TWI648003B - 碳化多胺粒子及其用途 - Google Patents
碳化多胺粒子及其用途 Download PDFInfo
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- TWI648003B TWI648003B TW106123718A TW106123718A TWI648003B TW I648003 B TWI648003 B TW I648003B TW 106123718 A TW106123718 A TW 106123718A TW 106123718 A TW106123718 A TW 106123718A TW I648003 B TWI648003 B TW I648003B
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- polyamine
- carbonized
- carbon quantum
- quantum dots
- spermidine
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- 229920000768 polyamine Polymers 0.000 title claims abstract description 109
- 239000002245 particle Substances 0.000 title claims abstract description 80
- ATHGHQPFGPMSJY-UHFFFAOYSA-N Spermidine Chemical compound NCCCCNCCCN ATHGHQPFGPMSJY-UHFFFAOYSA-N 0.000 claims description 42
- 229940063673 spermidine Drugs 0.000 claims description 21
- PFNFFQXMRSDOHW-UHFFFAOYSA-N Spermine Chemical compound NCCCNCCCCNCCCN PFNFFQXMRSDOHW-UHFFFAOYSA-N 0.000 claims description 20
- 229940063675 spermine Drugs 0.000 claims description 10
- 239000007787 solid Substances 0.000 claims description 4
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- 238000005336 cracking Methods 0.000 claims description 2
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- BWKOZPVPARTQIV-UHFFFAOYSA-N azanium;hydron;2-hydroxypropane-1,2,3-tricarboxylate Chemical compound [NH4+].OC(=O)CC(O)(C(O)=O)CC([O-])=O BWKOZPVPARTQIV-UHFFFAOYSA-N 0.000 description 4
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- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 2
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- XLOMVQKBTHCTTD-UHFFFAOYSA-N zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-IGMARMGPSA-N (12)6C Chemical compound [12C] OKTJSMMVPCPJKN-IGMARMGPSA-N 0.000 description 1
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- HVOCVPNSEYAYFS-UHFFFAOYSA-N 1,13-diaminotridecane-4,7,10-trione Chemical compound NCCCC(=O)CCC(=O)CCC(=O)CCCN HVOCVPNSEYAYFS-UHFFFAOYSA-N 0.000 description 1
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- LCNBIHVSOPXFMR-UHFFFAOYSA-N N'-(3-aminopropyl)butane-1,4-diamine;hydron;trichloride Chemical compound Cl.Cl.Cl.NCCCCNCCCN LCNBIHVSOPXFMR-UHFFFAOYSA-N 0.000 description 1
- XLDKUDAXZWHPFH-UHFFFAOYSA-N N,N'-bis(3-aminopropyl)butane-1,4-diamine;hydron;tetrachloride Chemical compound Cl.Cl.Cl.Cl.NCCCNCCCCNCCCN XLDKUDAXZWHPFH-UHFFFAOYSA-N 0.000 description 1
- BPTXRMBKOXSOGJ-UHFFFAOYSA-N N-chloro-N-phenylhydroxylamine Chemical compound ON(Cl)C1=CC=CC=C1 BPTXRMBKOXSOGJ-UHFFFAOYSA-N 0.000 description 1
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- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
- A61K47/6923—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
- A61K47/6927—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
- A61K47/6929—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
- C01B32/00—Carbon; Compounds thereof
- C01B32/15—Nano-sized carbon materials
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/08—Luminescent, e.g. electroluminescent, chemiluminescent materials containing inorganic luminescent materials
- C09K11/65—Luminescent, e.g. electroluminescent, chemiluminescent materials containing inorganic luminescent materials containing carbon
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
本發明是關於一種碳化多胺粒子領域,特別是關於一種帶正電荷碳化多胺粒子,及其應用於抗菌之用途。本發明還有關於製備帶正電荷碳化多胺粒子及組合物的方法。
Description
本發明是關於一種碳化多胺粒子領域,特別是著重於帶正電荷碳化多胺粒子,及其應用於抗菌之用途。本發明還有關於製備帶正電荷碳化多胺粒子及組合物的方法。
碳化多胺粒子表面帶有多價正電荷,可增加細菌表面積接觸並與其交互作用,所述結果可能導致破壞細菌之細胞膜的通透性與呼吸功能。此外,內吞碳化多胺粒子可以透過與蛋白質、DNA、RNA和其他重要分子的交互作用來抑制細菌活性之功能。
具有抗微生物性質的奈米材料可以抑制微生物生長,並透過比傳統抗生素藥物更複雜的機制來破壞微生物。根據報導,吸附在細菌上的氧化鋅碳化多胺粒子可以通過與細胞膜上的脂質和蛋白質交互作用而破壞其功能。有許多基於貴金屬的抗菌物質,例如:銀奈米粒子,據報導經由釋放Ag+
所展現的抗菌性,能夠破壞細胞膜、干涉電子傳遞鏈以及造成DNA受損;銅奈米粒子則會造成蛋白質失活,並通過銅奈米粒子釋放遊離的Cu2+
離子以產生活性含氧物(ROS)來破壞細胞中的胺基酸和DNA合成;二氧化鈦奈米粒子也可以產生ROS,並且對細胞膜和細胞壁造成損害。多數的抗菌金屬和金屬氧化物奈米粒子已被用為微生物的廣效抗生素,其多重抗菌機制使細菌發展抗藥性的可能性大幅降低。然而,許多抗菌金屬與金屬氧化物奈米粒子對多數人類的細胞而言毒性甚強,因而限制了它們的用途。
多胺為兩個或多個由胺基團組成的小分子。其存在於食品與生物體所產生,其中包含丁二胺(putrescine)、屍胺(cadaverine)、亞精胺(spermidine)和精胺(spermine)等,對於許多細胞功能而言,多胺的存在是很重要的,先關功能在DNA穩定化、離子通道功能和受體-配位子的交互作用,基因轉錄和基因轉譯,以及細胞生長和細胞增生等機制中。多胺於細胞中存在較高的毫莫耳濃度範圍,其因多價陽離子且具有良好的生物相容性等,可應用於碳量子點的表面修飾。當多胺修飾於碳量子點表面後,使此碳化多胺粒子將高度帶電且具有高生物相容性。多胺修飾之碳量子點因與細胞大分子交互作用的廣泛性質,已成為生物醫學應用之標的。
碳量子點是一種新型的螢光奈米材料,因其高量子產率(quantum yield,QY)、光穩定性、可調激發性與放射性、低毒性及高生物相容性等特點,近年已備受的關注,這些特點使得功能性碳量子點適用於廣範的細菌和動物細胞之生物螢光顯影與細胞追蹤之無毒奈米探針。報導指出已有以甘露糖修飾之碳量子點標記大腸桿菌及以葉酸標的癌細胞之螢光成像的運用。據報導指出4,7,10-三氧-1,13-十三烷二胺的表面鈍化碳量子點,已被用於非洲綠猴腎纖維細胞株(african green monkey kidney fibroblast-like cell line,COS-7)之螢光檢測。
由於抗菌金屬和金屬氧化物奈米粒子對大多數人類細胞具有毒性,故其使用受限。當前,需要更有效、更安全且可用於治療感染的新型抗菌劑。
本發明所述之碳化多胺粒子,可以根據其與碳量子點共軛的多胺數量,而具有不同的表面正電荷。
本發明提供一種製備一帶正電荷碳化多胺粒子的方法,包括以下步驟:(a)熱裂解製備一碳量子點;(b)將該碳量子點與一多胺混合;以及(c)於140 ~300 ℃的一溫度下加熱該碳量子點與該多胺以得到該帶正電荷碳化多胺粒子。
本發明另提供一種製備一帶正電荷碳化多胺粒子的方法,包括以下步驟:於140~300 ℃的一溫度下熱裂解一多胺以得到該帶正電荷碳化多胺粒子。
根據上述構想,其中該多胺為固態多胺。
根據上述構想,其中該多胺選自一包含丁二胺、精胺或亞精胺的群組。
根據上述構想,其中該溫度介於180~210 ℃、210~240 ℃、240~270 ℃或270~300 ℃之中。
根據上述構想,進一步包含一步驟:將該帶正電荷碳化多胺粒子溶於一水溶液中,並離心取得上清液。
本發明提供一種根據上述構想所製備的該帶正電荷碳化多胺粒子,其包括:(a)一碳量子點;以及(b)一與該碳量子點共軛的至少一多胺,其中該碳量子點的表面具有該多胺分佈。
本發明另提供一種帶正電荷碳化多胺粒子,其包括:(a)一碳量子點;以及(b)一與該碳量子點共軛的至少一多胺,其中該碳量子點的表面具有該多胺分佈。
根據上述構想,其具有10 mV至65 mV zeta電位的正表面電荷。
根據上述構想,其直徑介於2 nm至7 nm。
根據上述構想,其包括:(a)一碳量子點層;以及(b)一多胺層,覆蓋於該碳量子點層表面。
根據上述構想,其中該多胺層具有一正表面電荷。
本發明提供一種抗菌組合物,包括一有效量之根據上述構想所製備之帶正電荷碳化多胺粒子。
本發明提供一種製備一抗菌組合物的方法,包括根據上述製備一帶正電荷碳化多胺粒子所述之方法,以及將該帶正電荷碳化多胺粒子加至包含至少一藥學上可接受之載體的一組合物中。
根據上述構想,其中該多胺選自包含丁二胺、精胺或亞精胺的群組。
根據上述構想,其中該溫度介於180~210 ℃、210~240 ℃、240~270 ℃或270~300 ℃之中。
本發明提供一種用於處理一感染狀況或一病症的方法,其包括:給予需要的一個體一有效劑量之一帶正電荷碳化多胺粒子。
根據上述構想,其中該帶正電荷碳化多胺粒子包含至少一多胺塗佈於一碳量子點上,且,該感染狀況或該病症因一微生物增生所引起,且該微生物選自包含一非多重抗藥性細菌及/或一多重抗藥性細菌的群組。
根據上述構想,其中該碳量子點裂解自檸檬酸銨,該多胺選自一包含丁二胺、精胺或亞精胺的群組。
根據上述構想,其中該非多重抗藥性細菌選自一包含大腸桿菌、金黃色葡萄球菌、枯草芽孢桿菌或綠膿桿菌的群組,且其中該多重抗藥性細菌包含抗藥性葡萄球菌。
本發明提供一種促進DNA轉染到一目標細胞中的組合物,包括一有效劑量之根據上述構想所製備之帶正電荷碳化多胺粒子。
根據上述構想,如專利申請範圍第20項所述之組合物,其中該目標細胞為一哺乳動物細胞或一人類細胞。
本發明提供一種製備一DNA轉染組合物的方法,包括製備一帶正電荷碳化多胺粒子所述之方法,以及將該帶正電荷碳化多胺粒子加至包含一可接受之載體的一組合物中。
根據上述構想,其中該多胺選自一包含丁二胺、精胺或亞精胺的群組。
根據上述構想,其中該溫度介於180~210 ℃、210~240 ℃、240~270 ℃或270~300 ℃之中。
本發明提供一種促進一DNA轉染到一目標細胞中的方法,包括:將一DNA加載於一有效劑量之一帶正電荷碳化多胺粒子組合物與該目標細胞混合並培養。
根據上述構想,其中該目標細胞為一哺乳動物細胞或一人類細胞。
根據上述構想,其中該帶正電荷碳化多胺粒子組合物包含至少一多胺塗佈於一碳量子點上。
根據上述構想,其中該碳量子點裂解自檸檬酸銨,該多胺選自一包含丁二胺、精胺或亞精胺的群組。
本發明將藉由以下圖式、實施例和描述,使所述技術領域具有通常知識者更容易理解本案所公開的前述內容、其它特性與多數優點。
本案公開了關於一種帶正電荷碳化多胺粒子及其用途的方法、結構以及組合物。所述技術領域具有通常知識者將能夠參考下述實施例與描述以實踐本案。
前述碳化多胺粒子,可以根據其與碳量子點共軛的多胺數量,而具有不同的正表面電荷。圖1的示意圖,是本發明中碳化多胺粒子之一的亞精胺覆蓋碳量子點結構之實施例。直接裂解固體狀態的檸檬酸銨以製備碳量子點。 將研磨製得的碳量子點與多胺混合後,進一步加熱。多胺分子通過亞精胺的胺基與碳量子點上的羧基和/或羥基間的醯胺鍵,錨定在碳量子點表面。
碳化多胺粒子的合成
二步合成
在一實施例中,於180℃下直接裂解2 g的固態檸檬酸銨2小時以合成碳量子點。所述合成方法詳細描述於Dong, et al. 2012 (Carbon 12, 4738-4743),併入本文以作為參考。在部分實施例中,研磨製得碳量子點,接著將碳量子點0.025 g與多胺溶液0.1 M(亞精胺三氫氯化物、精胺四氫氯化物或丁二胺二氫氯化物:1.0 mL;多胺與碳量子點的質量比〜1.02)混合,在溫度範圍140 ℃至300 ℃進一步加熱2小時。然後,將本發明合成的黑褐色碳化多胺粒子分散在去離子水(5 mL)中。滲析純化碳化多胺粒子後,測定碳化多胺粒子的尺寸和zeta電位示性。
一步合成
在另一實施例中,自丁二胺(putrescine)、 亞精胺(spermidine)或精胺(spermin)等多胺中以210℃、240℃、270或300℃進行熱裂解反應3小時可得到碳化多胺粒子(CQDPAs
)。在部分實施例中,上述所得的碳化多胺粒子(CQDPAs
)再加入去離子水5毫升,以超音波振盪30分鐘,再以離心力20,000g離心60分鐘去除較大的顆粒後,收集上清液中的碳化多胺粒子(CQDPAs
)並以每小時更換一次去離子水共五小時的透析方法純化之。在210℃至270℃的條件下,較精胺或丁二胺組別,自亞精胺中可以得到產量較高的碳化多胺粒子(CQDSpds
)。
表1為分別於(A)210℃、(B)240℃以及(C)270℃下熱裂解合成之CQDSpds
之元素分析(Elemental analysis)以及螢光生命期(fluorescence lifetimes)結果。
表1
碳化多胺粒子的定性
I.
尺寸和
zeta
電位
使用Tecnai 20 G2 S-Twin穿透式電子顯微鏡(Philips / FEI,Hillsboro,OR,USA),以獲得碳化多胺粒子的穿透式電子顯微鏡(TEM)影像。使用Zetasizer(Nano ZS,Malvern Instruments,Worcestershire,UK),以評估碳化多胺粒子的zeta(ζ)電位。
表2 試樣的尺寸與zeta電位
在部分實施例中,(a)碳量子點和(b)亞精胺覆蓋碳量子點的TEM影像(圖2A)和動態光散射(DLS)光譜(圖2B)顯示了碳化多胺粒子的粒徑分佈(4.6 ± 0.8 nm)。
在部分實施例中,亞精胺覆蓋碳量子點顯示了高的表面正電荷(zeta電位= 60.6 ± 3.1 mV)。
在部分實施例中,如圖3所示,在(b)140 °C、(c)180 °C、(d)220 °C、(e)260 °C和(f)300 °C合成的亞精胺覆蓋碳量子點之碳化多胺粒子包括不同的zeta電位。
在另一實施例中,於270°C的溫度下熱裂解亞精胺所製備之CQDSpds
碳化多胺粒子其粒徑為6 nm, zeta電位為+ 45 mV。
II.
螢光和
UV-Vis
吸收光譜
使用單色微量盤分光光度計(Synergy 4 Multi-Mode; Biotek Instruments,Winooski,VT,USA)記錄所製備之碳化多胺粒子的螢光和UV-Vis吸收光譜。 在365 nm的激發波長下,測量所製備之碳量子和亞精胺覆蓋碳化多胺粒子在5 mM磷酸鈉緩衝液(pH 7.4)中的螢光光譜。
在部分實施例中,碳量子點在440 nm的肩峰(shoulder band)顯示在340 nm的光吸收帶(曲線,圖4A(a)),分別歸因於π
®π
* 躍遷(C = C鍵)和n
®π
* 轉換(C = O和/或C = N鍵)。亞精胺覆蓋碳量子點在接近紫外光區域中表現出寬的吸收帶(圖4A(b)),可能是由於碳量子點表面上裂解亞精胺躍遷的n
®π
* 強轉變與共軛π
®π
* 轉變。
在部分實施例中,亞精胺和/或其裂解產物在碳量子點上共軛,導致亞精胺覆蓋碳量子點(2.8%, FIG. 4B(b))的量子產率(QY),與奎寧(QY 53% in 0.1 M H2
SO4
)的碳量子點(18.1%, FIG. 4B(a))相較之下較低。
在另一實施例中,於270°C的溫度下熱裂解合成之CQDPuts
、CQDSpds
以及CQDSpms
碳化多胺粒子於UV-Vis吸收光譜(圖5A)和螢光光譜(圖5B)之結果。
III. X
光光電子能譜
使用ES-CALAB 250光譜儀(VG Scientific,East Grinstead,UK)的Al Kα X光輻射作為用於激發的X射線源測定XPS光譜。以284.6 eV的C 1s峰為標準來校正結合能。
在部分實施例中,碳量子點(圖6A)和亞精胺覆蓋碳量子點(圖6B)的C1s XPS光譜顯示六種碳鍵類型的存在。亞精胺覆蓋碳量子點的C-N(39.6%)和C = N(3.1%)成分的量大幅增加。 亞精胺和/或其裂解分子在碳量子點上的縮合反應導致了富氮和帶正電荷碳化多胺粒子。
在另一實施例中,一步合成之CQDSpds
碳化多胺粒子的C1s XPS光譜(圖7),顯示四種碳鍵類型的存在,其C-N(35.6%)、C = C(22.3%)以及C-C(26.0%)的成分較高。
碳化多胺粒子的抗菌性能
碳化多胺粒子的最小抑菌濃度(MIC)值,是以標準稀釋法在多種測試細菌菌株中測定,其中包括兩種非多重抗藥性(non-MDR)革蘭氏陽性(金黃色葡萄球菌和枯草芽孢桿菌、兩種non-MDR革蘭氏陰性(大腸桿菌和綠膿桿菌)和一種多重抗藥性(MDR)革蘭氏陽性(MRSA)細菌。
在部分實施例中,碳化多胺粒子(圖8A)的MIC值,包括丁二胺覆蓋和精胺覆蓋碳量子點的MIC值,遠低於丁二胺或亞精胺的MIC值,結果表明碳化多胺粒子具有抗菌活性潛力。在部分實施例中,研究了抗菌活性的機制,結果表明亞精胺覆蓋碳量子點對細菌膜造成了顯著損害。
在部分實施例中,亞精胺覆蓋碳量子點的抑制活性不僅對四種non-MDR細菌菌株有效,對MDR細菌菌株也有效果(圖8B)。MDR菌株(MRSA)的亞精胺覆蓋碳量子點(~0.9 mg mL− 1
)的MIC值,比亞精胺(~26 mg mL− 1
)的MIC值低 >25,000倍。於實驗組中,亞精胺覆蓋碳量子點之MIC值,比Ag NPs的MIC值低 >10倍(~12 μg mL− 1
)。碳量子點上增強特徵( supercation feature)的高密度亞精胺,有助於亞精胺覆蓋碳量子點與細菌膜的強力交互作用,從而導致其分裂。
在部分實施例中,大腸桿菌細胞和MRSA細胞在(a)處理前,和經過(b)亞精胺、(c)碳量子點、和(d)亞精胺覆蓋碳量子點之(b−d)處理後的SEM影像(圖9A和圖9B)表明,被亞精胺覆蓋碳量子點處理過的細菌膜出現了膜狀態不平整、膜破裂等現象(圖9A(d)、圖9B(d))。
在另一實施例中,以銀奈米粒子(Ag NPs)、合成之碳化多胺粒子(CQDSpds
)、磺胺類抗生素眼藥水(SMX 4%或0.4%)對金黃色葡萄球菌感染誘發的細菌性角膜炎兔子進行局部給藥,以測試上述材料之體內治療效果。對照組(Ctrl)則僅以磷酸鹽緩衝液處理而無奈米材料或抗生素處理。經過材料處理14天後,將動物犧牲取下角膜組織進行進一步的測試。圖10A為放大鏡視野下角膜組織的樣本。圖10B為甘露醇鹽培養基對角膜組織進行細菌培養。圖10C為感染角膜組織內金黃色葡萄球菌的定量。誤差線代表六重複試驗的標準差。星號表示與對照組比較具統計上的顯著差異(*p < 0.05, ***p < 0.001; n = 6)。以H&E染色法(圖10D)及革蘭氏染色法(圖10E)對角膜組織切片進行染色。圖10D中的箭號代表發炎細胞的浸潤。Ep:上皮層; S:基質; En:內皮層。比例尺分別為100 微米(圖10D)及50微米(圖10E)。發炎或感染疾病造成的角膜傷害,常因不透明的細胞外基質生成導致角膜組織基質的重置而導致角膜霧化,在感染金黃色葡萄球菌(S. aureus
)14天後的兔子角膜組織中,對照組(Ctrl)及銀奈米粒子處理組(Ag NPs-treated,Ag NPs)的角膜組織呈現嚴重的霧化情形,而碳化多胺粒子(CQDSpds
)處理組及SMX4%
(市售 sulfamethoxazole (SMX) 眼藥水配方 4%)處理組則可以明顯觀察到角膜組織霧化情形得到改善(圖10A)。值得注意的是,在SMX0.4%
處理組的角膜組織水腫雖不明顯,但仍有輕微腫脹的情形。此結果與上述角膜透明度與厚度測量之結果互相呼應,並顯示需有足夠的抗生素才能使得抗菌治療成功。在部分實施例中,以甘露醇鹽培養基(MSA)隔夜培養來定量金黃色葡萄球菌感染角膜上的菌數,相較於銀奈米粒子處理組及SMX0.4%
處理組有大量菌落生成結果,碳化多胺粒子CQDSpds
)處理組及SMX4%
處理組則沒有菌落的生成 (圖10B及C),更加支持了碳化多胺粒子(CQDSpds
)的抗菌能力。在處理14天後的組織H&E染色切片中也可以發現,對照組及銀奈米粒子處理組呈現不正常角膜結構伴隨嚴重的發炎細胞浸潤現象,而在碳化多胺粒子(CQDSpds
)處理組及SMX4%
處理組的發炎細胞浸潤現象則非常輕微(圖10D)。以革蘭氏染色法可以發現對照組及銀奈米粒子處理組的角膜組織因金黃色葡萄球菌的感染使得角膜上皮層不完整及細胞基質被破壞。特別的是,碳化多胺粒子(CQDSpds
)處理組與SMX0.4%
處理組相比,角膜組織較薄且較無腫脹情形(圖10E)。此結果支持了在兔子角膜感染實驗中,碳化多胺粒子(CQDSpds
)的抗菌能力相當於市售含4% SMX成分的眼藥水,且治療所需濃度只需市售眼藥水之10分之一。
碳化多胺粒子與
DNA
的交互作用
在部分實施例中,使用凝膠電泳法來評估碳化多胺粒子的質體DNA(圖11A)和小干擾RNA(siRNA)(圖11B)的結合能力。質體DNA(200 ng)和siRNA (1.5 μg),在(a)1:0、(b)1:0.25、(c)1:0.5、(d)1:1、(e)1:3和(f)1:6的六種不同質量比下,與亞精胺覆蓋碳量子點結合,並且在2%瓊脂糖凝膠上施加20 V cm− 1
電場,執行1小時又10分鐘。其結果表示,亞精胺覆蓋碳量子點與質體DNA和siRNA具有很強的交互作用。
碳化多胺粒子的合成溫度對抑制活性的影響
細菌的生長和測定:金黃色葡萄球菌、枯草芽孢桿菌、MRSA、大腸桿菌和綠膿桿菌,分別在LB培養基(Luria Broth,LB)中生長。將每個菌株的單個菌落從LB培養基上取出,並接種在LB介質(10 mL)中。培養菌在37 °C下振盪(200 rpm)生長,直到600 nm處的吸光度(OD600
)達到1.0(光程長度:1.0 cm)。將每個細胞混合物的一部分(1.0 mL)離心(RCF 3,000 g、10 min、25 °C),並且在進一步使用之前,用5 mM磷酸鈉緩衝液(pH 7.4)洗滌兩次。
在部分實施例中,在LB培養基上未經碳量子點處理的MRSA (圖12A),及以於140 °C、180 °C、220 °C、260 °C和300 °C合成的亞精胺覆蓋碳量子點處理之MRSA(圖12B至圖12F)。亞精胺覆蓋碳量子點的抑制活性隨著合成溫度從140 ℃到260 ℃而升高,然後在高於260 ℃的溫度下降低。
碳化多胺粒子組合物的抗菌性能
碳化多胺粒子的傷口癒合功效,是通過史道二氏(Sprague Dawley,SD)雄性大鼠(5〜6週、體重150~175 g、每組3隻)的體內實驗來評價。用含有1 × 108
CFU的MRSA懸浮液之無菌生理食鹽水100 μL來感染傷口(直徑1 cm)。使用經抗菌劑(50 μg mL− 1
碳化多胺粒子0.2 mL、Ag NPs(直徑〜12 nm)或3M 舒適繃含藥型(含抗菌劑、羥基氯苯胺))處理過的紗布(1.0 cm × 1.0 cm),在手術後兩天應用於受感染的傷口。
在部分實施例中,大鼠的MRSA感染傷口研究結果顯示,當亞精胺覆蓋碳量子點被用作敷料材料時,有較快的癒合速度和較佳的上皮形成和膠原蛋白纖維形成(圖13)。
本案所述的實施例,其係包含該組其中之一的成員表現於、用於或與其相關的所述產品或過程。本發明所包含的多個實施例,其係包含多於一個或所有組員表現於、用於或與其相關的所述產品或過程。
所述技術領域具有通常知識者將藉由不超過常規的實驗,以識別或查明本發明所述的特定實施例之許多同等設備。本案的(保護)範圍並不限於所公開的特定實施例,而是包括落入所附申請專利範圍內的所有實施例。此外,可以理解為適於本案的教導而將儀器、情況或材料進行改良而不脫離其本質範圍。
無
圖1顯示本發明一實施例的碳化多胺粒子示意圖。
圖2A、圖2B分別顯示(a)碳量子點和(b)亞精胺覆蓋碳量子點(spermidine-capped carbon quantum dots)的穿透式電子顯微鏡(TEM)影像和動態光散射粒徑分析儀(DLS)光譜。
圖3顯示在多種溫度下合成的(a)碳量子點和(b-f)亞精胺覆蓋碳量子點的zeta電位。
圖4A、圖4B分別顯示(a)碳量子點和(b)亞精胺覆蓋碳量子點的UV-Vis吸收光譜和螢光光譜。
圖5A、圖5B分別顯示熱裂解合成之CQDPuts
、CQDSpds
以及CQDSpms
碳化多胺粒子的UV-Vis吸收光譜(圖5A)和螢光光譜(圖5B)。
圖6A、圖6B分別顯示所製備的碳量子點和亞精胺覆蓋碳量子點的C1s XPS光譜。
圖7顯示所製備的CQDSpds
碳化多胺粒子的C1s XPS光譜。
圖8A、圖8B分別顯示碳化多胺粒子對五種細菌(大腸桿菌、綠膿桿菌、抗藥性葡萄球菌(Methicillin-resistant Staphylococcus aureus ,MRSA)、金黃色葡萄球菌和枯草芽孢桿菌(B. subtilis)的抗菌性能。
圖9A、圖9B分別顯示(a)處理前和經(b)亞精胺、(c)碳量子點、(d)亞精胺覆蓋碳量子點處理後的大腸桿菌細胞和MRSA細胞的SEM影像。
圖10A~圖10E顯示在不同處理下對金黃色葡萄球菌感染誘導的細菌性角膜炎兔子治療的角膜組織分析結果。
圖11A、圖11B分別顯示膠體電泳的結果,證明碳化多胺粒子、質體DNA以及六種不同質量比之小干擾核甘核酸(siRNA)的結合力
圖12A~圖12F顯示在不同溫度下合成的亞精胺覆蓋碳量子點存在或不存在下,LB培養基上的MRSA代表性菌落生成評估。
圖13顯示MRSA感染傷口未經處理和經Ag NPs、3M繃帶或亞精胺覆蓋碳量子點處理的代表性照片。
Claims (4)
- 一種製備一帶正電荷碳化多胺粒子的方法,包括以下步驟:於140~300℃的一溫度下熱裂解一多胺以得到該帶正電荷碳化多胺粒子;其中該多胺為固態多胺。
- 如專利申請範圍第1項所述之方法,其中該多胺選自一包含丁二胺、精胺或亞精胺的群組。
- 如專利申請範圍第1項所述之方法,其中該溫度介於180~210℃、210~240℃、240~270℃或270~300℃之中。
- 如專利申請範圍第1項所述之方法,進一步包含一步驟:將該帶正電荷碳化多胺粒子溶於一水溶液中,並離心取得上清液。
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