在高分子微胞系統中，複合型奈米微胞(multi-component micelle, mixed micelle)已被廣泛應用在藥物載體系統(Drug Delivery System, DDS)。本研究以兩種不同「雙團聯共聚物」之型態，混合製成藥物載體之奈米微胞，發展並建立一全新之「多功能性複合型奈米微胞」。
本研究主要以開發新系統、組成材料及製程來製備高分子/高分子複合型奈米微胞為主軸，首先將兩種不同的「雙團聯共聚物」之型態的高分子混合製備微胞，一為具有臨界微胞濃度(Criticak Micelle Concentration, CMC)的DiblockⅠ(mPEG-b-PLA)，可穩定奈米微胞結構，並可接上顯影分子(如Cy5.5)，作為顯影標定之用；一為具有臨界微胞濃度與溫度/酸鹼應答性的團聯共聚物，再分為具有溫度應達之DiblockⅡ(mPEG-b-P(HPMA-co-Lac))與具有溫度/酸鹼雙重應答性之DiblockⅢ(mPEG-b-P(HPMA-co-Lac-HPMA-co-His))，以熱衝擊的製備方法(hot shock protocol)，使其自我組裝(self-assembly)形成具有核殼結構(core-shell)的複合型奈米微胞，並具有粒徑小(50-100nm)及分佈均一(PDI<0.2)之生物相容性(biocompatible)奈米微胞。為了取得最佳的複合型奈米微胞之組成比例，並以動態光散射粒徑分析儀(Dynamic Light Scattering, DLS)測量混合後的微胞粒徑大小與分佈，並觀察在不同的酸鹼度下微胞的變化，最後將複合型奈米微胞溶於含4wt.％BSA的緩衝溶液中，模擬微胞在體內環境的穩定性。
本研究以熱衝擊的方式製備出包覆疏水性藥物－Doxorubicin的複合型奈米微胞，其藥物包覆率約為10-15％，於體外模擬藥物釋放，當所處環境酸鹼值為pH5.4時，其藥物釋放率可高達80％以上，且處於生理環境時，因為藥物突釋(initial brust)的關係使藥物釋放效率保持在40％左右。此外，將包覆藥物之奈米微胞與初級乳癌細胞(MCF-7)、初級子宮頸癌細胞(HeLa) 、轉移性乳癌細胞(ZR-75-1)與轉移性非小細胞型肺癌細胞(H661)與共同培養24、72小時後，可發現奈米藥物微胞相對於裸藥Dox•HCl對轉移性癌細胞更具有毒殺性，且未包覆藥物之奈米微胞完全不具材料毒性。並經由共軛焦顯微鏡(Confocal Laser Scanning Microscopy, CLSM)可觀察藥物在細胞內分布與釋放之行為，乃經由胞飲作用後進入細胞，使藥物累積於細胞質而後進入細胞核，且同時間下微胞釋放之藥物累積於細胞量高於裸藥Dox•HCl。最後，以靜脈注射的方式送入體內，經由EPR效應累積於腫瘤組織，並藉由Cy5.5-PEG-PLA標定微胞，再以非侵入式活體分子影像系統(In Vivo Imaging System, IVIS)觀察微胞於體內的累積情形，且因為環境的變化(如溫度、酸鹼度等)使得微胞不穩定，而於腫瘤組織內釋放藥物做為治療之用。
本研究製備的「多功能性複合型奈米微胞」具以下特點：(1) HPMA-co-Lac為感溫性疏水性鏈段，微胞核心提供疏水藥物的reservoir，當環境溫度變化皆會加速lactate水解，造成微胞疏水核心逐漸親水性化，使低臨界微胞溫度(Lower Critical Solution Temperature, LCST)往高溫方向移動，造成微胞在人體因病理組織環境變化，進而促使微胞結構不穩定而逐漸釋出藥物，造成微胞結構的破壞而釋放藥物，使藥物能在腫瘤組織內大量釋放。（2）HPMA-co-Boc-His為酸鹼應答共聚物，當環境中的pH值低於Histidine的pKa時，Histidine質子化(protonation)而帶有正電荷，使靜電排斥力增加、疏水作用力減低，造成微胞澎潤而釋放藥物。(3)當雙性團聯共聚物的濃度高於CMC，其疏水作用力會互相吸引、聚集而形成奈米微胞，使其微胞進入生物體內不會因為在血液中濃度驟降而瓦解。藉由(1)及(2)的特性，可以雙重控制奈米微胞釋放藥物的速率，且此兩特性互相影響，當環境中的溫度或酸鹼度產生變化，而加速lactate側鏈的水解與Histidine的酸鹼應答性，造成環境偏向高溫及酸性環境，使微胞內的疏水作用力降低而增加其親水性，導致微胞結構崩解並釋放藥物。綜合以上所述，本研究的多功能性複合型奈米微胞具有溫度及酸鹼應答性、生物相容性、控制藥物釋放的能力等優點，於體內循環時能穩定且累積於腫瘤組織，而後再經由溫度、酸鹼應答與水解的方式控制藥物的釋放，使藥物達到最佳的治療效果，因此在藥物傳輸上極具開發的潛力。

關鍵字：複合型微胞、mPEG-b-P(HPMA-co-Lac-HPMA-co-His)、熱衝擊方法、雙重控制釋放、酸鹼應答、溫度應答、臨界微胞濃度、低臨界微胞溫度

In the system of polymeric micelle, it has been widely applied to the drug delivery system (DDS). This research aims to develop and construct a multifunctionally mixed micelle which comes from mixing two different diblock copolymers, and can be used as drug carriers.
The main points of this research are developing new system, materials and programs to construct polymer with polymer-mixed and nano-sized micelle. First, combine methoxy poly(ethylene glycol)-block-poly(D,L-lactide)(mPEG-b-PLA, DiblockⅠ) with methoxy poly(ethylene glycol)-block-poly(N-(2-hydroxypropyl) methacrylamide-co-lactate)(mPEG-b-P(HPMA-co-Lac), DiblockⅡ) or methoxy poly (ethylene glycol)-block-poly (N-(2-hydroxypropyl) methacrylamide-co-lactate- N-(2-hydroxypropyl) methacrylamide-co-L-Histidine)(mPEG-b-P(HPMA-co-Lac-HPMA-co-His), DiblockⅢ) to prepare the mixed micelle.
DiblockⅠhas critical micelle concentration (CMC) property. DiblockⅡ and DiblockⅢ have critical micelle temperature (CMT), critical micelle concentration (CMC), and thermal sensitive properties. In addition, DiblockⅢ also has pH sensitivity property due to L-Histidine. DiblockⅠ respectively mixed with DiblockⅡ and DiblockⅢ to prepare core-shell structure and nano-size mixed micelle via hotshock protocol. Such micelle has well biocompatibility, biodegradability, uniform size about 50-100nm, and narrow polydispersity (PDI) below 0.2 at 37℃ buffer solution. DiblockⅠ stabilize and compact the structure against collapsing in blood because of micelle concentration shrinking. The temperature- and pH-sensitivity properties help micelle collapsing and dug releasing by the different temperature and pH in different tissues. The side chain groups of lactate can hydrolysis at physiological condition, contributing to the core of micelle hydrophilization, and upper the lower critical solution temperature (LCST). The controlled instability of micelle improves slowly in vivo degradation. Owing to these advantages, the mixed micelle has a candidate as drug carriers for cancer therapy.
The traits of multifunctional mixed micelle are as follow. First, HPMA-co-Lac is the hydrophobic segment with temperature-sensitivity, providing a reservoir for hydrophobic drugs. When the temperature of the surroundings changed, the lower critical solution temperature move to high temperature due to the hydrolysis of lactate boosting, the behavior impel to micelle collapsing and drug releasing. Secondly, HPMA-co-Boc-His is pH-sensitive copolymer. When pH of the surroundings below pKa of Histidine, Histidine was protonated and positive charge, leading to the electronic repulsion and hydrophobic interaction of micelle decreased, and dug released. Finally, when the concentrations of copolymers are higher than CMC, copolymers draw others and aggregated, then form nano-micelle. By the above of advantages, we can double control nano-micelle to release drug. When the temperature and pH of the surroundings changed, the side chain group hydrolysis and contribute to the core of micelle changed from hydrophobic to hydrophilic, after all, the structure of the micelle collapsed and released drug.
The temperature- and pH- sensitivity properties of the mixed micelle can be measured by UV-Vis spectrometer at 542nm and Zetasizer. The lower critical solution temperature occurred at 3-30℃ and gradually increased reducing environment pH. Furthermore, the use of pyrene as probe for fluorescence spectroscopic measurement could observe that the I337/I335 decreased with raising surrounding temperature, indicating that probe diffused from aqueous phase to the core of mixed micelle.
The characteristics and morphologies of mixed micelle were analyzed from 1H-NMR, DLS, zeta potential, fluorescence spectrometer, UV-Vis spectrometer, GPC, and TEM. Additionally, Doxorubicin (Dox) was incorporate into mixed micelle for cancer therapy. In neutral surroundings, the release of Dox from mixed micelle was less. On the contrast, a significant release of Dox was observed in acidic surroundings about pH<6. The amount of drug released from mixed micelle was isolated from mixed micelle buffer solution by ultra-filtration and measured by UV-Vis spectrometer at 485nm in a time-course produre.
The result of confocal laser scanning microscopy (CLSM) observation indicated that the loading drug successfully released in the acidic organelles due to the deformation of the micelle structure.
Above all, the release of drug from mixed micelle could be accurately controlled by pH changes. From these results, the innovative mixed micelle showed high potential for drug carrier in intracellular drug delivery.

Keyword: Metastatic cancer therapy, block copolymer, mixed micelle, hot shock protocol, dual controlled release, pH sensitivity, temperature sensitivity, CMT, CMC, LCST,

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