TW202342761A - 利用奈米膠囊藥物傳送系統且用於控制血糖水平的組成及方法 - Google Patents
利用奈米膠囊藥物傳送系統且用於控制血糖水平的組成及方法 Download PDFInfo
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- TW202342761A TW202342761A TW112109824A TW112109824A TW202342761A TW 202342761 A TW202342761 A TW 202342761A TW 112109824 A TW112109824 A TW 112109824A TW 112109824 A TW112109824 A TW 112109824A TW 202342761 A TW202342761 A TW 202342761A
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Abstract
本文公開了具有加強調節血糖水平能力的組合物及方法。該組合物被裝載在用於口服藥物遞送的奈米載體中,該組合物包含一第一載體及一第二載體,該第一載體編碼一個或多個mRNA,該一個或多個mRNA 編碼具有GLP-1 活性的胜肽,並標記有一個或多個衣殼蛋白結合標記,該第二載體編碼一個或多個衣殼蛋白,該一個或多個衣殼蛋白結合該一個或多個mRNA上的該一個或多個衣殼蛋白結合標記。
Description
本公開關於組合物及使用方法,特別是關於具有加強調節人或動物受試者血糖水平的能力的治療組合物,其透過使用基於奈米膠囊的藥物遞送系統遞送。本公開的組合物和方法特別適用於一系列病症,包括糖尿病前期、糖尿病和相關病症。
生物體以血液中的葡萄糖作為獲得能量的主要來源,血糖的恆定性攸關生理機能是否能正常運作,一旦失調將導致多種疾病,許多疾病常見於血液中異常的糖分,如持續性高血糖就會引發糖尿病,進而增加心臟病發作、中風、慢性腎臟疾病、視力喪失和認知損傷等疾病的風險,患有糖尿病的人胰島素濃度低或胰島素抵抗高。
在生理學上,胰島素是由胰臟分泌的一種內源性胜肽,在控制血糖水平方面起著至關重要的作用。血糖濃度除了受胰臟分泌之胰島素調控外,也會受到其他内源性胜肽類的影響,例如:類升糖素胜肽-1(glucagon-like peptide 1, GLP-1)等。以GLP-1來說,已發現的GLP-1被研究並用作主要生物活性胜肽,用於血糖濃度控制和體重控制的醫學研究,合成的GLP-1衍生物透過改變食慾有效控制血糖濃度和體重。因此,GLP-1衍生物目前是美國食品藥物管理局(FDA)批准的藥物。然而,在密切地觀察使用這些GLP-1衍生物的患者之血清濃度及其半衰期後,發現兩個問題:(i) 血清中GLP-1衍生物濃度比內源性GLP-1高一千倍,以及 (ii) GLP-1衍生物的半衰期比內源性GLP-1長四千多倍,許多議題都在爭論以上兩個問題會不會引起健康問題,還有待更多長期使用的效果和數據來評估。
本公開提供了一種用於調節血糖水平的組合物,該組合物包含一第一載體以及一第二載體。該第一載體包含SEQ ID NO: 1之核苷酸序列,以及一衣殼蛋白辨識序列,該第一載體編碼一個或多個編碼有GLP-1活性之胜肽的mRNA,並且該一個或多個mRNA標記有一個或多個衣殼蛋白結合標記。該第二載體包含一個或多個編碼有一個或多個衣殼蛋白的核苷酸序列,該一個或多個衣殼蛋白可自組裝成一個或多個包裝有該一個或多個mRNA的病毒樣顆粒,使該組合物被製成奈米膠囊。
本公開還提供了一種用於調節血糖水平的組合物,該組合物包含一第一載體以及一第二載體。該第一載體包含SEQ ID NO: 6之核苷酸序列。該第二載體包含SEQ ID NO: 3之核苷酸序列。其中,SEQ ID NO: 3之核苷酸序列編碼一個或多個衣殼蛋白,並且該一個或多個衣殼蛋白可自組裝成一個或多個封裝有一個或多個由SEQ ID NO: 6編碼之核苷酸序列的mRNA的病毒樣顆粒,使該組合物被製成奈米膠囊。
本公開還提供了一種調節一受試者血糖水平的方法。該方法包含向該受試者施用包含一個或多個奈米膠囊及/或含有該一個或多個奈米膠囊之膠囊化微生物細胞的組合物,其中該一個或多個奈米膠囊由一第一載體及一第二載體形成,該第一載體編碼一個或多個mRNA,其中該一個或多個mRNA編碼一具有GLP-1活性之胜肽,並且該一個或多個mRNA標記有一個或多個衣殼蛋白結合標記,該第二載體包含一個或多個編碼有一個或多個衣殼蛋白的核苷酸序列,其中該一個或多個衣殼蛋白可自組裝成一個或多個封裝有該一個或多個mRNA的病毒樣顆粒,使該組合物被製成該一個或多個奈米膠囊及/或膠囊化微生物細胞。
本公開所使用的術語“載體(vector)”意為能夠運輸已與其連接的另一種核酸的核酸分子,術語“表達”被定義為特定核苷酸序列由其啟動子驅動的轉錄及/或轉譯。
本公開所使用的術語“奈米載體(nanocarrier)”意為能夠承載及/或輸送特定分子的奈米級結構,包括但不限於上述的載體(vector)。
本公開涉及一個或多個編碼有GLP-1活性之胜肽的核苷酸序列,其特別可以組裝成可被封裝至益生菌細胞中的奈米膠囊,用於調節或控制血糖水平。因此,可以將該一個或多個核苷酸序列摻入合適口服施用藥物及/或治療組合物中。
本公開揭露一第一載體及一第二載體,該第一載體編碼一個或多個編碼有GLP-1活性之胜肽的信使核糖核酸(messenger RNA,mRNA),且該一個或多個mRNA標記有一個或多個衣殼蛋白結合標記(capsid protein tag);該第二載體編碼一個或多個衣殼蛋白(capsid protein,CP),該些衣殼蛋白可自主裝形成一個或多個中空的病毒樣顆粒(virus-like particle,VLP),VLP是奈米級顆粒且可作為攜帶核酸的奈米載體。由該第二載體編碼所形成的一個或多個衣殼蛋白可與該一個或多個mRNA上的該一個或多個衣殼蛋白標記結合並為其提供結構域特異性,使該一個或多個mRNA可被封裝進(encapsidated)於該一個或多個VLP中以形成奈米膠囊,也就是說,編碼具有GLP-1活性之胜肽的該一個或多個mRNA被攜帶在VLP中,並且將在口服給藥後以奈米膠囊的形式遞送。
在一些方面,藥物及/或治療組合物包含從本公開中描述的該第一載體及該第二載體轉錄或轉譯的生物產物或化合物。
藥物及/或治療組合物可用於防止人或動物受試者的血糖水平飆升。因此,在一方面,預期本公開的組合物和方法用於治療代謝綜合病徵、糖尿病前期、糖尿病及/或預防糖尿病的進展。
在一方面,本公開涉及一個或多個可被封裝至益生菌細胞中的奈米膠囊,其由該第一載體及該第二載體轉錄或轉譯而成的一個或多個生物產物組裝而成,該生物產物可以是mRNA或衣殼蛋白。
另一方面,本公開涉及一個或多個奈米膠囊,其由該第一載體及該第二載體轉錄或轉譯而成的一個或多個生物產物組裝而成,該生物產物可以是mRNA或衣殼蛋白。
在另一方面,本公開涉及一個或多個VLP,其由該第一載體及該第二載體轉錄或轉譯而成的一個或多個生物產物組裝而成,該生物產物可以是mRNA或衣殼蛋白。
另一方面,本公開提供的藥物及/或治療組合物在製備用於治療代謝綜合病徵、糖尿病前期、糖尿病及/或預防糖尿病進展的藥物。
另一方面,本公開提供了一種治療代謝綜合病徵、糖尿病前期、糖尿病及/或預防糖尿病進展的方法,其包括施用本公開的藥物及/或治療組合物或其製劑。
根據某些實施方案,糖尿病選自由第1型糖尿病、第2型糖尿病和妊娠糖尿病組成的群組。
於一實施例中,該第一載體包含SEQ ID NO: 1之核苷酸序列,以及一衣殼蛋白辨識序列。該第一載體經轉錄後形成帶有該一個或多個衣殼蛋白結合標記的mRNA,該mRNA編碼具GLP-1活性之胜肽,可於一人體或動物受試者的細胞中作為轉譯模板以生成出具GLP-1活性之胜肽,使生物體於體內(in vivo)內源性地形成GLP-1。又,該一個或多個衣殼蛋白結合標記為該衣殼蛋白辨識序列形成的二級結構而可與衣殼蛋白的特定區域結合。於一實施例中,該衣殼蛋白辨識序列包含SEQ ID NO: 2之核苷酸序列,且其形成的該一個或多個衣殼蛋白結合標記具有一髮夾(hairpin)結構。
進一步,該第二載體包含一個或多個編碼有該一個或多個衣殼蛋白的核苷酸序列,在一實施例中,該些衣殼蛋白是源自噬菌體的外殼蛋白,例如AP205噬菌體、Qbeta噬菌體、MS2噬菌體、P22噬菌體等。在另一實施例中,該第二載體包含SEQ ID NO: 3之核苷酸序列,其所編碼之衣殼蛋白可和由包含SEQ ID NO: 2之核苷酸序列所形成的該一個或多個衣殼蛋白結合標記結合。
該組合物的該第一載體及該第二載體分別表現編碼具GLP-1活性之胜肽的該一個或多個mRNA和該一個或多個衣殼蛋白,且該一個或多個mRNA上的該一個或多個衣殼蛋白結合標記使該些衣殼蛋白和該一個或多個mRNA對應結合。因此,該一個或多個衣殼蛋白再透過自主裝而形成該一個或多個病毒樣顆粒,其可透過奈米膠囊的形式遞送編碼具有GLP-1活性之胜肽的該一個或多個RNA。
進一步,該第一載體可包含一內部核糖體進入位點(internal ribosome entry site,IRES),該內部核糖體進入位點包含SEQ ID NO: 4之核苷酸序列。該內部核糖體進入位點介於SEQ ID NO: 1之核苷酸序列以及該衣殼蛋白辨識序列之間。又,該第一載體可進一步包含SEQ ID NO: 5之核苷酸序列,其編碼一分泌訊號(secretion signal),用於促進具GLP-1活性之胜肽的合成。又,該第一載體可包含一啟動子(promoter)和一終止子(terminator),以供RNA聚合酶進行轉錄作用(transcription),舉例來說,可採用P11啟動子以及T1dh終止子,但不限於此。
除了上述實施例外,本公開還提供該組合物的另一種實施例,其同樣具有一第一載體和一第二載體,該第一載體包含SEQ ID NO: 6之核苷酸序列,編碼有一個或多個衣殼蛋白結合標記以及一個或多個mRNA,該一個或多個mRNA編碼具GLP-1活性之胜肽;而該第二載體包含SEQ ID NO: 3之核苷酸序列,其編碼一個或多個衣殼蛋白,由包含SEQ ID NO: 3之核苷酸序列編碼的該一個或多個衣殼蛋白可和由包含SEQ ID NO: 6之核苷酸序列編碼的該一個或多個衣殼蛋白結合標記對應結合。
本公開進一步提供一種基於奈米膠囊的藥物傳遞系統,用於將一個或多個mRNA遞送到人或動物受試者的體內以調節或控制人或動物受試者的血糖水平。在一實施例中,該基於奈米膠囊的藥物傳遞系統係透過口服藥物傳遞載體(如膠囊化的微生物細胞)實現,在一實施例中,該微生物細胞可以是益生菌。該微生物細胞包括一第一載體以及一第二載體,該第一載體編碼一個或多個編碼有GLP-1活性之胜肽的mRNA,並且該一個或多個mRNA標記有一個或多個衣殼蛋白結合標記,該第二載體編碼一個或多個衣殼蛋白,該一個或多個衣殼蛋白與位於該一個或多個mRNA上的一個或多個衣殼蛋白結合標記結合。
在一實施例中,該第一載體及該第二載體被轉殖到一轉殖細胞內,該第一載體以及該第二載體的遺傳資訊透過該轉殖細胞的生理機制表達。在一例子中,該轉殖細胞為一細菌細胞,在轉殖的過程中,該第一載體及該第二載體經轉錄、轉譯生成mRNA或衣殼蛋白,然後上述生物產物自組裝成VLP並封裝在細菌細胞中。在另一例子中,該轉殖細胞為益生菌細胞(probiotic),在轉殖的過程中,該第一載體及該第二載體經轉錄、轉譯生成mRNA或衣殼蛋白,然後上述生物產物自組裝成VLP並封裝在益生菌細胞中。
具體地,該第一載體藉由該轉殖細胞表達以產生具有該一個或多個衣殼蛋白結合標記的該一個或多個mRNA,並且該一個或多個mRNA編碼在人或動物受試者體內具有GLP-1活性之胜肽。該第二載體藉由該轉殖細胞表達以形成一種或多種衣殼蛋白。該第一載體及該第二載體的產物可以透過該一個或多個衣殼蛋白結合標記和該至一個或多個衣殼蛋白的結合而在轉殖細胞中自組裝成奈米膠囊。
進一步,該口服給藥載體可以口服的形式供患者食用,使該奈米膠囊透過該轉殖細胞的承載傳輸至生物體中,並在到達腸道時被釋出。此時腸道上皮細胞可透過胞吞作用(endocytosis)將被釋出的該奈米膠囊攝取進腸道上皮細胞中。在被釋放出的該奈米膠囊中的該一個或多個mRNA經上皮細胞的轉譯機制將該mRNA轉譯生成具GLP-1活性之胜肽。由此,本公開可促使人體或動物受試者自行生成具GLP-1活性之胜肽,其相較於人工合成的GLP-1衍生物更接近內源性GLP-1,有助於提升穩定血糖和控制體重的功效,並降低人工合成的GLP-1對人或動物的身體產生的負擔及副作用。
於一實施例中,該轉殖細胞為益生菌細胞(probiotic),可從細菌培養物中快速獲得和培養,該益生菌細胞較佳可為食用級之德氏乳桿菌(Lactobacillus delbrueckii)。
透過以下實驗例證實本公開的組合物可在生物體於體內(in vivo)內源性地形成GLP-1,從而有效地維持血糖的恆定性及控制體重。以下實例僅用於說明本公開的目的,本公開的範圍並不受實施例的限制。熟諳本公開的技術者可無需過度實驗,可利用本公開的揭露與教示來產生其他具體實施例、態樣與變化。
實驗例1:
於此實驗例中,德氏乳桿菌作為該第一載體以及該第二載體的轉殖載體。該第一載體採用pT7CFE1-NHA載體,並包含有SEQ ID NO: 6之核苷酸序列;該第二載體採用pCDF-1b載體,並包含有SEQ ID NO: 3之核苷酸序列,並將該第一載體和該二載體轉殖至該德氏乳桿菌中,形成重組益生菌。
將餵食50mg糖水的試驗倉鼠作為對照組,並將同一隻試驗倉鼠餵食50mg糖水和重組益生菌作為實驗組。
在實驗第0天,給試驗倉鼠口服50mg糖水,試驗倉鼠的血清血糖濃度如『圖1』實心圓圈所示。在實驗第1天,給同一隻試驗倉鼠口服50mg糖水及該重組益生菌,試驗倉鼠的血清血糖濃度如『圖1』空心圓所示。在實驗第2天,給同一隻試驗倉鼠口服50mg糖水及該重組益生菌,試驗倉鼠的血清血糖濃度如『圖1』空心方塊所示。
實驗組在實驗第1天血糖濃度變化趨勢與對照組相似,然而,與對照組相比,實驗組在實驗第1天的血糖濃度峰值(第一個小時)降低了約15%。另外,第1天實驗組的血糖濃度在4小時後恢復到正常範圍(即服用糖水前的濃度),比對照組短。
在實驗第1天結束後,再次餵食同一隻測試倉鼠糖水及該重組益生菌。於實驗第2天,實驗組的血糖濃度峰值與第1天幾乎相同,但抑制了血糖濃度的劇烈變化,即維持了血糖穩態。
該益生菌可以如上所述在胃腸道中遞送和釋放奈米膠囊,其中奈米膠囊透過胞吞作用進入上皮細胞。然後被胞吞的奈米膠囊打開並釋放內容物(由該第一載體中攜帶的核苷酸序列所形成的mRNA),該內容物作為密碼子轉譯的模板並透過宿主細胞的轉譯機制生成GLP-1。一旦GLP-1在細胞中產生,細胞質中的 GLP-1 將被輸出到生物體的循環系統中。
『圖1』顯示了試驗倉鼠維持血糖穩態的曲線圖。
TW202342761A_112109824_SEQL.xml
Claims (10)
- 一種用於調節血糖水平的組合物,包含: 一第一載體,包含SEQ ID NO: 1之核苷酸序列,以及一衣殼蛋白辨識序列,該第一載體編碼一個或多個編碼有GLP-1活性之胜 肽的mRNA,並且該一個或多個mRNA標記有一個或多個衣殼蛋白結合標記;以及 一第二載體,包含一個或多個編碼有一個或多個衣殼蛋白的核苷酸序列,該一個或多個衣殼蛋白可自組裝成一個或多個病毒樣顆粒,該一個或多個病毒樣顆粒封裝有該一個或多個mRNA,使該組合物被製成奈米膠囊。
- 如請求項1所述的組合物,其中,該第一載體的該衣殼蛋白辨識序列包含SEQ ID NO: 2之核苷酸序列,且該第二載體包含SEQ ID NO: 3之核苷酸序列。
- 如請求項1所述的組合物,其中,該第一載體進一步包括一介於SEQ ID NO: 1之核苷酸序列以及該衣殼蛋白辨識序列之間的內部核糖體進入位點(IRES)。
- 如請求項1所述的組合物,其中,該第一載體進一步包括SEQ ID NO: 5之核苷酸序列。
- 一種用於調節血糖水平的組合物,包含: 一第一載體,包含SEQ ID NO: 6之核苷酸序列;以及 一第二載體,包含SEQ ID NO: 3之核苷酸序列; 其中,SEQ ID NO: 3之核苷酸序列編碼一個或多個衣殼蛋白,並且該一個或多個衣殼蛋白可自組裝成一個或多個病毒樣顆粒,該一個或多個病毒樣顆粒封裝有一個或多個由SEQ ID NO: 6之核苷酸序列編碼的mRNA,使該組合物被製成奈米膠囊。
- 一種調節一受試者血糖水平的方法,包含: 向該受試者施用包含一個或多個奈米膠囊及/或含有該一個或多個奈米膠囊之膠囊化微生物細胞的組合物,其中該一個或多個奈米膠囊由一第一載體及一第二載體形成,該第一載體編碼一個或多個mRNA,其中該一個或多個mRNA編碼一具有GLP-1活性之胜 肽,並且該一個或多個mRNA標記有一個或多個衣殼蛋白結合標記,該第二載體包含一個或多個編碼有一個或多個衣殼蛋白的核苷酸序列,其中該一個或多個衣殼蛋白可自組裝成一個或多個病毒樣顆粒,該一個或多個病毒樣顆粒封裝有該一個或多個mRNA,使該組合物被製成該一個或多個奈米膠囊及/或膠囊化微生物細胞。
- 如請求項6所述的方法,其中,該第一載體包含SEQ ID NO: 1之核苷酸序列,以及一衣殼蛋白辨識序列。
- 如請求項7所述的方法,其中,該第一載體的該衣殼蛋白辨識序列包含SEQ ID NO: 2之核苷酸序列,且該第二載體包含SEQ ID NO: 3之核苷酸序列。
- 如請求項7所述的方法,其中,該第一載體包括SEQ ID NO: 5之核苷酸序列。
- 如請求項6所述的方法,其中,該第一載體包含SEQ ID NO: 6之核苷酸序列,且該第二載體包含SEQ ID NO: 3之核苷酸序列。
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