CN1164829A - 将分子导入细胞溶质 - Google Patents
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Abstract
描述了一种将分子释放入细胞溶质中但并不杀死大多数细胞的方法，它允许由核内体，溶酶体或其它细胞分隔腔摄取该分子并用光激活光敏化合物以使核内体，溶酶体或其它的细胞分隔腔的膜的破裂。
Description
本发明涉及一种将分子导入细胞的方法，即通过光动力学处理，在不大量杀伤细胞的情况下，破坏核内体和溶酶体膜，将分子导入细胞。
多数分子并不容易通过细胞膜。将分子导入活细胞溶质的方法是调控和研究生物学过程的有用工具。现今，最常用的方法包括显微注射，红细胞血影介导的融合及脂质体融合，胞饮小体的渗透性溶解，刮擦负荷试验，电穿孔，磷酸钙和病毒介导的转染方法。这些技术对于研究培养中的细胞是有用的，尽管在许多情况下并不实际，可能导致时间消耗，无法有效导入或诱导显著的细胞死亡。因此，这些技术对于那些细胞需要保持功能的生物学。医学研究或治疗并不是最好的方法。
众所周知，卟啉及许多其它光敏化合物可诱导对细胞和组织的细胞毒作用。这些作用是根据当光敏化合物在光照情况下会释放单线态氧(′O2)，单线态氧分解细胞膜和细胞结构，如果损伤广泛，最终会杀死细胞。这种作用已被用于几种肿瘤疾病的治疗。此治疗命名为光动力学疗法(PDT)，先注射一种光敏感的并具有肿瘤定位能力的染料，接着用光照射肿瘤区域。这种细胞毒作用主要是通过单线态氧的形成来介导的。这个活性中间产物在细胞中有一个非常短的寿命(＜0.04μs)。这样，PDT主要的细胞毒作用在光照下被执行，并且非常靠近于′O2的形成位点。′O2和蛋白质(组氨酸，色氨酸，蛋氨酸，半胱氨酸，酪氨酸)，DNA(鸟嘌呤)，不饱和脂肪酸，胆固酸反应并氧化它们。PDT的优点之一是未暴露于光下的组织不受影响。有大量的文献关于使用PDT破坏不需要的细胞群如肿瘤细胞。有几个专利涉及到单独使用光动力化合物或者与定向到肿瘤细胞受体决定镁的免疫球蛋白偶联使得复合物更具有细胞特异性。某些光化学化合物，如血卟啉衍生物，而且具有天生浓聚于恶性细胞的能力。这些用于破坏不需要的细胞的方法和化合物在挪威专利号173319，挪威专利申请号90 0731，90 2634，90 1018，941548，85 1897，93 4837，92 4151和89 1491中得到说明。
在PCT/US 93/00683中描述了一种药物运输系统，它包括一种抗肿瘤药和附着于共聚物载体的光激活药物。该复合物在服用后通过胞饮和胞吞作用进入细胞内部，并定位于核内体和溶酶体内部。在溶酶体内，抗肿瘤化合物和聚合物之间的键被水解，前者经溶酶体膜被动扩散到细胞溶质。因此，此方法仅限于能够穿透溶酶体膜的小分子化合物。经过一段时间延迟扩散之后，施用合适的波长和能量的光源激活可光激活的化合物。抗癌药物及可光激的药物的组合效应破坏了细胞，因此，所有已知的可光激活的化合物的使用都是导致广泛地破坏细胞结构以导致细胞死亡。通过定位破坏核内体和溶酶体膜，使不能穿透这些膜的小分子释放进入细胞溶质的方法还尚属未知。
因此本发明的目的在于提供一种将分子转运到培养或组织活细胞中的方法，它是通过：将细胞暴露于可光激活的化合物，能被转送到细胞溶质中的分子(多种分子)，二者的摄取可以被各种载体易化。将细胞暴露于有合适波长和能量的光下以破坏核内体和溶酶体膜，在不破坏大多数细胞的功能的情况下，将分子释放入细胞溶质中，光敏物质和要被转运入细胞溶质的分子可以结合或分别与合适的载体一起施用，任选对目标分子摄取的易化。
本发明达到了以所附权利要求为特征的本发明的目标。
本发明涉及到一种将任何分子转运到活细胞溶质的方法。此后，细胞溶质中可以找到此分子而细胞仍保持功能活性。此方法过程如下：将细胞暴露于可光激活的化合物中，此化合物可被细胞吸收并定位于核内体。溶酶体或其它细胞分隔腔(compartment)内，此可光激活的化合物或者分别与载体分子一起和靶向免疫球蛋白偶联，分子被转运到细胞溶质，并且当细胞暴露于适当波长的光照下时，激活光敏化合物，这样核内体，溶酶体或其它细胞分隔腔膜被破坏，分子释放进入细胞溶质，而未使细胞由于光活化的化合物和核内体/溶酶体内容物的可能作用而失去其功能。
本发明的详细描述及图示如下文：
图1：描述了通过本发明的方法分子如何被导入细胞溶质。光敏物质
(S)和所选的分子经细胞内吞(I.示启幼内吞过程中质膜的凹
入)和两种物质终于同一小泡内(II)。当这些小泡暴露于光下
时，小泡膜破裂，内容物释放(III)；图2：在NHIK 3025细胞中，经gelonin处理，含或不含TPPS2a，光照
50秒后蛋白质合成情况。符号：○，TPPS2a+光；●，-TPPS2a-
光；，+TPPS2a-光；，-TPPS2a+光。细胞经3.2μg/ml
TPPS2a和所显示的gelonin浓度过夜处理，每一例给予相同剂量
的光照。蛋白质的合成是通过光照后24小时，3[H]亮氨酸掺入蛋
白质的量来测定。图3：显示仅经过TPPS2a和光照处理后的剂量反应曲线(○)或者与
0.2μg/ml()或2.0μg/ml gelonin(●)如图2所描述的联合作
用的剂量反应曲线。图4：显示在NHIK 3025细胞中经3.2μg/ml TPPS2a，光照，有或无0.2μg
/ml gelonin处理的条件下蛋白质合成情况。符号：●，TPPS2a-
gelonin；○，TPPS2a+gelonin。这些细胞在有或无gelonin条
件下经TPPS2a过夜处理，并且暴露于所显示剂量的光照下。蛋白
质的合成通过3[H]亮氨酸掺入蛋白质的量来测定。图5：说明在V79细胞中，在缺乏和存在1μg/ml gelonin条件下经25μg
/ml AlPcS2和光照处理蛋白质的合成情况。符号：●光敏物质+毒
素○光敏物质。图6：说明在H146细胞中，在缺乏和存在1μg/ml gelonin条件下用0.3μg
/ml TPPS2a和光照处理，蛋白质的合成情况。符号；如图5示，图7：说明在V79细胞中，在缺乏和存在lμg/ml gelonin条件下，用1μg
/ml TPPS2a和光照处理，蛋白质的合成情况。符号：如图5示，图8：说明在NHIK 3025细胞中，在缺乏或存在1μg/ml gelonin条件下，
用3.2μg/ml TPPS2a和光照处理，蛋白质的合成情况。符号：如图
5示，图9：说明在NHIK 3025细胞中，在缺乏或存在1μg/ml agrostin条件下，
用3.2μg/ml TPPS2a和光照处理，蛋白质的合成情况，符号：如图5
所示。图10：说明在NHIK 3025细胞中，在缺乏或存在1μg/ml皂草素条件下，
用0.25μg/ml 3-THPP和光照处理，蛋白质的合成情况。符号：
如图5所示，图11：说明在COS-7细胞中，在缺乏或存在1μg/ml gelonin条件下，
用3μg/ml TPPS2a和光照处理，蛋白质的合成情况。符号：如图5
所示，图12：说明在NHIK 3025细胞中，在缺乏或存在TPPS4条件下，用gelonin
处理后光照50秒，蛋白质的合成情况。符号；■TPPS4+光；
-TPPS4-光；◇+TPPS4-光。这些细胞经75μg/ml TPPS4和
所示浓度gelonin过夜处理，在所有情况下给予相同剂量照。蛋白
质的合成通过光照后24小时3[H]亮氨酸掺入量来测定；图13.说明在OHS细胞中，在光照之前，在缺乏或存在3μg/ml gelonin
条件下，先用3μg/ml TPPS2a处理18小时接着4小时无TPPS2a，
此时蛋白质合成情况。细胞于50μM氯喹或10μM氯化胺中处理4
小时以抑制溶酶体蛋白降解。
已报道许多药物包括二和四磺基铝酞菁，磺化四苯基卟吩(TPPSn)，尼罗蓝，二氢卟吩ε6衍生物，尿卟啉I，叶赤素和可能的血卟啉和亚甲基蓝在培养中定位于核内体和溶酶体中。在大多数情况下是由于内吞活性。发明者显示溶酶体中含有光敏物质的细胞在光照下会导致溶酶体的通透性，释放光敏物质。在一些情况下，如TPPS2a和TPPS1，以PDT以后，在细胞溶质中发现大量的溶酶体酶活性。表明在不失去其活性的情况下，溶酶体内容物可以释放到细胞溶质中。总的来说根据目前的调查，光敏染料的作用可用于从核内体和溶酶体中释放内吞的分子。
将分子导入细胞质的过程是通过以下过程实现的：首先，把细胞或组织暴露于光敏染料中，需要转移到细胞溶质内的分子与或不与载体分子和免疫球蛋白一起，所有这些优先定位于核内体和/或溶酶体中。其次，组织或细胞暴露于合适波长和能量的光下以诱导光动力学反应。这些光动力学反应将导致溶酶体和/或核内体膜的裂解，这些小泡的内容物将释放到细胞溶质中。
本发明的原理在图1中得到说明。光敏物质和要导入细胞的分子位于同一细胞分隔腔中是必要的。另一需要强调的是外加的分子也许会聚集在除了溶酶体，核内体之外的其它的细胞内分隔腔中如高尔基体和内质网。在这种情况下，假如光的剂量与光敏化合物的联合作用并不破坏细胞的功能，位于同一分隔腔内的光敏化合物也许与光联合作用用于同一目的。
本发明是根据我们体外的显示：光敏物质，如TPPS2a，在邻近苯基上带有2个磺基的四苯基卟吩与光联合作用在不杀死大部分细胞的情况下能够诱导释放功能完整的溶酶体内容物。单独使用其它光敏化合物或者与用作载体的其它分子或颗粒联合也可以得到相同作用，这些载体可以将光敏物质定位到核内体/溶酶体或其它细胞内分隔腔中。这样的载体可以是组织或细胞特异性抗体或其它配基，它们能连结到细胞表面，通过受体介导的细胞内吞提高光敏物质的吸收。另一载体可以使用重建的LDL-颗粒。这些颗粒也能被受体介导的细胞内吞所吸收。对比于天然LDL的预连结，每个LDL颗粒上的光敏物质分子数和LDL-颗粒上的连结数通过此法得到提高。
本发明不仅限于体外使用，也可以用于体内，或者通过原位处理，或者通过注射处理的细胞先体外后体内处理。如象上述描述的体外处理的方式，吸收进入核内体和溶酶体的能力可以加强。只要光敏物质能被靶细胞吸收，光照被合适转递，所有组织都能被处理。
本发明根据光敏物质和光照。光照必须被光敏物质吸收或间接诱导光敏物质的兴奋状态。因此，使用的波长区域依赖于光敏物质。光照并不需要单色光或平行光。能够发射合适波长的任一光源都能使用。
令人惊奇的是根据目前研究，光动力学反应似乎中和了释放溶酶体内容物的潜在的细胞毒作用。因此作者提出在培养的NHIK 3025细胞中，溶酶体的组织蛋白酶被TPPS2a的光动力学(fotodynamic)反应显著抑制。这是本发明的一个令人惊奇的效应，通过裂解核内体/溶酶体的膜将分子转移进细胞溶质，它有助于维持细胞的存活和功能。实验与临床应用的实施例1)肿瘤治疗
几种光敏物质优先聚集在肿瘤组织中，对于肿瘤组织的选择通常超过周围组织的2-3倍，但此系数在某些情况下比如脑组织也许会更高，即达到30。那些对于治疗肿瘤有临床意义的分子，但限于低的或根本无法摄入细胞溶质，可以经过本发明的方法导入细胞溶质，如下列例子中的Gelonin，即是这样的一种分子。几种其它的分子，或者单独使用，或者连结到别的分子上(如抗体，转铁蛋白，光敏物质，重建LDL-颗粒上的apoB)使用。这种联合治疗的优点是：1)因为低剂量或亚毒性剂量的光照足够裂解溶酶体和核内体，加强了肿瘤组织深层的细胞毒效应；2)因为PDT仅用于肿瘤区域，加强了毒素的特异性。2)基因治疗
基因治疗，即治疗性转移基因到病人细胞中，对于治疗许多遗传性疾病如肿瘤，膀胱纤维化，心血管疾病和许多其它疾病是一种有前途的方法。目前主要问题是转染必须在体内执行或在某些情况下先体外后体内。目前最常用的载体，即帮助转移DNA分子进入细胞的结构，是不同类型的病毒，尤其是逆转录病毒和腺病毒。这些方法的缺点是载体的稳定性不高，有限制的特异性，低产率及把病毒DNA导入人体细胞。
借助于光化学诱导的核内体或/和溶酶体的破裂，DNA或反义DNA，整个基因都能进入细胞。此处理可以在体内执行。3)实验应用
本发明可用于导入大范围的分子进入培养的细胞，如基因，抗体，处理的蛋白和化合物，这些通常不透过质膜的分子。
本发明通过下列非限定性的实施例做进一步说明。实施例1.此实例说明光动力学处理释放了一种抑制蛋白质合成的化合
物进入细胞溶质
许多植物毒素通过进入细胞溶质，酶促灭活核糖体的功能而杀死细胞的。大部分细胞毒植物蛋白含有两条多肽链，A链和B链，经二硫键连在一起。B链的功能是连结蛋白至细胞表面，而A链则含有酶促活性。Gelonin是一种植物毒素，它能在无细胞系统中有效抑制蛋白质合成，但对于完整细胞则极少或完全没有作用。对于完整细胞低的细胞毒作用可能由于gelonin中缺乏B链。
NHIK 3025细胞在暴露于光之前，先用TPPS2a(通式I)和gelonin分别或一起孵育18小时，接着在含有TPPS2a而无gelonin的培养基中孵育1小时。曝光后24小时测定蛋白质的合成。光动力学处理，单独使用将杀死10-20％的细胞，降低蛋白质合成30-40％(图2)。如在图2中所见到的：在缺乏或存在光照的情况下单独使用gelonin在某种程度上抑制蛋白质合成。然而联合使用PDT和IC50＝0.2μg/ml gelonin可完全抑制蛋白质的合成。因此在无光动力学处理的情况下，gelonin基本上不进入细胞溶质。此例说明TPPS2a和光照可以用于将功能完整的大分子导入细胞溶质。实施例2.
此例说明光的剂量(用染料所吸收的波长)如何来决定细胞存活级分的大小。
根据实施例1的设计，NHIK 3025细胞用TPPS2a和gelonin孵育。
曝光后24小时测定细胞克隆的存活。正如图3所显示，事实上当曝光量增加时，TPPS2a和光杀死了所有的细胞。这与以前关于用PDT杀死不需要的细胞的技术是一致的。当gelonin加入时，由于gelonin对蛋白合成的抑制作用，存活率下降。表明gelonin释放到细胞质中。增加gelonin的浓度导致更多的gelonin存在于细胞溶质中，在图中显示为增加了细胞对光激活的敏感性。
因此，本发明提供了在每一种情况下设置存活水平，选择光敏化合物和曝光量的组合来保持所需的活细胞组分的可能性。实施例3.
本例说明如何改变光剂量来控制gelonin释放到细胞溶质中的量，此量由相对的蛋白合成来决定。
根据实施例1的设计，NHIK 3025细胞用TPPS2a和gelonin来孵育。
图4表明超过50秒的毒性剂量以上的光剂量增加了gelonin在细胞溶质中的组成，此组成由相对的蛋白合成来决定。
实施例4-11说明根据本发明在不同细胞系，不同的光敏物质和毒素中方法的使用。光敏物质细胞内定位是溶酶体(TPPS4，TPPS2a，AlPcS2a)和溶酶体外(3-THPP)。下列简写被使用：AlPcS2a指在邻近苯环上带有2个磺基的铝酞菁；TPPS4指带有4个磺基的中-四苯基卟吩；TPPS2a指在邻近苯环上带有2个磺基的中-四苯基卟吩；3-THPP指四羟苯基卟吩。所使用的细胞系是人子宫颈原位癌细胞(NHIK3025)，中国仓鼠肺成纤维细胞(V79)，SV40-转化的非洲绿猴肾(CV1-猴成纤维状细胞)(COS-7)，人成骨肉瘤细胞(OHS)和小细胞肺癌细胞(H146)。所有的实验和实施例1设计相同。实施例4.
本例涉及到在V79细胞中，在有/无gelonin作为毒素的条件下使用光敏物质AlPcS2a(图5)。通过选择特定的光剂量(照射时间)，图5表明，在无毒素时，只有极少量的细胞受到破坏，表示为在蛋白合成中只有少量降低，而在有gelonin时，蛋白合成显著下降，这表明尽管AlPcS2a细胞内定位是溶酶体，gelonin分子通过溶酶体转运到胞浆内基本上不损伤细胞(Moan，J.，Berg，K.，Anholt，H.and Madslien，K.(1994)磺化铝酞菁做为光化学治疗中的敏感剂。在V79细胞中小剂量光照对定位，荧光染料和光敏感性的作用。Int.J.Cancer 58：865-870)。实施例5.本例说明在基本不影响细胞生存的条件下将毒素gelonin转递到H146细胞中(图6)。已知TPPS2a定位于细胞的溶酶体中(Berg，K.，Western，A.，Bommer，J和Moan，J.(1990)磺化中-四苯基卟吩在人癌细胞系中的细胞内定位。photochem.Photobiol.52：481-487；Berg，K.，Madslien，K.，Bommer，J.C.，Oftebro，R.，Wmkelman，J.C.和Moan，J.(1991)。在NHIK 3025细胞中，光诱导的磺化中-四苯基卟吩的重新定位和剂量级分的作用。photochem.photobiol.53：203-210；Berg，K.和Moan，J.(1994)，作为光化学靶子的溶酶体。Int.J.Cancer.59：814-822)。实施例6.本例说明根据发明在V79细胞中用TPPS2a为光敏物质的方法(图7)。实施例7.本例说明使用TPPS2a为光敏物质，将毒素agrostin转入NHIK3025细胞中(图8)。实施例8.本例说明用TPPS2a将毒素saporin转入NHIK 3025细胞中(图9)。实施例9.这是一个对照例子，它说明并不进入内吞小泡(即核内体和溶酶体)的感光剂(3-THPP)(Peng，Q.，Danielsen，H.E.和Moan，J.(1994)肿瘤光动力学治疗中强大的光敏物质：应用共聚焦激光扫描显微镜荧光检测肿瘤细胞和组织中的光敏荧光团。在生物医学的显微镜术，全息照相术和干涉测定法中。SPIE Vol.2083：71-82)，在有或无gelonin(图10)时，3-THPP对蛋白合成的作用并无显著差别。因此gelonin并未运送到细胞溶质中。实施例10.
本例说明根据发明使用TPPS2a将gelonin运送到COS-7细胞中(图11)。实施例11.
本例说明根据发明使用TPPS2a将gelonin运送到OHS细胞中(图13)。在此细胞系中，溶酶体内蛋白有显著降解，此降解在本实例中可以在50μM氯喹或10mM氯化铵中孵育4小时得到抑制。实施例12.与实施例1类似，本实例说明当细胞用TPPS4和不同浓度gelonin孵育，并暴露于光时，将gelonin运送到NHIK 3025细胞中，gelonin浓度的功能(图12)。当细胞单独用gelonin孵育并暴露于光或用TPPS4和gelonin共同孵育不暴露于光，没有gelonin运送到细胞中。
此例说明使用不同的感光剂和不同剂量的光，不同的分子可以被导入多种广泛的细胞的溶质中。只要想导入的分子和光敏物质被运送至同一细胞分隔腔中，在不杀死细胞的光敏物质和光照之后，外源性分子能被导入细胞溶质。对于生物分隔腔的光化学作用依赖于那个细胞分隔腔中的光敏物质的量，施用的光剂量和光源的光谱特性。因此，评估对培养的细胞的光化学作用的最好的方法是处理后24小时或更长时间内测量细胞的存活。如上述处理以后24小时对细胞的杀伤作用和对蛋白合成的抑制之间有良好的相关性(数据没有列出)。
Claims (16)
1.通过使用光敏化合物和被光敏化合物吸收的光照，将分子导入活细胞溶质的方法，
其特征在于：
a).光敏化合物，任选载体分子和将被运送的分子，它们结合在一起或各自被施用于活细胞和；
b).经内吞或其它方式转运到核内体，溶酶体或其它细胞内膜限制的细胞分隔腔(Compartment)中；其中
c).根据光敏化合物的吸收光谱，细胞被暴露于合适波长的光照下，光照的不同剂量取决于所需的存活率，这样核内体，溶酶体或其它细胞内分隔腔的膜破裂，要导入细胞溶质的分子释放到细胞溶质中，并且光激活的光敏化合物的本身并不杀伤大多数的细胞。
2.根据权利要求1的方法，
其特征在于，释放到细胞溶质的分子选自DNA、寡(脱氧)核苷酸、mRNA、反义DNA、糖、蛋白质、肽、非膜通透性药物，其它非膜通透性分子，和上述分子共价或非共价键合的组合。
3.根据权利要求1的方法，
其特征在于，释放到细胞溶质的分子选自能够修饰蛋白合成活性的物质。
4.根据权利要求2的方法，
其特征在于，释放到细胞溶质的化合物有gelonin、皂草素或agrostin或这些化合物任意的组合。
5.根据权利要求1的方法，
其特征在于，使用的光敏化合物选自卟啉类化合物、酞菁(phtalocyanines)类化合物、红紫素类化合物、二氢卟酚类化合物、苯并卟啉类化合物、napthalocyanines类化合物、阳离子染料类化合物、四环素类化合物和趋溶酶体的弱碱类化合物及其衍生物。
6.根据权利要求5的方法，
其特征在于使用的光敏化合物为在邻近的苯基上带有2个磺基的四苯基卟吩(TPPS2a)，带有4个磺基的中-四苯基卟吩(TPPS4)或者在其邻近的苯环上带有2个磺基的铝酞菁或其任意组合。
7.根据权利要求1的方法，
其特征在于：使用的载体分子是位点定向的分子或者能促进光敏化合物或要释放进细胞溶质的分子的吸收的增强剂(enhancer)。
8.根据权利要求1的方法，
其特征在于通过选择与光敏化合物浓度有关的光照剂量来调节存活细胞的组分(fraction)。
9.在温血动物或细胞培养中修饰成瘤和其它细胞过程的组合物包含要释放进细胞溶质的化合物和光敏物质及载体，
其特征在于，它包含选自如下的成员：
a)有助于向细胞内分隔腔如核内体，溶酶体或其它细胞内分隔腔运送的载体，其上粘附有要在细胞溶质中释放的细胞加工-修饰化合物和通过光激活裂解细胞内分隔腔膜的光敏化合物，
b)几个所说的载体，其中至少一个载体上粘附有要在细胞溶质中释放的化合物，另一个相似或不相似的载体上粘附有光敏化合物和，
c)载体分别与要在细胞溶质中释放的化合物以及光敏化合物一起形成的混合物。
10.根据权利要求9的组合物，
其特征在于，所说的要在细胞溶质中释放的化合物是抗肿瘤化合物。
11.根据权利要求10的组合物，
其特征在于，抗肿瘤化合物是gelonin。
12.根据权利要求9的组合物，
其特征在于，在细胞溶质中释放的化合物选自DNA、寡(脱氧)核苷酸、mRNA、反义DNA、糖、蛋白质、肽、非膜通透性药物、其它非膜通透性分子，上述提及的分子的共价或非共价连接的组合。
13.根据权利要求9的组合物，
其特征在于，光敏化合物是从下面一组含有卟啉类化合物、酞菁(phtalocyanines)类化合物、红紫素类化合物、二氢卟吩类化合物、苯并卟啉类化合物、napthalocyanines类化合物、阳离子染料类化合物、四环素类化合物和趋溶酶体的弱碱类化合物及其衍生物。
14.根据权利要求11的组合物，
其特征在于光敏化合物是在邻近苯基上有两个磺基的四苯基卟吩。
15.根据权利要求9的组合物，
其特征在于载体选自具有位点定向的分子或能促进光敏化合物或者在细胞溶质中释放的分子的吸收的增强剂。
16.实施根据权利要求1的方法的试剂盒，
其特征在于，它包括光敏化合物以及修饰细胞膜运输的，有助于某些细胞群或其它相关的功能的其它化合物。
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| JP2019530718A (ja) | 2016-10-14 | 2019-10-24 | ピーシーアイ バイオテック エイエス | ゲムシタビンのＴＰＣＳ−２ａ誘導性光化学的内在化を用いた胆管癌の処置 |
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| CN112055596A (zh) * | 2017-11-10 | 2020-12-08 | Pci生物技术有限公司 | 用于治疗细胞内细菌感染的组合物 |
| CN111787952A (zh) * | 2018-01-24 | 2020-10-16 | Pci生物技术有限公司 | 方法 |
| CN110711249A (zh) * | 2019-09-19 | 2020-01-21 | 北京化工大学 | 一种溶酶体膜包覆纳米颗粒的制备方法 |
| CN114163508A (zh) * | 2020-09-11 | 2022-03-11 | 王月志 | 能破坏细胞的氨基酸序列及相关核苷酸序列和相关的应用 |
| WO2022053050A1 (zh) * | 2020-09-11 | 2022-03-17 | 王月志 | 能破坏细胞的氨基酸序列及相关核苷酸序列和相关的应用 |
| CN114729021A (zh) * | 2020-09-11 | 2022-07-08 | 王月志 | 能破坏细胞的氨基酸序列及相关核苷酸序列和相关的应用 |
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