expostos na proteína, tal como amina, carbóxilo, tiol, hidróxilo podem ainda ser utilizados para acoplar covalentemente o oligonucleótido de interesse utilizando química adequada.
Numa concretização, oligonucleótidos modificados numa posição terminal (na posição 3' ou 5' terminal) com aminas (por ex. oligonucleótidos modificados com amino) encontram-se ligados covalentemente a BSA utilizando uma reacção EDAC (l-etil-3-(3-dimetilaminopropil)carbodiimida (ver por ex. D. Seligal et al., Analytical Biochemistry 218:87091(1994)). A reacção covalente resulta na formação de uma ligação amina entre o grupo amina e o terminal do oligonucleótido e grupos carboxilo na BSA. A reacção é ilustrada na Fig. 1. 5 A superfície funcionalizada é a superfície de uma esfera, ou de uma micropartícula que pode ser constituída por vários materiais, incluindo polímeros, resinas poliméricas, vidro, látex ou outros que podem ser funcionalizados para imobilização de um polielectrólito. Foram efectuadas experiências comparando esferas revestidas por BSA com albumina do soro humano ("HSA"), outro exemplo de polielectrólito, e também com Neutravidina. Os resultados das experiências de hibridização indicaram que as esferas revestidas com BSA eram capazes de ligar maiores concentrações de oligonucleótidos às esferas.
Breve Descrição das Figuras A Fig.l ilustra a ligação de BSA a esferas funcionalizadas e a ligação de uma sonda oligonucleótidica à BSA utilizando uma reacção EDAC. A Fig. 2 mostra os sinais de hibridização de esferas oligo-funcionalizadas acopladas a BSA como função da quantidade de sonda aminada adicionada para acoplamento. Uma sonda de perfeito emparelhamento foi ligada a dois conjuntos de esferas acopladas a BSA. BSA foi acoplado ao primeiro conjunto de esferas a 65°C e a um segundo conjunto a 37°C. Foi notada uma eficiência de hibridização muito mais elevada (sinal superior) no primeiro conjunto de esferas ao qual BSA foi acoplado a 65°C. Um terceiro conjunto de esferas acopladas com BSA a 65°C e funcionalizadas com uma sonda de controlo de não emparelhamento mostra uma hibridização desprezável, indicando deste modo que o sinal reforçado não resulta de uma ligação não específica acrescida. A Fig. 3 apresenta resultados de titulação de esferas acopladas a BSA. Como na Fig. 2, a eficiência de hibridização é superior para as esferas acopladas com BSA a uma temperatura mais elevada do que a uma temperatura mais 6 baixa como demonstrado pela diferença no sinal de hibridização de um alvo colocado em contacto com uma sonda oligonucleótidica ligada a esferas acopladas a BSA em que a BSA foi acoplada a um conjunto de esferas a 37°C, e em que a BSA foi acoplada a um outro conjunto de esferas a 65°C (ver Exemplo 4) A Fig. 4 indica uma diferença na eficiência de acoplamento de BSA a esferas funcionalizadas com tosilo a temperaturas diferentes, determinado utilizando um ensaio de hibridização em que as sondas oligonucleótidicas se encontram ligadas a BSA imobilizada nas esferas e depois feitas reagir com um alvo complementar marcado com fluorescência, (ver Exemplo 6) A Fig. 5 indica que para a incubação a 65°C durante cerca de 1 hora para a reacção de acoplamento de BSA a esferas activadas com tosilo a eficiência de ligação de BSA à superfície da esfera não é afectada como demonstrado pela diferença no sinal de hibridização a partir de um alvo colocado em contacto com uma sonda oligonucleótidica ligada a esferas acopladas a BSA. (ver Exemplo 7). A Fig. 6A mostra que esferas funcionalizadas com tosilo revestidas com BSA dão um sinal mais uniforme e forte, a seguir à ligação de sondas e hibridização com um alvo, do que uma esfera de tosilo revestida com Neutravidina. (ver Exemplo 8) A Fig. 6B apresenta o coeficiente de variação dos sinais da Fig. 6A.
A Fig. 7 apresenta uma diferença significativa, quando HSA, em vez de BSA é o polielectrólito revestido sobre as esferas funcionalizadas com tosilo, em que as sondas oligonulceótidas são ligadas respectivamente a BSA ou HSA 7 imobilizado sobre as esferas e depois feito reagir com um alvo complementar marcado com fluorescência.
Descrição Detalhada da Invenção
Exemplo 1: Preparação de esferas funcionalizadas com tosilo revestidas com BSA É preparada uma solução de BSA na concentração de 5 mg/ml dissolvendo 50 mg de BSA em 10 mL de PBS. É adicionado 2,0 ml de PBS-T a um tubo de centrífuga de 15 mL. Transfere-se 1 mL de esferas coradas por fluorescência na concentração de 1% de sólidos (10 mg) para o tubo de centrífuga e mistura-se bem num vórtice. As esferas são centrifugadas a 3500 rpm durante 4 ±0,5 minutos, e o sobrenadante é decantado. As esferas são novamente suspensas adicionando 3,0 mL de PBST para o tubo, e bem misturadas em vórtice. As esferas são novamente centrifugadas a 3500 rpm durante 4 ±0,5 minutos, e o sobrenadante é eliminado. Adiciona-se às esferas 3,0 ml de uma solução de BSA (5 mg/ml) e bem misturadas em vórtice. Os tubos são colocados num agitador num incubador a 37°C, e as esferas são deixadas reagir de um dia para o outro com agitação a 250 rpm. A seguir, as esferas são centrifugadas a 3500 rpm durante 4 minutos e o sobrenadante é eliminado. As esferas são então lavadas adicionando 3,0 ml de PBS-T ao tubo e misturadas num misturador de vórtice. As esferas são então novamente centrifugadas a 3500 rpm durante 4 ±0,5 minutos, e o sobrenadante é eliminado. Os passos de lavagem e de centrifugação são então repetidos. 8 3,0 ml de tampão de armazenagem (0,1 M PBS contendo 0,1% de NaN3) são adicionados e misturados num misturador de vórtice. As esferas são novamente centrifugadas a 3500 rpm durante 4 ±0,5 minutos, e o sobrenadante é eliminado. As esferas são então novamente suspensas em lml de tampão de armazenagem através de agitação em vórtice. As esferas encontram-se numa concentração de 1% de sólidos (10 mg/ml), e são armazenadas a 4-6°C. Estão prontas para a ligação de biomateriais contendo amina, através da reacção EDAC, como descrito abaixo no Exemplo 3.
Exemplo 2: Preparação de esferas funcionalizadas com carbóxilo revestidas com BSA. O acoplamento de BSA a partículas carboxiladas é efectuado como se segue. 100 μΐ de partículas carboxiladas a uma concentração de 1% de sólidos são transferidos para um tubo de Eppendorf de 2 ml. As esferas são então agregadas por centrifugação e o sobrenadante é removido. Seguidamente as esferas são lavadas lx com 1 ml de tampão MES (0,05 M)(pH 4,5). Separadamente é preparada uma solução mãe de BSA (5 mg de BSA/ml) em tampão MES e EDC (20 mg/ml) em tampão MES. 100 μΐ de uma solução mãe de BSA é adicionada ao agregado de esferas e a suspensão é bem misturada em vórtice. Seguidamente, 400 μΐ da solução de armazenagem de EDC é adicionada à suspensão de esferas bem misturada em vórtice e deixada reagir à temperatura ambiente durante 1 h com agitação orbital. Após 1 h de incubação, 100 μΐ de PBS-T é adicionado à suspensão e as esferas são centrifugadas. O agregado é lavado duas vezes com 1 ml de PBS-T por ciclo de centrifugação-redispersão, 9 e as esferas são finalmente suspensas em 100 μΐ de tampão de armazenamento (0, 1 M PBS contendo 0,1% de azida de sódio, NaN3) e armazenada a 4-6°C.
Exemplo 3: Reacção EDAC para acoplamento de sondas oligonucleótidicas aminadas a esferas de BSA O acoplamento de sondas oligonucleótidicas aminadas às esferas preparadas de acordo com o Exemplo 1 e 2 foi efectuado como se segue. Uma série de tubos Eppendorf de 1,5 ml foi retirada e marcada para identificar o tipo de microparticula e a sonda oligonucleótidica a ser acoplada. Seguidamente adicionou-se 500 μΐ de PBST para cada tubo, seguindo-se 100 μΐ de esferas acopladas a BSA a uma concentração de 1% de sólidos. Os tubos foram bem misturados num agitador de vórtice durante 10 segundos. As esferas foram então centrifugadas a 9500 rpm durante 2+0,5 min e o sobrenadante foi eliminado. Uma aliquota de 500 μΐ de tampão MES 0,05 M (pH 4,5) foi adicionada ao agregado e bem misturada em vórtice. As esferas foram então centrifugadas a 9500 rpm durante 2+0,5 min, e o sobrenadante foi eliminado. Adicionou-se às esferas uma aliquota de 500 μΐ de EDAC 0,05M em tampão MES (preparada mesmo antes da utilização) e misturou-se bem em vórtice. Seguidamente adicionou-se 10 μΐ de cada uma das sondas de ADN modificada com um grupo amino (por ex. uma sonda MS508N25, adquirida a Integrated DNA Technologies, Inc., Coralville IA) a uma concentração de 100 μΜ a cada um dos tubos contendo as suspensões de esferas, e misturou-se bem. 10
Deixou-se a reacção prosseguir durante 1 hora à temperatura ambiente (20-25°C) com agitação orbital.
Após incubação, 100 μΐ de PBS-T é adicionado a cada tubo e misturado em vórtice. As esferas são então centrifugadas a 9500 rpm durante 2+0,5 min, e o sobrenadante é eliminado. As esferas são então lavadas duas vezes com 500 μΐι de PBS-T utilizando o ciclo de redispersão da centrifugação.
As esferas são então suspensas em 100 μΐ de PBST para levar a concentração final a 1% de sólidos, e armazenada a 4-6°C para utilização posterior. O desempenho da hibridização de partículas funcionalizadas com oligonucleótidos (ver protocolo no Exemplo 4) como uma função da quantidade adicionada de oligo (0,25, 0,4, 1, 2, 4, 8 μΐ ou 100 μΜ/ 200 μρ partículas) é apresentada na Fig. 2. A quantidade descrita acima 10 μΐ ou 100 μΜ/lmg representa assim uma concentração de saturação. Também as esferas com BSA acopladas a temperatura mais elevada apresentam um desempenho de hibridização melhorado como descrito em detalhe mais tarde.
Exemplo 4: Ensaio de hibridização utilizando esferas de oligonucleótidos funcionalizadas 1. Misturas de esferas são reunidas em 8 chips diferentes. Uma solução de armazenamento marcada com fluorescência (MS508-90meros-CY5) é preparada em tampão de hibridização (lxTMAC. Oito diluições em série diferentes são preparadas 11 a partir da solução mãe alvo. Adiciona-se então 20 μΐ de cada solução alvo diluída em série a oito chips separados. 2. Uma lâmina contendo os chips é colocada num aquecedor/agitador de hibridização e incubada a 55°C durante 20 minutos a 100 rpm. 3. A lâmina é removida e aquecida à temperatura ambiente e a solução de hibridização é removida com a pipeta de transferência. 4. Adiciona-se 20 μΐ de lxTMAC a cada chip e o chip é lavado pipetando a solução de 8 a 10 vezes. 5. A solução de lavagem é removida e 5 ml de solução de montagem (lxTMAC) é adicionada a cada chip, e o sinal do ensaio (CY5) é lido num microscópio de fluorescência utilizando uma lamela. 6. A curva de titulação é representada graficamente representando o sinal de hibridização (CY5) em função da concentração da sonda de ADN.
Exemplos de curvas de titulação são indicadas na Fig. 3.
Exemplo 5
Foram efectuadas experiências para comparar o efeito de adicionar EDAC por duas vezes à suspensão de sonda-esferas (EDAC é conhecido por hidrolizar muito rapidamente a pH acídico) para avaliar se isto conduz a uma ligação acrescida de sondas à camada de BSA. Primeiro a sonda MS-508-N25 foi acoplada a esferas revestidas com BSA em cada uma das seguintes condições: (10 μΐ 100 μΜ sonda/100 μΐ de 1% de esferas) . Metade das esferas foram removidas de lx tubo após uma hora de reacção, e EDCA fresco foi 12 adicionado, e depois a reacção prosseguiu nesse tubo durante mais uma hora. 0 processo completo foi então repetido para a sonda não emparelhada SSP 36. Cada conjunto de esferas foi reunido com esferas não especificas e reunidos num chip, e depois todos os conjuntos foram colocados em contacto com um alvo MS508-40 meros-CY5 em condições de hibridização. Os resultados foram então registados e encontram-se sumarizados na tabela II abaixo. A adição 2xEDAC disponibilizou sinais de hibridização mais elevados.
Tabela II
Concentração da sonda Sinal do ensaio modelo Cy5 CV Sinal Cy5 não especifico CV 1XEDAC 536.1 0.17 79.9 0.26 2X extra EDAC 732.9 0.17 53.3 0.19
Exemplo 6: Acoplamento de BSA a esferas activadas com tosilo a diferentes temperaturas e suas caracteristicas de hibridização
Adicionou-se 2,0 ml de PBST a cada um dos cinco tubos de centrífuga de 15 ml e adicionou-se 1 ml de esferas coloridas por fluorescência a uma concentração de 1% de sólidos (10 mg), e depois as esferas foram misturadas em vórtice. As esferas foram centrifugadas a 3500 rpm durante 4±0,5 minutos, e o sobrenadante foi decantado. As esferas foram então novamente suspensas em 3,0 ml de PBST e bem misturadas em vórtice e novamente centrifugadas a 3500 rpm durante 4+0,5 minutos, e o sobrenadante foi despejado. 13
Adicionou-se a cada tubo 2 ml de PBS (pH 7,2) e 1 ml de uma solução de BSA (50 mg/ml em PBS) e bem misturada em vórtice. A temperatura ambiente num incubador foi regulada para cada um dos tubos como se segue: tubo A - 22°C, tubo B -37°C, tubo C -50°C, tubo-D-65°C e tubo E -75°C, e as esferas foram deixadas a reagir com BSA durante 14 horas à temperatura designada com agitação orbital. Os tubos foram então arrefecidos à temperatura ambiente e as esferas foram centrifugadas a 3500 rpm durante 4 minutos, e o sobrenadante foi vertido. As esferas foram então lavadas adicionando 3,0 ml de PBST ao tubo, misturadas num misturador de vórtice e centrifugadas a 3500 rpm durante 4+0,5 minutos. O sobrenadante foi despejado.
Foi adicionado 1 ml de tampão de lavagem (PBS contendo 0,1% de NaN3) e os tubos foram misturados num misturador de vórtice. A concentração das esferas era de 1% de sólidos (10 mg/ml). As esferas acopladas a BSA foram armazenadas a 4-6°C. A sonda de oligonucleótido biotinilado N25 MS-508 de 25 meros foi conjugada com cada conjunto de esferas através do método de acoplamento EDAC descrito acima. Cada conjunto de esferas foi então feito contactar com uma concentração fixa de alvo marcado (um oligonucleótido de 90 meros marcado com Cy-5) para a sonda em condições de hibridização. A quantidade de marcador nas esferas correlaciona-se com a concentração da sonda nas esferas.
Como indicado na Fig. 4, as esferas que foram acopladas com BSA a temperaturas mais elevadas exibiram maior ligação do alvo em relação a sondas oligonucleótidas existentes sobre a superfície da sonda. Isto indica que existe uma maior concentração de sondas à superfície de tais esferas, o que pode ser, porque a 65°C BSA desnatura e 14 abre apresentando locais de ligação mais disponíveis em relação às sondas.
Exemplo 7 Comparação da influência de diferentes tempos de incubação no acoplamento de BSA a partículas funcionalizadas com tosilo
Foi efectuada uma experiência para estudar o progresso da reacção de acoplamento de BSA sobre partículas tosiladas. Seguindo o mesmo protocolo que nos exemplos 1 e 5 acima, 12 tubos separados cada um contendo uma mistura reaccional BSA-partícula tosilo foram incubadas a 65°C num forno, e um tubo de controlo foi incubado a 37°C. Cada tubo foi retirado após um período de pré-determinado de incubação, lavado e depois acoplado com uma sonda oligonucleótidica (incluindo uma sonda de controlo) seguindo o processo descrito no Exemplo 3. Seguidamente foi efectuada uma reacção de hibridização e a intensidade do ensaio foi registada (ver Exemplo 4) . Os resultados são apresentados na Fig. 5 que ilustra que a reacção de acoplamento a BSA fica essencialmente completa em menos de uma hora.
Exemplo 8: Comparação entre o Acoplamento Convencional Biotina-Avidina Oligonucleótido e a Química de Revestimento da NeutrAvidina
Foi efectuada uma experiência para comparar a captura e eficiência de hibridização de esferas oligoconjugadas funcionalizadas com BSA com uma esfera biotinilada oligoconjugada de NeutrAvidina. As proteínas foram acopladas à superfície da esfera a 37°C utilizando um protocolo como descrito no Exemplo 1. Seguidamente, oligos biotinilados (e também aminados) foram conjugados com 15 partículas (como no exemplo 3) e um ensaio de hibridização foi efectuado com um alvo cognato.
Duas partículas revestidas com BSA codificadas de diferente maneira, mas de resto idênticas foram retiradas e uma sonda de emparelhamento foi ligada a um grupo e uma sonda de não emparelhamento foi ligada ao outro grupo. De forma semelhante duas outras esferas funcionalizadas com NeutrAvidina foram retiradas e ligadas a sondas biotiniladas emparelhadas e não emparelhadas.
Os resultados do ensaio são apresentados nas Figs. 6A e 6B. É evidente que o revestimento com BSA disponibiliza uma proporção mais uniforme (CV mais baixo) e uma razão sinal ruido mais elevada (a intensidade de hibridização da sonda desemparelhada foi considerada como ruído) do que a conseguida utilizando a química de captura da NeutrAvidina.
Exemplo 9: Comparação com revestimento HSA HSA (Albumina do Soro Humano) foi acoplada em condições idênticas aquelas utilizadas para acoplamento de BSA a partículas funcionalizadas com tosilo. As partículas de HSA funcionalizadas foram então acopladas com sondas oligonucleótidicas e hibridizadas (tituladas) com ADN modelo alvo marcado com fluorescência (como no Exemplo 4). Os resultados são apresentados na Fig. 7. Indicam que o revestimento de HSA não é tão eficaz como o revestimento de BSA para ligar as sondas de oligonucleótidos não obstante o facto de tal como BSA, HSA possuir muitos grupos carboxilo disponíveis para se ligarem às sondas oligonucleótidicas.
Exemplo 10: Variação lote a lote do acoplamento de BSA 16
Três lotes de esferas, cada um com 10 mg foram acoplados separadamente com BSA a 65°C durante 14 horas, em que a razão BSA esferas foi de 5 (p/p, mg/mg) . O volume reaccional de acoplamento foi de 3 ml. Um lote de esferas foi acoplado a BSA a 37°C para ser utilizado como um controlo. A eficiência de acoplamento foi determinada com base na intensidade de sinal para hibiridização de sondas de ADN acopladas com as esferas dos alvos cognatos. A hibridização foi efectuada a 55°C durante 20 minutos em lxTMAC, e o alvo foi MS508-90-meros-CY5 a uma concentração de 400 nM. O tempo de integração para leitura do ensaio é de 200 ms. Os resultados são indicados na Tabela I.
Tabela I
Lote Intensidade CY5 (100 ms) 1 6864 2 6515 3 6431 Controlo 3964 A 65°C os lotes possuíam uma intensidade consistentemente mais elevada do que o lote acoplado a 37°C e também a variabilidade lote a lote era pequena.
Os termos expressões e exemplos acima são fornecidos apenas a título de exemplo e não são limitativos, e a invenção é apenas definida nas reivindicações que se seguem e incluem todos os equivalentes da matéria das reivindicações.
Lisboa, 12 de Dezembro de 2011.
Claims (6)
1 Reivindicações 1. Processo de ligar moléculas de ácido nucleico a uma microparticula compreendendo: a ligação covalente a uma temperatura de 65°C da albumina do soro de bovino à superfície funcionalizada de uma microparticula feita de um polímero, uma resina polimérica, vidro ou látex e ligar covalentemente moléculas de ácido nucleico possuindo extremidades 3' ou 5' funcionalizadas à albumina do soro de bovino nas extremidades 3' ou 5' funcionalizadas das moléculas de ácido nucleico.
2. Processo de acordo com a reivindicação 1, em que as moléculas de ácido nucleico estão ligadas à albumina do soro de bovino, através de uma ligação amida formada através de uma reacção com l-etil-3-(3- dimetilaminopropil)carbodiimida.
3. Processo de acordo com a reivindicação 1, em que a superfície da microparticula se encontra funcionalizada com grupos funcionais tosilo.
4. Processo de acordo com qualquer uma das reivindicações 1 a 3, em que as moléculas de ácido nucleico encontram-se ligadas a albumina de soro de bovino através dos grupos carbóxilo ou amina da albumina de soro de bovino.
5. Processo de acordo com qualquer uma das reivindicações 1-4, em que a molécula de ácido nucleico é um oligonucleótido. 2
6. Processo de acordo com a reivindicação 5, em que o nucleótido é funcionalizado na sua posição 3' ou 5' com um grupo amino primário. Lisboa, 12 de Dezembro de 2011.
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AU2004276761A1 (en) | 2005-04-07 |
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JP2007506108A (ja) | 2007-03-15 |
TW200521436A (en) | 2005-07-01 |
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US7595279B2 (en) | 2009-09-29 |
JP4564959B2 (ja) | 2010-10-20 |
CA2539824A1 (en) | 2005-04-07 |
IL174323A0 (en) | 2006-08-01 |
NZ546072A (en) | 2009-08-28 |
EP1664722A4 (en) | 2007-10-31 |
ES2375962T3 (es) | 2012-03-07 |
CA2539824C (en) | 2015-02-03 |
US20050260611A1 (en) | 2005-11-24 |
CN1882699A (zh) | 2006-12-20 |
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