这项工作得到台湾科技部（MOST 104-2221-E-131-010，MOST 105-2622-E-131-001-CC2）的财政支持，部分得到原子分子科学研究所的支持，中央研究院

1.表面改性，水分散磁性纳米粒子，Fe 3 O 4和Fe 3 O 4 -NH 2的合成<ol><li>加入14.02g FeCl 3，8.6g FeCl 2 ·4H 2 O和250mL水加入到500mL烧杯中。 </li><li>连接转子和控制器，进行机械搅拌。将溶液在室温（RT）下以300rpm混合30分钟。 </li><li>在室温下向溶液中加入25mL氢氧化铵（33％），并保持搅拌（300rpm）30分钟。保持烧杯开放。 小心:如果吸入，氢氧化铵会引起鼻部刺激。此步骤必须在适当的通风橱内进行。 </li><li>收集磁性氧化铁（Fe 3 O 4 ），去除机械搅拌。将磁铁放在烧杯下面收集黑色颗粒。 <ol><li> Fe 3 O 4纳米颗粒完全沉淀后，小心除去上清液。不要动摇b在倒出上清液时避免Fe 3 O 4的损失。 </li><li>取出磁铁，并向烧杯中加入50 mL淡水。 </li><li>摇动烧杯重新分散Fe 3 O 4 。重复步骤1.4至1.4.2三次以净化Fe 3 O 4 。 </li></ol></li><li>最后一次洗涤后，将所有的Fe 3 O 4 （10g）转移到100 mL玻璃瓶中。加水至总溶液体积为100mL。大力摇动玻璃瓶直到没有肿块可见。 注意:协议可以在这里暂停。制备Fe 3 O 4纳米颗粒。 </li><li>用氨基硅烷（Fe 3 O 4 -NH 2 ）改变Fe 3 O 4 。 <ol><li>取来自步骤1.5的100mL溶液并转移到1,000mL烧杯中。向烧杯中加入10 mL氨水溶液，90 mL水和900 mL乙醇。 </li><li>使用磁力搅拌棒将溶液混合在一起300 rpm。在室温下向烧杯中滴加500μL（3-氨基丙基）三乙氧基硅烷（APTES），再搅拌12小时。 </li></ol></li><li>如第1.4节所述净化并收集Fe 3 O 4 -NH 2 。 </li><li>将1g Fe 3 O 4 -NH 2 （来自步骤1.7）重新分散在具有20mL水的20mL玻璃瓶中。 注意:协议可以在这里暂停。制备Fe 3 O 4 -NH 2纳米颗粒。 </li></ol> 2.通过热诱导乳液合成有机 - 无机杂化微凝胶<ol><li> 溶液1-1和1-2的制备。 <ol><li>对于溶液1-1，将0.25g PNIPAAm，5mL Fe 3 O 4溶液（来自步骤1.5）和0.2g PEI加入到50mL玻璃瓶中。加入20mL水，并用磁力搅拌棒在300rpm搅拌30分钟。 </li><li>对于溶液1-2，重复步骤2.1.1，但将Fe 3 O 4替代为Fe3 O 4 -NH 2溶液（来自步骤1.8）。 </li></ol></li><li>为了制备溶液2 ，向50mL玻璃瓶中加入0.8g PEI和18.2mL水。使用水浴将溶液加热至70°C 30分钟。准备第二瓶解决方案2 。 </li><li> PNIPAAm / Fe 3 O 4的制备。 <ol><li>使用超声波细胞破碎机超声波（50w），磁力搅拌棒搅拌（300rpm）和水浴以加热溶液2 （70℃）。 </li><li>使用3-mL注射器以1mL / min的速率将溶液1-1滴加到加热的溶液2中。 </li><li>继续超声处理，搅拌和在70℃加热30分钟。 </li><li>将解决方案冷却到RT。从细胞破碎器和水浴中取出溶液。 </li><li>将磁铁靠近玻璃瓶收集微凝胶。 </li><li>取出上清液微小凝胶已经沉淀到玻璃瓶的底部。 </li><li>向玻璃瓶中加入另外25 mL的水，并通过涡旋重新分散微凝胶。该溶液是PNIPAAm / Fe 3 O 4 。 注意:协议可以在这里暂停。 </li></ol></li><li> PNIPAAm / Fe 3 O 4 -NH 2的制备。 <ol><li>使用超声波细胞破碎机超声波（50w），磁力搅拌棒搅拌（300rpm）和水浴以加热溶液2 （70℃）。 </li><li>使用3-mL注射器以1mL / min的速率将溶液1-2滴加到加热的溶液2中。 </li><li>继续超声处理，搅拌和在70℃加热30分钟。 </li><li>将解决方案冷却到RT。从细胞破碎器和水浴中取出溶液。 </li><li>将磁铁靠近玻璃瓶收集微凝胶。 </li><li>一旦微凝胶沉淀，取出上清液。 </li><li>向玻璃瓶中加入另外25 mL的水，并通过涡旋重新分散微凝胶。该溶液是PNIPAAm / Fe 3 O 4 -NH 2 。 注意:协议可以在这里暂停。 </li></ol></li></ol> 3.载有姜黄素的微凝胶（Cur-PNIPAAm / Fe 3 O 4 -NH 2 ）的制备注意:这些步骤必须在黑暗中进行。 <ol><li>将100毫升的Cur和20毫升乙醇加入到20毫升的玻璃瓶中。 </li><li>取2mL的Cur溶液并转移到PNIPAAm / Fe 3 O 4 -NH 2溶液（步骤2.4.7）。以400rpm和室温搅拌过夜。 </li><li>在400rpm和室温下搅拌过夜后，使用磁铁收集PNIPAAm / Fe 3 O 4 -NH 2 ，如步骤2.4.5和2.4.6所述。 </li><li>向玻璃瓶中加入另外25 mL的水，并通过涡旋重新分散微凝胶。这个解决方案是C<html> ur-PNIPAAm / Fe 3 O 4 -NH 2 。 </li></ol>磁性触发药物释放<ol><li>转移10 mL Cur-PNIPAAm / Fe 3 O 4 -NH 2溶液，并加入2 mL水至15 mL离心管中。 </li><li>将离心管放置在线圈的中心，以应用HFMF 20 。在15KHz下应用HFMF 20分钟。 </li><li>取出0.5 mL HFMF溶液，每隔2分钟更换新鲜的0.5 mL水，同时应用HFMF。 </li><li>将取出的溶液转移到1-mL比色杯中。 </li><li>通过UV / Vis在482nm测量吸出的溶液21 。 </li><li>通过使用来自标准校准曲线22的吸收和浓度的关系来确定释放的药物的浓度。 注意:标准校准关系为: <html> s / ftp_upload / 55648 / 55648eq1.jpg"/&gt; 相关系数为0.9993。 </li></ol> 5.磁性微凝胶的表征<ol><li>热重分析仪（TGA） 23 。 <ol><li>测量PNIPAAm / Fe 3 O 4和PNIPAAm / Fe 3 O 4 -NH 2与TGA在空气气氛下的温度的重量损失。 <ol><li>将样品从RT加热至100°C，并在该温度下保持10分钟以消除湿度。以10℃/ min的速度将样品从100℃加热至800℃。称量样品。 </li><li>绘制PNIPAAm / Fe 3 O 4和PNIPAAm / Fe 3 O 4 -NH 2的重量损失与温度的关系。 注意:残渣重量为Fe 3 O 4或Fe 3 O 4 -NH 2 ，而重量为PNIPAAm。 </li></ol></li></ol></li><li> FT-IR"&gt; 24。 <ol><li>干燥10毫克样品与1克KBr在100℃过夜。 </li><li>按照以下步骤（5.2.2.1 - 5.2.2.5）中所述将步骤5.2.1的混合物压成颗粒: <ol><li>使用研钵和研杵将步骤5.2.1中的材料研磨成细粉。 </li><li>将组装的装置（砂浆和杵）放入颗粒压机中。将设备对准印刷机的正中间。 </li><li>泵压机直至达到20,000 psi的压力。让颗粒坐在那个压力下5分钟。 注意:将设备与印刷机的正中间对准，否则样品将从砂浆中分散出来，造成人身伤害。 </li><li>从压机上取出包含颗粒和活塞的模具。 </li><li>将其倒置并泵送活塞以迫使颗粒物流出。 </li></ol></li><li>通过FT-IR在400至4000 cm -1的频率记录样品的FT-IR吸收光谱</sup&gt; 4厘米-1分辨率24 。 </li></ol></li><li> TEM的形态学观察25 。 <ol><li>将样品溶液放在涂有火棉花的铜格栅上，然后在室温或70°C烘箱中干燥过夜。 </li><li>采用TEM图像。 注意:强电子束可能会损坏样品。因此，应尽可能快地拍摄TEM图像。 </li></ol></li><li>聚合物和微凝胶的水分散能力。 <ol><li>为了制备PNIPAAm溶液，将7mg PNIPAAm和7mL水加入到7-mL玻璃瓶中。使用涡流混合溶液，直到没有聚集体。 </li><li>为了制备PNIPAAm / Fe 3 O 4 -NH 2溶液，将0.7mL的PNIPAAm / Fe 3 O 4 -NH 2溶液（步骤2.4.7）转移到7-mL玻璃瓶中并加入6.3mL水。使用涡流混合溶液，直到没有沉淀。 </li><li>准备Cur-PNIPAAm / Fe 3 O 4 -NH 2溶液，将0.7mL的Cur-PNIPAAm / Fe 3 O 4 -NH 2溶液（步骤3.4）转移到7mL玻璃瓶中并加入6.3mL水。使用涡流混合溶液，直到没有沉淀。 </li><li>使用数码相机拍摄解决方案（步骤5.4.1 - 5.4.3）。 </li><li>将溶液放入烘箱中并将温度设定在70°C。等待2小时直到平衡。 </li><li>再来看一下解决方案。为了保持温度，请在1分钟内拍照。避免摇晃玻璃瓶，因为这样可以重新分散沉淀物。 </li></ol></li><li>对于微凝胶的磁集合，将强磁体靠近Cur-PNIPAAm / Fe 3 O 4 -NH 2溶液（步骤5.4.3）。等到微凝胶完全收集，然后拍照。 <ol><li>取出磁铁并旋转微凝胶溶液直到完全分散。再拍一张照片/ LI&gt; </ol></li></ol>

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P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Synthesis+and+characterization+of+polystyrene+coated+iron+oxide+nanoparticles+and+asymmetric+assemblies+by+phase+inversion.">Synthesis and characterization of polystyrene coated iron oxide nanoparticles and asymmetric assemblies by phase inversion.</a> Journal of Applied Polymer Science. 132 (5), (2015).</li></ol>

作者没有什么可以披露的。

制备的最重要步骤在方案第2节中，用于通过热诱导乳液合成磁性微凝胶。 如图2 （TEM图）所示，由于由PNIPAAm（酰胺基），PEI（胺基）之间的强H键而产生的物理交联，微凝胶的球形结构可以保持在RT（低于LCST）和Fe 3 O 4 -NH 2 （胺基）。基于图4的比较，磁性微凝胶在低（25℃）或高（70℃）温度下良好分散。微凝胶也可以由磁体收集并再分散成均匀的溶液， 如图5所示。 用疏水和亲水单体合成的水凝胶的传统制备通常需要引入交联剂以获得3D网络4,5,6,7 。然而，交联剂难以除去并且常常在其应用中引起副作用。 PNIPAAm可以在高温下聚集或自组装成颗粒，当温度低于其LCST时，也可以重新分散成均质溶液。交联和化学修饰通常用于水凝胶制备，以防止3D网络的崩溃。这里应用热诱导的氢键交联来代替化学反应，从而简化合成和制备过程。 水凝胶制备成功的关键是聚合和无交联的方法和疏水性药物的包封。没有聚合，水凝胶可以去除通常导致的未反应的引发剂和单体毒性强。在这里，我们通过表面改性和溶剂引入成功地完成了无机化合物（氧化铁）和疏水性分子（姜黄素）的分散和包封。 通过体外释放试验（ 图7 ），我们发现磁性微凝胶通过磁感应加热（高热）效应在外部磁场（HFMF）中有效地提高了温度和释放百分比。通过上述性质，这些基于PNIPAAm的磁性微凝胶是磁和热触发，靶向递送肿瘤治疗的潜在候选者。

水凝胶是三维（3D）聚合物网络，其不能溶解但可在水溶液中溶胀1 。聚合物网络具有亲水结构域（其可以水合以提供水凝胶结构）和交联构象（其可以防止网络崩溃）。已经研究了制备水凝胶的各种方法，例如乳液聚合，阴离子共聚，相邻聚合物链的交联和反相微乳液聚合2 。通过这些方法引入物理和化学交联以获得结构稳定的水凝胶1,3 。化学交联通常需要连接聚合物的主链或侧链的交联剂的参与。与化学交联相比，物理交联是fabr的更好选择<html>由于这些试剂对于实际应用而言通常是有毒的，因此避免了交联剂的酸化水凝胶。已经研究了几种用于合成物理交联水凝胶的方法，例如用离子相互作用的交联，结晶，两亲嵌段之间的键合或聚合物链上的接枝以及氢键4,5,6,7。 近来，受不同环境条件（ 即温度，pH，光，离子强度和磁场）影响的构象，化学或物理性能变化的刺激敏感性聚合物近来引起了人们的注意，作为控制释放系统的潜在平台，药物输送和抗癌治疗8,9 ，xref"&gt; 10,11,12 ，研究人员正在关注热敏聚合物，其中可以容易地控制固有温度PNIPAAm是一种热敏聚合物，其含有亲水性酰胺基和疏水性异丙基，并且具有较低的临界溶解温度（LCST） 13 。酰胺基和水分子之间的氢键在低温下（低于LCST）提供了PNIPAAm在水溶液中的分散性，而聚合物链之间的氢键在高温（高于LCST）下发生，并且不包括水分子，使得聚合物网络崩溃，关于这种独特的性质，已经出版了许多报道，通过调节聚合物链长度的疏水性和亲水性比例如共聚，接枝或侧链来制备温度触发的自组装水凝胶，制药连锁改造cal平台14,15,16,17 。 磁性材料如铁，钴和镍在过去几十年中也受到越来越多的关注，用于生物化学应用18 。在这些候选物中，由于其稳定性和低毒性，氧化铁被广泛使用。纳米级铁氧化物立即响应于磁场并表现为超顺磁性原子。然而，这样的小颗粒容易聚集;这降低了表面能，因此失去了分散性。为了提高水分散性，接枝或涂层以保护层通常不仅用于分离每个单独的颗粒以获得稳定性，而且还使反应位点进一步官能化。 在这里，我们制造了基于PNIPAAm的磁性微型凝胶作为控制释放系统的药物载体。合成过程如图1所示。代替复杂的共聚和化学交联，采用PNIPAAm的新型温度诱导乳液进行物理交联，得到无需附加表面活性剂或交联剂的微凝胶。这简化了合成并防止了不期望的毒性。在这种简单的制备方案中，合成的微凝胶为磁性氧化铁纳米颗粒和疏水性抗癌药物姜黄素提供了水分散性。 FT-IR，TEM和成像提供了分散和包封的证据。由于嵌入的Fe 3 O 4 -NH 2 ，磁性微凝胶显示出在HFMF下作为控制释放的微器件的潜力。

<table border="0" cellpadding="0" cellspacing="0" width="773">
	<tbody>
		<tr height="21">
			<td height="21" style="height:21px;width:311px;">Poly(N-isopropylacrylamide)</td>
			<td style="width:139px;">Polyscience, Inc</td>
			<td style="width:119px;">21458-10</td>
			<td style="width:205px;">Mw~40000</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">(3-aminopropyl)trimethoxysilane</td>
			<td>Sigma-Aldrich</td>
			<td>440140</td>
			<td>&#62; 99 %</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Iron(II) chloride tetrahydrate</td>
			<td>Sigma-Aldrich</td>
			<td>44939</td>
			<td>99%</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Iron(III) chloride</td>
			<td>Sigma-Aldrich</td>
			<td>157740</td>
			<td>97%</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Curcumin</td>
			<td>Sigma-Aldrich</td>
			<td>00280590</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Ammonia hydroxide</td>
			<td>Fisher Chemical</td>
			<td>A/3240/PB15</td>
			<td>35%</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Phosphate Buffered Saline</td>
			<td>Sigma-Aldrich</td>
			<td>806552</td>
			<td>pH 7.4, liquid, sterile-filtered</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Polyethylenimine (PEI)</td>
			<td>Sigma-Aldrich</td>
			<td>P3143</td>
			<td>50 % (w/v) in water</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">High-frequency magnetic field (HFMF)</td>
			<td>Lantech Industrial Co., Ltd.,Taiwan</td>
			<td>LT-15-80</td>
			<td>15 kV, 50&#8211;100 kHz</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Ultraviolet-Visible Spectrophotometry</td>
			<td>Thermo Scientific Co.</td>
			<td>Genesys</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Transmission electron microscopy (TEM)</td>
			<td>JEM-2100</td>
			<td>JEOL</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Fourier transform infrared spectroscopy (FTIR)</td>
			<td>PerkinElmer</td>
			<td>Spectrum 100</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Thermogravimetric analyzer</td>
			<td>PerkinElmer</td>
			<td>Pyris 1</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Ultrasonic cell disruptor</td>
			<td>Hielscher Ultrasonics</td>
			<td>UP50H</td>
			<td></td>
		</tr>
	</tbody>
</table>

magnetic and thermal-sensitive poly(n-isopropylacrylamide)-based microgels for magnetically triggered controlled release

设计并制造了具有包封的抗癌药物姜黄素（Cur）的磁感和热敏聚（ N-异丙基丙烯酰胺）（PNIPAAm）/ Fe 3 O 4 -NH 2微凝胶用于磁触发释放。通过温度诱导的乳液制备具有球形结构的基于PNIPAAm的磁性微凝胶，然后通过混合PNIPAAm，聚乙烯亚胺（PEI）和Fe 3 O 4 -NH 2磁性纳米粒子进行物理交联。由于其分散性，将Fe 3 O 4 -NH 2纳米颗粒嵌入聚合物基质内。暴露在Fe 3 O 4 -NH 2和PEI表面上的胺基通过与PNIPAAm的酰胺基团物理交联来支撑球形结构。疏水性抗癌药物姜黄素在包封入微凝胶后可以分散在水中。表征微凝胶通过透射电子显微镜（TEM），傅里叶变换红外光谱（FT-IR）和UV-Vis光谱分析。此外，在外部高频磁场（HFMF）下研究了磁触发释放。由于磁感应加热（热疗）效应，将HFMF应用于微凝胶后，观察到姜黄素的显着"爆发"。该手稿描述了Cur-PNIPAAm / Fe 3 O 4 -NH 2包封的姜黄素的磁触发控制释放，其可以潜在地用于肿瘤治疗。

PNIPAAm / PEI / Fe 3 O 4 -NH 2微凝胶的合成示意图如图1所示。应用TGA估计有机化合物相对于整个微凝胶的相对组成。由于只有有机化合物PNIPAAm可以燃烧，因此确定了PNIPAAm和Fe 3 O 4 （或Fe 3 O 4 -NH 2 ）的相对组成，如表1所示。为什么PNIPAAm / Fe 3 O 4 -NH 2微凝胶显示更好的分散性，但含有较低的氧化铁含量？由于与PNIPAAm / Fe 3 O 4相比，PNIPAAm / Fe 3 O 4 -NH 2的相互作用更强，分散性更好，Fe 3 O 4 -NH 2比Fe 3 O 4更容易交联PNIPAAm。结果，PNIPAAm / Fe 3 O的产率<sub&gt; 4 -NH 2微凝胶比PNIPAAm / Fe 3 O 4高得多。由于收集过程（步骤2.3.3-2.3.5和2.4.3-2.4.5），用上清液除去未交联的PNIPAAm，因为只有具有微凝胶的磁性氧化铁才能被磁吸收。因此，微胶凝中PNIPAAm的重量百分比为32.37％（PNIPAAm / Fe 3 O 4 ）和68.56％（PNIPAAm / Fe 3 O 4 -NH 2 ）。与Fe 3 O 4纳米颗粒相比，Fe 3 O 4 -NH 2纳米颗粒可以物理交联更多的PNIPAAm。 PNIPAAm溶液和磁性微凝胶的TEM图像在室温下由数码相机拍摄。 如图2a所示，室温下纯PNIPAAm溶液中没有特定的结构。然而，规则的球形氧化铁parti在PNIPAAm / Fe 3 O 4 （ 图2c ）和PNIPAAm / Fe 3 O 4 -NH 2 （ 图2d ）的微凝胶中观察到Cles（ 图2b ），这提供了由PNIPAAm和PEI之间的氢键合产生的物理交联的证据。大多数Fe 3 O 4纳米颗粒只能吸附在基于PNIPAAm的基体的表面上并产生聚集簇（ 图2c ）。然而，与裸露的Fe 3 O 4纳米颗粒相比，由于磁性纳米颗粒的水分散性和较小尺寸（ 图3d ），APTES改性的氧化铁纳米颗粒Fe 3 O 4 -NH 2可以嵌入颗粒中。加载姜黄素后，Cur-PNIPAAm / Fe 3 O 4 -NH 2 （ Fi由于Cur的疏水特性，磁性微凝胶的隔离度远远高于磁性微凝胶。结果还表明，Cur不仅封装在内部，而且还吸收在微凝胶表面。 通过FT-IR分析鉴定微凝胶制剂和治疗分子包封， 如图3所示。与文献19,26中的Fe 3 O 4相比，2927,1203,1387和472cm -1处新出现的吸收峰归因于CH拉伸，Si-O-Si拉伸，Si-O拉伸和Si-O弯曲，这表明APTES的成功改性以覆盖Fe 3 O 4纳米颗粒的表面。在PNIPAAm / Fe 3 O 4中也观察到Fe-O振动峰（584cm -1 ） </sub&gt;和PNIPAAm / Fe 3 O 4 -NH 2 。然而，PNIPAAm / Fe 3 O 4中Fe-O振动的相对强度高于PNIPAAm / Fe 3 O 4 -NH 2的相对强度，这也支持我们对组成的描述，即更好的水分散性导致更好的结构分布。加载过程后，Cur-PNIPAAm / Fe 3 O 4 -NH 2的 FT-IR光谱分别出现在1509和3511cm -1处的姜黄素的特征吸收峰，分别表示芳香族C = C弯曲和OH拉伸，其中表明姜黄素的成功封装。 在25℃或70℃下各种微凝胶的照片如图4所示，其中乳状和棕色溶液分别代表PNIPAAm和氧化铁的聚集体。与图4a- </strong&gt; c ，在室温（25℃）下，PNIPAAm，PNIPAAm / Fe 3 O 4 -NH 2和Cur-PNIPAAm / Fe 3 O 4 -NH 2溶液中没有明显的可见聚集。当PNIPAAm溶液和磁性微凝胶被加热到比PNIPAAm的LCST高时，其变得不透明， 如图4d - f所示 。两种磁性微凝胶都是乳状的，但没有任何沉淀分散，这表明PNIPAAm，Fe 3 O 4 -NH 2和姜黄素之间分散性强，物理结合强。 如图5所示，磁性微凝胶可以容易地与磁体收集并且在除去磁体之后重新分散到水溶液中而没有任何聚集。结果表明，这些磁性微凝胶可能潜在地应用于像人体f这样的含水输送系统或临床应用。 通过HFMF监测磁性微凝胶的体外释放行为。设置的实验装置如图6所示，其中离心管应位于带有磁场的线圈的中心。位于管中心的棕色沉淀物是磁性微凝胶，其在HFMF处理下与溶液分离。 监测和不使用HFMF的磁释放百分比， 如图7所示。与HFMF相同时间段（20分钟）内的释放百分率相比，HFMF处理下释放百分数提高了2.5倍，同时可以将本体溶液的温度提高到50℃以上。由于遏制热敏聚合物，PNIPAAm，磁性微凝胶可以挤出由PNIPAAm聚合物基质变成疏水性，然后在高温（50℃）下共轭的包封药物（Cur）。同时，通过应用HFMF可以释放姜黄素以完成抗癌治疗。即使疏水性Cur被期望在高温下与疏水性PNIPPAm结合，HFMF上的磁感应局部加热可以破坏Cur和PNIPPAm之间的结合。此外，磁性微凝胶的体积变化（从亲水到疏水，较低温度）也会挤出Cur。 记录本体溶液的温度升高，并在图7中显示为具有菱形符号的红色曲线。如图所示，温度首先随着加热时间增加，并在14分钟后稳定。高原应该是饱和的磁感应加热（热疗）在散装水中。然而，局部温度应该足够高以挤出Cur。 <img alt="图1" class="xfigimg" src="/files/ftp_upload/55648/55648fig1.jpg" /> 图1. PNIPAAm / PEI / Fe3O4-NH2微凝胶的示意图合成方法。 将PNIPAAm，Fe 3 O 4 -NH 2和PEI混合在一起，将混合物加热至70℃，以引入微凝胶制剂的H键。 <a href="https://ecsource-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/55648/55648fig1large.jpg" target="_blank">请点击此处查看此图的较大版本。</a> <img alt="图2" class="xfigimg" src="/files/ftp_upload/55648/55648fig2.jpg" /> 图2. PNIPAAm解决方案和磁性微凝胶的TEM图像。 a） PNIPAAm， b） Fe 3 O 4 ， c）PNIPAAm / Fe 3 O 4 ， d） PNIPAAm / Fe 3 O 4 -NH 2 ，和e） Cur-PNIPAAm / Fe 3 O 4 -NH 2 。采用TEM图像监测样品的分散性和形态。在室温下制备TEM样品。 <a href="https://ecsource-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/55648/55648fig2large.jpg" target="_blank">请点击此处查看此图的较大版本。</a> <img alt="图3" class="xfigimg" src="/files/ftp_upload/55648/55648fig3.jpg" /> 图3. PNIPAAm，Fe 3 O 4 -NH 2 ，PNIPAAm / Fe 3 O 4 ，PNIPAAm / Fe 3 O 4 -NH 2和Cur-PNIPAAm / Fe 3 O 4 -NH 2的 FT-IR光谱。将合成的微凝胶与KBr混合并压成颗粒。然后应用FRIR来澄清相互作用of PNIPAAm，Fe 3 O 4 -NH 2 ，PEI和姜黄素通过监测功能组的吸收变化。 <a href="https://ecsource-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/55648/55648fig3large.jpg" target="_blank">请点击此处查看此图的较大版本。</a> <img alt="图4" class="xfigimg" src="/files/ftp_upload/55648/55648fig4.jpg" /> 图4.在LCST下和上方的微凝胶的水分散能力: a） PNIPAAm， b） PNIPAAm / Fe 3 O 4 -NH 2 ，和c） Cur-PNIPAAm / Fe 3 O 4 -NH 2在25℃。 d） PNIPAAm， e） PNIPAAm / Fe 3 O 4 -NH 2 ，和f） Cur-PNIPAAm / Fe 3 O 4 -NH 2在70℃。样品溶液在室温下制备并加热至70℃。照片在RT和70℃下拍摄图，以观察合成的微凝胶的水分散性。 <a href="https://ecsource-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/55648/55648fig4large.jpg" target="_blank">请点击此处查看此图的较大版本。</a> <img alt="图5" class="xfigimg" src="/files/ftp_upload/55648/55648fig5.jpg" /> 图5.用磁铁收集含姜黄素的磁性微凝胶。将Cur-PNIPAAm / Fe 3 O 4 -NH 2分散在水溶液（左）中，并通过磁体（右）收集。 <a href="https://ecsource-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/55648/55648fig5large.jpg" target="_blank">请点击此处查看此图的较大版本。</a> <img alt="图6" class="xfigimg" src="/files/ftp_upload/55648/55648fig6.jpg" /> 图6.用于磁触发的实验装置<html>用HFMF发放。白色环是铜线圈。显示了含有磁性微凝胶的离心管。 <a href="https://ecsource-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/55648/55648fig6large.jpg" target="_blank">请点击此处查看此图的较大版本。</a> <img alt="图7" class="xfigimg" src="/files/ftp_upload/55648/55648fig7.jpg" /> 图7.在pH 7.4下用（方形符号）和无（圆形符号）HFMF控制释放Cur-PNIPAAm / Fe 3 O 4 -NH 2微凝胶。显示了施加HFMF的具有（黑色;正方形）和无（黑色;圆形）的磁性微凝胶的姜黄素释放百分比。具有HFMF的Cur-PNIPAAm / Fe 3 O 4 -NH 2微凝胶的温度升高以红色（菱形）显示。误差条表示SD。="_ blank"&gt;请点击此处查看此图的较大版本。 <table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always"><tbody><tr><td> 样品 </td><td> PNIPAAm（％） </td><td> Fe 3 O 4 （％） </td></tr><tr><td> PNIPAAm / Fe 3 O 4 </td><td> 32.37 </td><td> 68.63（Fe 3 O 4 ） </td></tr><tr><td> PNIPAAm / Fe 3 O 4 -NH 2 </td><td> 68.56 </td><td> 31.44（Fe 3 O 4 -NH 2 ） </td></tr></tbody></table> 表1.微凝胶中磁性纳米颗粒和PNIPAAm的相对组成（重量％）。使用TGA分析计算磁性微凝胶的相对组成。

Watch this Scientific Journal Video about Magnetic and Thermal-sensitive PolyN-isopropylacrylamide-based Microgels for Magnetically Triggered Controlled Release at JoVE.com

Magnetic and Thermal-sensitive PolyN-isopropylacrylamide-based Microgels for Magnetically Triggered Controlled Release

该手稿描述了通过温度诱导的乳液制备磁性和热敏性微凝胶而没有化学反应。通过混合聚（ N-异丙基丙烯酰胺）（PNIPAAm），聚乙烯亚胺（PEI）和Fe 3 O 4 -NH 2纳米粒子来合成这些敏感微凝胶，用于磁和热触发药物释放的潜在用途。

磁性和热敏性聚（<em&gt;ñ</em基于异丙基丙烯酰胺）的微凝胶用于磁触发控制释放

Magnetically and thermally sensitive poly(N-isopropylacrylamide) (PNIPAAm)/Fe3O4-NH2 microgels with the encapsulated anti-cancer drug curcumin (Cur) were ...

magnetic-thermal-sensitive-poly-n-isopropylacrylamide-based-microgels

Nanyang Technological University

Research

JoVE Journal

Bioengineering

Magnetic and Thermal-sensitive Poly(N-isopropylacrylamide)-based Microgels for Magnetically Triggered Controlled Release

8.8K 次观看.  National Taiwan University. 该手稿描述了通过温度诱导的乳液制备磁性和热敏性微凝胶而没有化学反应。通过混合聚（ N-异丙基丙烯酰胺）（PNIPAAm），聚乙烯亚胺（PEI）和Fe 3 O 4 -NH 2纳米粒子来合成这些敏感微凝胶，用于磁和热触发药物释放的潜在用途。 

视频: Magnetic and Thermal-sensitive PolyN-isopropylacrylamide-based Microgels for Magnetically Triggered Controlled Release

Magnetically-Assisted Remote Controlled Microcatheter Tip Deflection under Magnetic Resonance Imaging

X-ray fluoroscopy-guided endovascular procedures have several significant limitations, including difficult catheter navigation and use of ionizing radiation, which can potentially be overcome using a magnetically steerable catheter under MR guidance.
	The main goal of this work is to develop a microcatheter whose tip can be remotely controlled using the magnetic field of the MR scanner. This protocol aims to describe the procedures for applying current to the microcoil-tipped microcatheter to produce consistent and controllable deflections.
	A microcoil was fabricated using laser lathe lithography onto a polyimide-tipped endovascular catheter. In vitro testing was performed in a waterbath and vessel phantom under the guidance of a 1.5-T MR system using steady-state free precession (SSFP) sequencing. Various amounts of current were applied to the coils of the microcatheter to produce measureable tip deflections and navigate in vascular phantoms.
	The development of this device provides a platform for future testing and opportunity to revolutionize the endovascular interventional MRI environment.

Current applied to an endovascular microcatheter with microcoil tip made by laser lathe lithography can achieve controllable deflections under magnetic resonance (MR) guidance, which may improve speed and efficacy of navigation of vasculature during various endovascular procedures.

磁力辅助的远程控制微导管尖端偏转根据磁共振成像

X-ray fluoroscopy-guided  endovascular procedures have several significant limitations, including  difficult catheter navigation and use of ionizing ...

科研

生物工程

Characteristics of Precipitation-formed Polyethylene Glycol Microgels Are Controlled by Molecular Weight of Reactants

This work describes the formation of poly(ethylene glycol) (PEG) microgels via a photopolymerized precipitation reaction. Precipitation reactions offer several advantages over traditional microsphere fabrication techniques. Contrary to emulsion, suspension, and dispersion techniques, microgels formed by precipitation are of uniform shape and size, i.e.&#160;low polydispersity index, without the use of organic solvents or stabilizers. The mild conditions of the precipitation reaction, customizable properties of the microgels, and low viscosity for injections make them applicable for in vivo purposes. Unlike other fabrication techniques, microgel characteristics can be modified by changing the starting polymer molecular weight. Increasing the starting PEG molecular weight increased microgel diameter and swelling ratio. Further modifications are suggested such as encapsulating molecules during microgel crosslinking. Simple adaptations to the PEG microgel building blocks are explored for future applications of microgels as drug delivery vehicles and tissue engineering scaffolds.

This work describes the formation of poly(ethylene glycol) (PEG) microgels via a photopolymerized precipitation reaction. Increasing the PEG molecular weight increased microgel diameter and swelling ratio. Simple adaptations to the PEG microgel precipitation reaction are explored for future applications of microgels as drug delivery vehicles and tissue engineering scaffolds.

This work describes the formation of poly(ethylene glycol) (PEG) microgels via a photopolymerized precipitation reaction. Precipitation reactions offer ...

Imaging Denatured Collagen Strands In vivo and Ex vivo via Photo-triggered Hybridization of Caged Collagen Mimetic Peptides

Collagen is a major structural component of the extracellular matrix that supports tissue formation and maintenance. Although collagen remodeling is an integral part of normal tissue renewal, excessive amount of remodeling activity is involved in tumors, arthritis, and many other pathological conditions. During collagen remodeling, the triple helical structure of collagen molecules is disrupted by proteases in the extracellular environment. In addition, collagens present in many histological tissue samples are partially denatured by the fixation and preservation processes. Therefore, these denatured collagen strands can serve as effective targets for biological imaging. We previously developed a caged collagen mimetic peptide (CMP) that can be photo-triggered to hybridize with denatured collagen strands by forming triple helical structure, which is unique to collagens. The overall goals of this procedure are i)&#160;to image denatured collagen strands resulting from normal remodeling activities in vivo, and ii) to visualize collagens in ex vivo tissue sections using the photo-triggered caged CMPs. To achieve effective hybridization and successful in vivo and ex vivo imaging, fluorescently labeled caged CMPs are either photo-activated immediately before intravenous injection, or are directly activated on tissue sections. Normal skeletal collagen remolding in nude mice and collagens in prefixed mouse cornea tissue sections are imaged in this procedure. The imaging method based on the CMP-collagen hybridization technology presented here could lead to deeper understanding of the tissue remodeling process, as well as allow development of new diagnostics for diseases associated with high collagen remodeling activity.

Imaging Denatured Collagen Strands In vivo and Ex vivo via Photo-triggered Hybridization of Caged Collagen Mimetic Peptides

This procedure demonstrates in vivo near IR fluorescence imaging of collagen remodeling activities in mice as well as ex vivo staining of collagens in tissue sections using caged collagen mimetic peptides that can be photo-triggered to hybridize with denatured collagen strands.

成像变性的胶原股<em&gt;在体内</em&gt;和<em&gt;体外</em&gt;通过光引发杂交笼胶原蛋白仿生肽

Collagen is a major structural component of the extracellular matrix that supports tissue formation and maintenance. Although collagen remodeling is an ...

Magnetic Tweezers for the Measurement of Twist and Torque

Single-molecule techniques make it possible to investigate the behavior of individual biological molecules in solution in real time. These techniques include so-called force spectroscopy approaches such as atomic force microscopy, optical tweezers, flow stretching, and magnetic tweezers. Amongst these approaches, magnetic tweezers have distinguished themselves by their ability to apply torque while maintaining a constant stretching force. Here, it is illustrated how such a &#8220;conventional&#8221; magnetic tweezers experimental configuration can, through a straightforward modification of its field configuration to minimize the magnitude of the transverse field, be adapted to measure the degree of twist in a biological molecule. The resulting configuration is termed the freely-orbiting magnetic tweezers. Additionally, it is shown how further modification of the field configuration can yield a transverse field with a magnitude intermediate between that of the &#8220;conventional&#8221; magnetic tweezers and the freely-orbiting magnetic tweezers, which makes it possible to directly measure the torque stored in a biological molecule. This configuration is termed the magnetic torque tweezers. The accompanying video explains in detail how the conversion of conventional magnetic tweezers into freely-orbiting magnetic tweezers and magnetic torque tweezers can be accomplished, and demonstrates the use of these techniques. These adaptations maintain all the strengths of conventional magnetic tweezers while greatly expanding the versatility of this powerful instrument.

Magnetic tweezers, a powerful single-molecule manipulation technique, can be adapted for the direct measurements of the twist (using a configuration called freely-orbiting magnetic tweezers) and torque (using a configuration termed magnetic torque tweezers) in biological macromolecules. Guidelines for performing such measurements are given, including applications to the study of DNA and associated nucleo-protein filaments.

磁性镊子的扭曲和扭矩的测量

Single-molecule techniques make it possible to investigate the behavior of individual biological molecules in solution in real time. These techniques ...

Custom-designed Laser-based Heating Apparatus for Triggered Release of Cisplatin from Thermosensitive Liposomes with Magnetic Resonance Image Guidance

Liposomes have been employed as drug delivery systems to target solid tumors through exploitation of the enhanced permeability and retention (EPR) effect resulting in significant reductions in systemic toxicity. Nonetheless, insufficient release of encapsulated drug from liposomes has limited their clinical efficacy. Temperature-sensitive liposomes have been engineered to provide site-specific release of drug in order to overcome the problem of limited tumor drug bioavailability. Our lab has designed and developed a heat-activated thermosensitive liposome formulation of cisplatin (CDDP), known as HTLC, to provide triggered release of CDDP at solid tumors. Heat-activated delivery in vivo was achieved in murine models using a custom-built laser-based heating apparatus that provides a conformal heating pattern at the tumor site as confirmed by MR thermometry (MRT). A fiber optic temperature monitoring device was used to measure the temperature in real-time during the entire heating period with online adjustment of heat delivery by alternating the laser power. Drug delivery was optimized under magnetic resonance (MR) image guidance by co-encapsulation of an MR contrast agent (i.e.,&#160;gadoteridol) along with CDDP into the thermosensitive liposomes as a means to validate the heating protocol and to assess tumor accumulation. The heating protocol consisted of a preheating period of 5 min prior to administration of HTLC and 20 min heating post-injection. This heating protocol resulted in effective release of the encapsulated agents with the highest MR signal change observed in the heated tumor in comparison to the unheated tumor and muscle. This study demonstrated the successful application of the laser-based heating apparatus for preclinical thermosensitive liposome development and the importance of MR-guided validation of the heating protocol for optimization of drug delivery.

AN MRI-compatible&#160;custom-designed laser-based heating apparatus has been developed to provide local heating of subcutaneous tumors in order to activate release of agents from thermosensitive liposomes specifically at the tumor region.

定制设计的基于激光的加热装置顺铂触发释放的热敏脂质体与磁共振成像制导

Liposomes have been employed as drug delivery systems to target solid tumors through exploitation of the enhanced permeability and retention (EPR) effect ...

Composite Scaffolds of Interfacial Polyelectrolyte Fibers for Temporally Controlled Release of Biomolecules

Various scaffolds used in tissue engineering require a controlled biochemical environment to mimic the physiological cell niche. Interfacial polyelectrolyte complexation (IPC) fibers can be used for controlled delivery of various biological agents such as small molecule drugs, cells, proteins and growth factors. The simplicity of the methodology in making IPC fibers gives flexibility in its application for controlled biomolecule delivery. Here, we describe a method of incorporating IPC fibers into two different polymeric scaffolds, hydrophilic polysaccharide and hydrophobic polycaprolactone, to create a multi-component composite scaffold. We showed that IPC fibers can be easily embedded into these polymeric structures, enhancing the capability for sustained release and improved preservation of biomolecules. We also created a composite polymeric scaffold with topographical cues and sustained biochemical release that can have synergistic effects on cell behavior. Composite polymeric scaffolds with IPC fibers represent a novel and simple method of recreating the cellular niche.

Scaffolds for tissue engineering need to recapitulate the complex biochemical and biophysical microenvironment of the cellular niche. Here, we show the use of interfacial polyelectrolyte complexation fibers as a platform to create composite, multi-component polymeric scaffolds with sustained biochemical release.

界面聚电解质纤维的生物分子在时间控释复合支架

Various scaffolds used in tissue engineering require a controlled biochemical environment to mimic the physiological cell niche. Interfacial ...

Alternating Magnetic Field-Responsive Hybrid Gelatin Microgels for Controlled Drug Release

Magnetically-responsive nano/micro-engineered biomaterials that enable a tightly controlled, on-demand drug delivery have been developed as new types of smart soft devices for biomedical applications. Although a number of magnetically-responsive drug delivery systems have demonstrated efficacies through either in vitro proof of concept studies or in vivo preclinical applications, their use in clinical settings is still limited by their insufficient biocompatibility or biodegradability. Additionally, many of the existing platforms rely on sophisticated techniques for their fabrications. We recently demonstrated the fabrication of biodegradable, gelatin-based thermo-responsive microgel by physically entrapping poly(N-isopropylacrylamide-co-acrylamide) chains as a minor component within a three-dimensional gelatin network. In this study, we present a facile method to fabricate a biodegradable drug release platform that enables a magneto-thermally triggered drug release. This was achieved by incorporating superparamagnetic iron oxide nanoparticles and thermo-responsive polymers within gelatin-based colloidal microgels, in conjunction with an alternating magnetic field application system.

We present a facile method to fabricate a biodegradable gelatin-based drug release platform that is magneto-thermally responsive. This was achieved by incorporating superparamagnetic iron oxide nanoparticles and poly(N-isopropylacrylamide-co-acrylamide) within a spherical gelatin micro-network crosslinked by genipin, in conjunction with an alternating magnetic field application system.

交变磁场敏感的混合明胶微凝胶药物控释

Magnetically-responsive nano/micro-engineered biomaterials that enable a tightly controlled, on-demand drug delivery have been developed as new types of ...

An Additive Manufacturing Technique for the Facile and Rapid Fabrication of Hydrogel-based Micromachines with Magnetically Responsive Components

Polyethylene glycol (PEG)-based hydrogels are biocompatible hydrogels that have been approved for use in humans by the FDA. Typical PEG-based hydrogels have simple monolithic architectures and often function as scaffolding materials for tissue engineering applications. More sophisticated structures typically take a long time to fabricate and do not contain moving components. This protocol describes a photolithography method that allows for facile and rapid microfabrication of PEG structures and devices. This strategy involves an in-house developed fabrication stage that allows for the rapid fabrication of 3D structures by building upwards in a layer-by-layer fashion. Independent moving components can also be aligned and assembled onto support structures to form integrated devices. These independent components are doped with superparamagnetic iron oxide nanoparticles that are sensitive to magnetic actuation. In this manner, the fabricated devices can be actuated using external magnets to yield movement of the components within. Hence, this technique allows for the fabrication of sophisticated MEMS-like devices (micromachines) that are composed entirely out of a biocompatible hydrogel, able to function without an onboard power source, and respond to a contact-less method of actuation. This manuscript describes the fabrication of both the fabrication set-up as well as the step-by-step method for the microfabrication of these hydrogels-based MEMS-like devices.

An additive manufacturing strategy for processing UV-crosslinkable hydrogels has been developed. This strategy allows for the layer-by-layer assembly of microfabricated hydrogel structures as well as the assembly of independent components, yielding integrated devices containing moving components that are responsive to magnetic actuation.

一种简便快速制备磁响应元件的水凝胶基微型机械的添加剂制造技术

Polyethylene glycol (PEG)-based hydrogels are biocompatible hydrogels that have been approved for use in humans by the FDA. Typical PEG-based hydrogels ...

Magnetic-, Acoustic-, and Optical-Triple-Responsive Microbubbles for Magnetic Hyperthermia and Pothotothermal Combination Cancer Therapy

The precision delivery of anti-cancer agents which aim for targeted and deep-penetrated delivery as well as a controlled release at the tumor site has been challenged. Here, we fabricate iron oxide nanoparticle shelled microbubbles (NSMs) through self-assembly, synergizing magnetic, acoustic, and optical responsiveness in one nanotherapeutic platform. Iron oxide nanoparticles serve as both magnetic and photothermal agents. Once intravenously injected, NSMs can be magnetically guided to the tumor site. Ultrasound triggers the release of iron oxide nanoparticles, facilitating the penetration of nanoparticles deep into the tumor due to the cavitation effect of microbubbles. Thereafter, magnetic hyperthermia and photothermal therapy can be performed on the tumor for combinational cancer therapy, a solution for cancer resistance due to the tumor heterogeneity. In this protocol, the synthesis and characterization of NSMs including structural, chemical, magnetic and acoustic properties were performed. In addition, the anti-cancer efficacy by thermal therapy was investigated using in vitro cell cultures. The proposed delivery strategy and combination therapy holds great promise in cancer treatment to improve both delivery and anticancer efficacies.

Presented here is a protocol for the fabrication of iron oxide nanoparticle-shelled microbubbles (NSMs) through self-assembly, synergizing magnetic, acoustic, and optical responsiveness in one nanotherapeutic platform for magnetic hyperthermia and photothermal combination cancer therapy.

磁性、声学和光学三响应性微泡，用于磁性高温和波托托热组合癌症治疗

The precision delivery of anti-cancer agents which aim for targeted and deep-penetrated delivery as well as a controlled release at the tumor site has ...

Low-Cost, Volume-Controlled Dipstick Urinalysis for Home-Testing

Dipstick urinalysis provides quick and affordable estimations of multiple physiological conditions but requires good technique and training to use accurately. Manual performance of dipstick urinalysis relies on good human color vision, proper lighting control, and error-prone, time-sensitive comparisons to chart colors. By automating the key steps in the dipstick urinalysis test, potential sources of error can be eliminated, allowing self-testing at home. We describe the steps necessary to create a customizable device to perform automated urinalysis testing in any environment. The device is cheap to manufacture and simple to assemble. We describe the key steps involved in customizing it for the dipstick of choice and for customizing a mobile phone app to analyze the results. We demonstrate its use to perform urinalysis and discuss the critical measurements and fabrication steps necessary to ensure robust operation. We then compare the proposed method to the dip-and-wipe method, the gold standard technique for dipstick urinalysis.

Dipstick urinalysis is a quick and affordable method of assessing one&#8217;s personal state of health. We present a method to perform accurate, low-cost dipstick urinalysis that removes the primary sources of error associated with traditional dip-and-wipe protocols and is simple enough to be performed by lay users at home.