CN117500526A - 从体液中去除生物合成纳米颗粒的组合物和方法 - Google Patents
从体液中去除生物合成纳米颗粒的组合物和方法 Download PDFInfo
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Abstract
诱饵和捕获方法及组合物，用于从体液中去除生物合成纳米颗粒。生物合成纳米颗粒与一半的诱饵诱捕，捕获复合物并冻干。诱捕的生物合成纳米颗粒被复溶并施用于受试者用于诊断或治疗目的。为了从身体中去除生物合成纳米颗粒，将含有诱捕的生物合成纳米颗粒的体液与诱饵和捕获复合物的捕获部分接触。已去除生物合成纳米颗粒的体液可返还受试者。
Description
技术领域
本发明涉及从体液和其他溶液中去除和/或分离生物合成纳米颗粒的方法和组合物。
背景技术
当库存血不可用或不符合需要时，需要使用人工氧(O2)载体。为了满足这一需求，发明人开发了一种首创的生物合成纳米细胞血液替代品ErythroMer(EM)。EM是自组装、可变形、基于杂交的脂质-低聚物纳米颗粒，包含每颗粒有效载荷高的血红蛋白(Hb)(图1)。“人工细胞”设计产生了一个原型，模拟红细胞(RBC)生理学的关键元素，代表了输血医学的创新补充。迄今为止，开发基于Hb的氧载体(HBOC)的努力因为设计缺陷失败，所述设计缺陷不能保护RBC的生理性相互作用，特别是：HBOC在肺中捕获O2，但不能有效地向组织释放O2，以及HBOC捕获内皮一氧化氮(NO)，导致血管收缩。EM设计(图1)通过以下方式克服了这些弱点：1)将Hb包封在具有新颖的几何形状的纳米颗粒中，具有优化的表面积与体积比；2)用设计新型小分子穿梭机控制O2捕获/释放，以降低Hb O2亲和力(RSR13，乙丙昔罗)；3)通过外壳特性减弱NO的摄取，4)通过共同包装还原系统来延缓高铁血红蛋白(metHb)的形成。此外，5)EM被设计为无菌冻干形式，并且在长时间的室温干燥储存后易于复溶。EM为复杂的需求提供了一种实用的方法，并旨在实现性价比高的规模化生产。
EM原型通过了严格的初始体外和体内“概念验证”测试。在一个新的小鼠模型中证明了O2递送，该模型使用转基因缺氧诱导因子(HIF-1α)生物发光构建体报告了输血后细胞O2递送。EM也在出血性休克和多发创伤的兔子模型中得到了验证。
发明内容
由于EM将无细胞形式的血红蛋白引入循环的血浆部分，因此由于血清和血浆颜色干扰或纳米颗粒外壳本身，给临床实验室带来了独特的挑战。在体内出现ErythroMer期间获得的血液样本出现了溶血。尽管溶血是临床实验室中一个众所周知的问题，但接受ErythroMer的患者可能达到了超过典型溶血患者的游离血红蛋白浓度。此外，ErythroMer是一种纳米颗粒，可能会影响光散射分析方法，在分析过程中无法实际避免，除非以在分析前形成空白或完全去除颗粒。
EM被设计用于主要在损伤点使用，以过渡到临床环境，并在那里提供进一步救生护理。为了在临床环境中管理创伤，进行全血细胞计数(CBC)和综合代谢检查(CMP)以评估血液中各种细胞、蛋白质和物质的数量和浓度，这些细胞、蛋白质和物质通过向身体其他部位输送氧气和能量影响血液急性维持生命的能力。血红蛋白丰度(携氧能力)、血小板丰度(凝血能力)和血细胞比容(血红蛋白占全血的百分比)的评估受EM影响。每15至30分钟对失血患者进行一次这些评估，并考虑血压的变化，以确定临床环境中进一步输血的需要。初步数据显示EM强烈干扰用于确定CBC(图2B)和CMP(图2A，C)的光学方法。因此，迫切需要一种从血液样本中选择性去除EM的策略。
本发明旨在制定一种稳健的“诱饵和捕获”策略，以基于金刚烷(“ADM”)和β-CD的宿主-客体相互作用的超分子组装，有效地从全血样本中去除EM。该靶向捕获策略包括将金刚烷标记为“诱饵”和β-CD官能化的PS珠作为捕获模型。(图4)根据本发明，具有ADM官能基的EM在树脂上形成具有表面丰富β-CD官能基的强包涵体复合物，并允许从血液中选择性去除EM。ADM和β-CD作为“诱饵和捕获”对的选择是经过深思熟虑的，因为它们具有很强的结合亲和力(K＝5.2×104M-1)和优异的生物相容性。已知碳质的ADM诱导最小的生物应答，而与其他普遍存在的生物物质(如人血清白蛋白、球蛋白等)相比，β-CD与分子形成更强的包涵体复合物。
根据本发明的进一步实施方案，金刚烷标记的EM被冻干以包装、运输和/或储存。冻干的金刚烷诱饵EM是一种粉末，包括EM两亲性前体、胆固醇和PEG-PE血红蛋白以及别构效应物、金刚烷标签，可选地还包括冷冻保护剂。通过用PBS/水简单混合实现原始EM生产浓度(或浓缩)的复溶。
因此，本发明提出了一种独特设计的靶向捕获策略，以解决从全血样本中去除EM的未满足需求，以临床监测血样。尽管有上述内容和本文提供的实施例，可以理解，本文所述靶向捕获策略和组合物可用于从全血、其他体液和任何其他溶液中去除任何类型的生物合成纳米颗粒。例如，本发明的冻干诱饵标记的EM组合物可以以预填充管或其他容器的形式包装、储存或运输，以便在使用现场进行复溶。类似地，捕获的组合物可以包装成血液灌流盒的形式，用于通过体外回路(例如透析系统、CPB系统等)从活体患者的血流中去除标记的EM。此外，捕获组合物可用于从离体器官/类器官制剂的灌流液中去除标记的EM。
附图说明
图1A和1B示出了，相对于HBOC，ErythroMer(EM)V2设计、特征和益处，其中两亲前体包括(a)控制别构效应物(RSR13)可用性的pH响应性基团，实现O2结合的情境响应性控制，以及(b)带负电荷的“头部”，促进外筋膜表面生物相容性。所述构建体模拟内源性生物分子，并在体内酶消化和完全降解为与“天然”肽和脂质相同的最终产物。
图2示出了EM干扰结果：有EM和无EM的人血浆的(A)代谢检查和(B)CBC检查；(C)叠加代谢检查光谱扫描(overlaid metabolic panel spectral scan)(300-900nm)。
图3示出了根据本发明实施方案的诱饵和捕获设计策略。两亲前体KC01003将与金刚烷-PE(4)共同自组装，以制备表面具有“诱饵”官能基的EM-1003。优化表面覆盖被优化以具有最小数量的“诱饵”分子，以避免不利的生物效应。柱填充有与β-环糊精官能基连接的聚苯乙烯(PS)珠。金刚烷和β-环糊精之间通过宿主-客体化学的高度选择性相互作用使EM从血液有效分离。
图4A示出了合成“诱饵”组分金刚烷官能化DPPE(ADM-DPPE)的方案。
图4B示出了捕获剂β-环糊精官能化PS珠(CD-PS)的合成方案。
图5示出了PS珠(与芘一起孵育；珠大小0.98nm)上β-DC官能化的确认。
图6A示出了使用纳米颗粒跟踪分析(ZetaView)通过颗粒计数对EM捕获的确认。
图6B示出了使用纳米颗粒跟踪分析(ZetaView)捕获后通过直径对EM捕获的确认。
图7示出了根据本发明的实施方案的冻干和最终冻干AM标记的EM产品。
图8示出了根据本发明的实施方案，AM标记的EM颗粒在冻干前、复溶4天后和复溶14天后的各种特征。
具体实施方式
根据本发明的实施方案，提出了一种生物工程的和可扩展的方法，用于从全血样本中去除EM。(图3)所提出的超分子方法提供了几个优点，例如：(i)在环境条件下容易形成包涵体复合物，使得在不引入任何特殊遗传学或生化技术的情况下进行试点规模研究成为可能；(ii)相对较小的分子金刚烷(“ADM”)标记预计对EM结构和功能几乎没有影响，和(iii)聚苯乙烯(PS)珠上β-环糊精(β-CD)官能化的最佳比率使柱子珠子的孔径产生微不足道的变化，从而安全清除血流。本发明将为人工RBC的翻译铺平道路。根据本发明的进一步实施方案，诱饵和捕获设计针对护理点处的可用性进行了优化。这涉及从患者血液样本中有效去除ErythroMer的机制，对现有血液采集和样本处理技术的干扰最小，包括定制现有的血液收集管，以便能够捕获并保留管本身中的ErythroMer，使全血成分免于进一步分析。这需要血液采集管中固定捕获系统的全面开发，滴定到一个浓度以有效地从血液中特异性地和完全地去除EM，并牢记具有特殊捕获功能的血液采集管是可扩展的，可以在对现有制造方法进行最小改造的情况下进行商业制造。同时，诱饵与ErythroMer的最终和最稳定形式的冷冻干燥过程兼容。
呈现有“诱饵”官能基的EM的设计、合成和物理化学表征。
实施例1：设计和合成“诱饵”标记的EM。制备了ADM标记的EM，并用含β-CD的树脂对小分子和纳米颗粒进行了超分子宿主-客体化学的物理化学表征。使用1-金刚烷羧酸N-羟基琥珀酰亚胺酯(ADM-NHS)用ADM标签对氨基(-NH2)基团1,2-二棕榈酰-sn-丙三基-3-磷酸乙醇胺(DPPE)进行官能化。(图4A)对这种化合物ADM-DPPE的纯度进行了分析表征，并以不同的摩尔比引入EM的纳米组装中。然后基于两个参数确定EM颗粒上ADM-DPPE标签的最佳浓度：(i)最高结合能力和(ii)最佳Hb包封效率。因此，具有不同ADM-标记比例的制剂首先与固定浓度的β-CD相互作用，并根据各自的等温量热曲线计算标记的EM颗粒的结合能力。选择结合效率最高的颗粒，并且ADM标记的浓度作为最佳颗粒的浓度。其次，将该优化的EM颗粒装载血红蛋白，并计算包封效率。
实施例2：物理化学特性。我们评估流体动力学粒径、多分散性、电泳电位、TEM、AFM和稳定性。为了确定EM-1003诱饵的长期储存稳定性，在-20℃、5℃、25℃，以及40℃的加速条件下进行了为期12个月的研究(冻干EM分布在玻璃盘上，以具有薄均匀层)。热(干热)加速应力稳定性分析在40℃、50℃和60℃下进行12个月，在80℃下进行一个月。在酸性(0.1MHCl:pH 1；0.01M HCl:pH 2；HCl:pH 4.5)和碱性(0.1MNaOH:pH 13；0.01M NaOH:pH 12)条件下，EM在25℃和40℃下也受到热应力长达7天。所有溶液的pH值均使用pH计于室温下测量。使用纳米尺寸仪ZS和ZetaView测量不同时间间隔内粒径和胶体稳定性。
“捕获”树脂的开发和表征以及分离能力的证明。
实施例3：捕获树脂的制备和表征：β-环糊精由于其水溶性、低细胞毒性和优越的生物相容性，经常用作宿主-客体超分子组件中的宿主载体。在这种情况下，我们更喜欢ADM/β-CD宿主-客体对作为良好建立的超分子系统。单-6-O-(对甲苯磺酰基)-β-环糊精由1-(对甲苯磺酰基)咪唑和β-环糊精合成。该化合物随后用于氨基聚苯乙烯(NH2-PS)珠的官能化，以在温和碱性条件下产生β-环糊精化PS(CD-PS)珠。(图4B)为了证实PS珠与β-环糊精的成功官能化，将CD-PS珠与芘的乙醇溶液混合，在10000rcf下离心2分钟，用乙醇洗涤两次以去除任何游离芘，然后在荧光显微镜下成像以将官能化珠的荧光可视化。成功官能化的PS珠显示高绿光发射，而未官能化珠不显示任何背景荧光。(图5)这证实了捕获树脂的成功制备，准备用ADM-DPPE标记的EM颗粒进行测试。
实施例4：从EM和血液混合物中EM捕获的证明：为了证明CD-PS珠介导的EM捕获，制备了带有荧光NBD-PE掺杂的优化的ADM标记的EM颗粒。以类似的方式，用这些荧光标记的EM颗粒处理CD-PS珠，悬浮在缓冲液中，离心，洗涤并在荧光显微镜下成像。在成功验证CD-PS珠捕获EM颗粒后，用血红蛋白加载ADM标记的EM颗粒。Hb加载的ADM标记的EM颗粒随后与血液一起悬浮，并从全血样本中监测EM颗粒的捕获。
实施例5：EM表面的证明和优化：通过pH滴定计算β-CD对PS珠的官能化百分比。比较了未官能化氨基PS珠和CD-PS珠之间中和pH的变化，并计算了每克PS珠β-CD的官能化百分比。然后，通过控制与氨基PS珠反应的单-6-O-(对甲苯磺酰基)-β-环糊精的浓度，来改变每克PS珠的β-CD比例。然后根据从全血样本中去除EM的最大效率选择β-CD最佳浓度。
实施例6：初步生物相容性研究。进行了初步补体活化分析和血液涂片制备研究。CH50酶免疫测定法(EIA)(Sigma)用于评估向人血清中添加EM-1003诱饵后的补体活化程度。根据制造商方案使用该试剂盒。进行血液涂片制备，以使用临床显微镜技术(常规光显微镜)，在高倍视野下观察淋巴细胞的形态变化和血液凝集。特别注意观察用EM-1003和EM-1003诱饵处理的血细胞的显著凝集或形态变化(血液：NP＝9:1)。
预期结果和风险因素。合成了表面具有ADM官能基团的EM颗粒。单-6-O-(对甲苯磺酰基)-β-环糊精由1-(对甲苯磺酰基)咪唑和β-CD合成，用于氨基聚苯乙烯(NH2-PS)珠的官能化以产生CD-PS珠。本发明验证了具有和不具有Hb包封的CD-PS珠对EM颗粒的捕获。加载有Hb的Ad标记的EM颗粒与血液一起悬浮，并监测EM颗粒的捕获。进一步的CBC和代谢检查分析旨在确认EM干扰的成功消失。本发明的超分子方法带来了许多优点，例如(i)在环境条件下容易形成包涵体复合物，使得在不引入任何特殊遗传学或生化技术的情况下进行试点规模研究成为可能；(ii)相对较小的ADM标记预计对EM结构和功能几乎没有影响，以及(iii)PS珠上β-CD官能化的最佳比率使柱子珠的孔径产生微不足道的变化，从而安全清除血流。
从我们的初步捕获研究中，发现EM被捕获树脂成功捕获。(图6)观察到，只有当用β-CD标记的捕获树脂处理时，EM颗粒的平均数量才会减少。CD-PS浓度的增加显著降低了EM颗粒(图6A)。进一步观察到，在β-CD标记的树脂介导的成功捕获后，EM颗粒的平均流体动力学直径增加(图6B)。如果EM稳定性成为一个问题，则可以优化“诱饵”官能基团以达到最大稳定性。
金刚烷标记的EM是冻干的，用于包装、运输和/或储存。冻干金刚烷诱饵EM是一种粉末，包括EM两亲性前体、胆固醇和PEG-PE血红蛋白以及别构效应物、金刚烷标记，可选地还包括冷冻保护剂。通过用PBS/水简单混合和温和涡流/搅拌，实现对原始EM生产浓度(或浓缩)的复溶。
值得注意的是，本文的诱饵和捕获方法及组合物可被用于从任何体液或其组成部分中去除任何类型的生物合成纳米颗粒。
虽然已在附图中描述和示出了当前发明的几个实施方案和方法，但本发明不旨在局限于此，因为其意图是本发明在范围上与本领域所允许的一样宽，并且说明书也被同样地解读。因此，上述说明不应作为限制，而应仅作为特定实施方案和方法的示例。本领域技术人员可以预见在本文所附权利要求范围内进行的其他修改。
Claims (9)
1.一种化合物，具有以下化学式：
2.一种组合物，包含权利要求1所述的化合物和生物合成纳米颗粒，其中权利要求1所述的化合物的金刚烷官能基团位于生物合成纳米颗粒的表面。
3.权利要求1所述的组合物，其中生物合成纳米颗粒是生物合成纳米细胞血液替代物。
4.一种冻干组合物，包含权利要求1所述的化合物和生物合成纳米颗粒，其中权利要求1所述的化合物的官能基团位于生物合成纳米颗粒血液替代物的表面。
5.根据权利要求4所述的冻干组合物，其中所述生物合成纳米颗粒是生物合成纳米细胞血液替代物。
6.一种组合物，包含单-6-O-(对甲苯磺酰基)-β-环糊精和氨基聚苯乙烯珠。
7.一种从体液中去除生物合成纳米颗粒的方法，包括将权利要求1所述的化合物络合到生物合成纳米颗粒，将与权利要求1所述的化合物络合的生物合成纳米颗粒施用于受试者，并随后用单-6-O-(对甲苯磺酰基)-β-环糊精官能化聚苯乙烯珠接触体液，以从所述体液中除去与权利要求1所述的化合物络合的所述生物合成纳米颗粒。
8.根据权利要求7所述的方法，其中生物合成纳米颗粒是生物合成纳米细胞血液替代物，所述体液是全血。
9.根据权利要求7所述的方法，进一步包括将所述络合步骤的结果冻干以包装和运输，并在所述施用步骤之前复溶所述冻干步骤的结果。
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| AU2014259617B2 (en) * | 2013-05-03 | 2019-04-11 | Washington University | Blood substitute composition and method of use |
| US11324827B2 (en) * | 2014-10-01 | 2022-05-10 | Xiamen Sinopeg Biotech Co., Ltd. | Multifunctionalized polyethylene glycol derivative and preparation method therefor |
| CN104877127B (zh) * | 2015-06-23 | 2017-11-10 | 厦门赛诺邦格生物科技股份有限公司 | 一种八臂聚乙二醇衍生物、制备方法及其修饰的生物相关物质 |
| CN111134116B (zh) * | 2020-01-02 | 2021-10-26 | 中化化工科学技术研究总院有限公司 | 一种甲维盐水分散粒剂及其制备方法 |
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| WO2022192619A1 (en) | 2022-09-15 |
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| IL305815A (en) | 2023-11-01 |
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