药学学报  2018, Vol. 53 Issue (6): 865-877   PDF    
抗肿瘤抗生素药物制剂的研究进展
刘薇, 陈丽青, 辛欣, 黄伟, 高钟镐     
中国医学科学院药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050
摘要: 抗肿瘤抗生素在抗肿瘤方面具有巨大的应用潜力,目前已有一些药物被成功开发,成为临床一线抗肿瘤用药,但抗肿瘤抗生素普遍存在水溶性低、稳定性差和全身毒副作用大等问题。选择合适的递送载体设计合理的递送系统尤其是智能递送系统,可以提高药物的靶向性和疗效,降低药物的不良反应。本文对抗肿瘤抗生素递送的载体及递送系统的研究进展进行了综述,包括现已上市的抗肿瘤抗生素药物制剂、处于临床研究阶段的抗肿瘤抗生素药物制剂和处于基础研究阶段的新型抗肿瘤抗生素药物制剂。
关键词: 抗肿瘤抗生素     药物载体     智能递送系统     靶向性    
Recent advances in the drug formulations of anti-tumor antibiotics
LIU Wei, CHEN Li-qing, XIN Xin, HUANG Wei, GAO Zhong-gao     
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
Abstract: Anti-tumor antibiotics exhibit great application potential in the anti-tumor therapy. Some drugs have become the first-line medication clinically. However, there are always various problems associated with anti-tumor antibiotics, such as poor solubility and instability as well as severe systemic side effects. It is important to choose suitable delivery carriers for a reasonable delivery system for a good targeting ability, enhanced anti-tumor efficacy and reduced adverse effects of the anti-tumor antibiotics, especially in the smart delivery systems. This review summarizes the carriers and the advances in the delivery systems of anti-tumor antibiotics, including anti-tumor antibiotic drugs currently on the market, in the clinical research stage and in the basic research stage.
Key words: anti-tumor antibiotics     drug carrier     smart delivery system     targeting ability    

抗肿瘤抗生素是一类由微生物产生的具有抗肿瘤活性的化学物质[1]。放线菌素D是第一个被应用在临床上的抗肿瘤抗生素, 用于治疗儿童肾母细胞瘤[2]。抗肿瘤抗生素因其较强的抗肿瘤活性、较宽的抗肿瘤谱, 以及丰富的来源等优点在抗肿瘤研究中扮演着重要的角色。目前, 随着对抗肿瘤抗生素的深入研究, 更多新型的抗肿瘤抗生素被开发成产品, 一些已经跻身为临床一线用药, 如多柔比星(doxorubicin, DOX)和柔红霉素(daunorubicin, DNR)等。目前常用的抗肿瘤抗生素有烯二炔类、糖肽类、蒽环类、大环内酯类、苯并二吡咯类和苯醌类等几大类, 以力达霉素(lidamycin, LDM)、卡奇霉素(calicheamicin)、博来霉素(bleomycin, BLM)、DOX、雷帕霉素(rapamycin, Rapa)、丝裂霉素C (mitomycin C, MMC)等为代表[1, 2]。一些抗真菌类抗生素药物在近些年也被发现具有抗肿瘤作用, 伊曲康唑(itraconazole, ITN)通过Hedgehog传导通路抑制血管生成从而具有抗肿瘤作用[3]; 著名的抗真菌药物涕必灵(thiabendazole)也显示出一定的抗肿瘤潜力, Zhang等[4]通过细胞实验和体内实验证明了涕必灵可以通过抑制血管内皮生长因子(vascular endothelial growth factor, VEGF)而发挥抗黑色素瘤的功效。

然而, 在诸多发现的抗肿瘤抗生素中, 只有少部分进入临床Ⅱ期, 极少部分获批上市。阻碍抗肿瘤抗生素发展的主要原因有: ①药物的非特异性带来的强毒副作用, 如蒽环类抗生素可引起心脏毒副作用, 博来霉素类可造成肺纤维化, 大环内酯类可产生红细胞毒性等[5-7]; ②一些药物的强疏水性限制了其在体内的溶解、吸收, 如Rapa, DNR等[8, 9]; ③由于结构特点, 大部分药物在体内循环时间较短, 且有效剂量范围窄, 需要多次间隔给药[10-12]; ④肿瘤多药耐药性的产生[13-15]。药物递送系统(drug delivery system, DDS)能够有效地提高药物的药理活性并减少毒副作用的产生[16], 新型药物递送系统的发展加快了新药上市的步伐, 设计抗肿瘤抗生素的新型DDS以解决上述问题, 充分发挥该类药物的药效, 降低药物的毒副作用, 成为研究热点之一。本文对已上市的、进入临床研究的和处在基础研究阶段的抗肿瘤抗生素递送策略进行了综述, 主要介绍了新型抗肿瘤抗生素药物制剂的研究和应用, 包括偶联物、脂质体、胶束、树状大分子、凝胶、无机纳米粒和微泡等。

1 已上市的抗肿瘤抗生素药物制剂

Doxil是目前被FDA批准上市的抗肿瘤抗生素制剂中比较有代表性的一类多柔比星脂质体制剂, 1995年于美国获批上市, 主要用于治疗复发性卵巢癌和转移性乳腺癌, Doxil的载体材料组成有二硬脂酰基磷脂酰乙醇胺(DSPE)-聚乙二醇(PEG)/氢化大豆磷脂(HSPC)/胆固醇(Chol), 脂质体的粒径在80~90 nm。相较DOX盐酸盐注射剂, 该制剂对心脏和骨髓的毒副作用有所缓解, 但是随着Doxil的使用, 患者会出现一种与补体系统激活相关的假性过敏现象(CARPA), 这种不良反应可以通过减慢药物滴注速度克服。其他抗肿瘤抗生素如DNR、Rapa等也有相关药物制剂获批上市[7]

除了脂质体, 单抗偶联物和聚合物偶联物等新剂型也推动着抗肿瘤抗生素加快进入市场的步伐。表 1[7, 17-21]为近30年部分获批上市的抗肿瘤抗生素药物制剂。

Table 1 Anti-tumor antibiotic drugs that have been approved in the last 30 years. PEG: Polyethylene glycol; DOX: Doxorubicin; MMAE: Monomethyl auristatin E; DNR: Daunorubicin; Rapa: Rapamycin
2 处于临床阶段的新型抗肿瘤抗生素药物制剂

随着新载体、新思路的应用, 许多抗肿瘤抗生素药物制剂已经进入临床试验。这些进入临床的递送系统也逐渐趋于智能化, 如DOX热敏感脂质体ThermoDOX[7]、DOX pH敏感前药INNO-206[22-24] Ⅲ期临床试验; MMC pH敏感前药进入Ⅰ期临床试验等[25]。其中, INNO-206是第一个进入临床、利用体内白蛋白作为运输载体的药物, DOX与6-马来酰亚胺己酸通过pH敏感腙键连接, 静脉注射进入体循环后, INNO-206与循环白蛋白的34位半胱氨酸结合, 从而加速药物进入实体瘤并提高药物在实体瘤的聚集, 进入肿瘤组织后, 腙键断裂从而释放出DOX[22, 24]表 2[3, 7, 19, 22-34]为近年来进入临床研究的抗肿瘤抗生素药物制剂。

Table 2 Antitumor antibiotics in the clinical studies. MMC: Mitomycin C; 17-AAG: 17-Allyl amino-17-dimethoxy-gridamycin
3 处于基础研究阶段的新型抗肿瘤抗生素药物制剂 3.1 药物偶联物 3.1.1 聚合物-药物偶联物

从第一个聚合物-药物偶联物莫斯卡灵-二肽-聚乙烯吡咯烷酮(PVP)诞生到现在, 聚合物-药物偶联物已经发展了60余年。区别于其他载药系统, 聚合物-药物偶联物中药物和聚合物以共价键的方式连接而非由聚合物包载药物。这种载药形式具有以下优点: ①增加疏水性药物的水溶性; ②可以依据不同目的灵活调整共价键类型, 实现在特定环境下药物的释放, 如pH敏感键、酶敏感键和光敏感键等; ③将药物与聚合物连接显著延长药物在体内循环半衰期; ④提高药物的实体瘤的通透和滞留效应(enhanced permeability and retention effect, EPR)。因此, 这类载体能够克服抗肿瘤抗生素选择性差、稳定性差以及部分药物水溶性差的问题。常用的聚合物有多糖类、PEG、聚氨基酸和多肽等[35]

为了解决DOX因靶向性差带来的心脏毒性, 提高DOX在靶组织的分布浓度而提高肿瘤抑制效果, Tu等[36]设计了一种基质金属蛋白酶2 (MMP2)敏感的二肽键聚合物-药物偶联物, 先将PEG和细胞穿膜肽(TAT)通过MMP2敏感二肽连接制得PEG-ppTAT, 再将TAT半胱氨酸残基的巯基与马来酰胺键合的DOX连接制得聚合物偶联物PEG-ppTAT-DOX/MMP2。这种偶联物能够在水溶液中自组装, 具有酶敏感特性而起到靶向效果, 相较于MMP2非敏感的聚合物, 该聚合物在A549细胞上的转染效率高出1倍; 高表达P-糖蛋白(P-gp)的细胞对于PEG-ppTAT-DOX/MMP2的药物摄取能力比游离DOX高2倍, 提示该偶联物能够逆转细胞的耐药性。基因药物与化学药物的共载能够通过发挥协同作用提高肿瘤抑制效果。Lu等[37]β-环糊精(β-CD)与聚乙烯亚酰胺600 (PEI600)连接制得的二嵌段共聚物poly-conjugate (PC)与DOX共价结合形成偶联物, 带正电荷的PEI可以通过静电作用固缩p53质粒, 该复合物体系PC-DOX/p53进入细胞后能够借助内涵体逃逸释放药物进入细胞核, 协同诱导细胞凋亡。体内生存率实验结果表明, 游离DOX组于给药24天后出现60%死亡率, 而PC-DOX/p53组在给药45天后荷瘤小鼠存活率为60%, 证明以PEI为载体共载p53质粒和DOX的偶联物在抑制肿瘤生长和提高生存期上有着一定优势。

3.1.2 单抗-药物偶联物

单抗-药物偶联物(antibody-drug conjugates, ADC)由单抗、药物和连接键三部分元件组成。其中, 单抗发挥靶向作用, 药物发挥细胞毒作用, 当给药系统进入靶部位时, 需要足够量的药物释放出来, 因此, 连接键的选择对于ADC的稳定性与释药性能至关重要。连接键主要分为两大类: ①可断裂的连接键, 化学键在溶酶体酶、酸性刺激和谷胱甘肽(GSH)还原下断裂; ②不可断裂的连接键, 药物的释放主要依赖于单抗在特定部位的降解[19]

Xu等[38]以LDM为模型药物, 基于EGFR和MMP2设计了一种双靶向型单抗偶联物。LDM由可拆分的发色团(AE)和蛋白辅基(LDP)组成。将靶向EFGR的寡核苷酸Ec和靶向MMP2的单抗TIMP-2与LDP通过(GlyGlyGlyGlySer)2连接起来, 形成融合蛋白, 最后装配AE, 最终制得的单抗-药物偶联物对非小细胞型肺癌有着较好的疗效。与游离LDM相比, 单抗偶联物对H460、A549的细胞毒作用更大[IC50: H460: 4.05×10-11 mol·L-1 (游离LDM), 5.24×10-12 mol·L-1 (单抗偶联物); A549: 6.67×10-10 mol·L-1 (游离LDM), 4.69×10-11 mol·L-1 (单抗偶联物)], 同时对H460异种种植的小鼠抑瘤率更高(0.2 mg·kg-1游离LDM: 55%; 0.2 mg·kg-1单抗偶联物: 74%)。Yang等[39]制备了一种结构简单的传统单抗偶联物, 旨在提高DOX的体内循环时间、解决DOX靶向性差而对靶组织毒性降低的问题, 结构修饰的DOX与免疫球蛋白G (IgG)共价连接, 通过对IgG进行叶酸(FA)-PEG修饰, 可以得到靶向FA受体的长循环载药系统。相较于无PEG修饰的载体, 该偶联物在体内的循环时间多两倍, 与无FA修饰的单抗偶联物相比, 该偶联物对HeLa、KB细胞的细胞毒作用高8倍, 因此FA-PEG-IgG-DOX可以作为一种ADC给药策略。

3.2 脂质体

脂质体作为一种纳米级别的递送载体, 由于其膜材良好的生物相容性和低毒性以及表面可修饰性, 能够显著提高药物疗效并减少药物对正常组织的毒副作用, 被广泛地应用于药物制剂研究[40, 41]。然而脂质体存在着稳定性低、药物释放缓慢和肝脏/脾脏易聚集等缺陷[41], 因此, 长循环靶向型、环境敏感型脂质体是目前开发热点。肿瘤细胞内富含GSH, 这为环境响应释药型递送载体提供了设计前提[42]。基于此, Patil等[43]设计了一种FA受体靶向还原响应型脂质体, 许多肿瘤细胞表面高表达FA受体, 尤其是上皮细胞, FA作为靶头具有分子质量小、无毒、无免疫原性和受体亲和力强等优点, 作者将MMC与脂质通过二硫键连接形成MMC前药实现还原响应。以该脂质体复合物为载体递送MMC能够提高MMC的半衰期并显著增加MMC的肿瘤靶向性, 该系统有望提高MMC治疗腹膜癌扩散及浅表性膀胱癌的能力。Liu等[44]基于肿瘤组织的缺氧环境特点研究了一种治疗脑胶质瘤的、由硝基咪唑类组成的载DOX缺氧敏感型脂质体, 硝基咪唑在缺氧条件下转变为氨基咪唑从而释放药物发挥治疗作用。硝基咪唑递送系统能够提高DOX穿过血脑屏障的效率, 并减少脑胶质瘤因其生理结构而产生的易抗药性。硝基咪唑对辐射敏感, 研究者以此思路将化疗与放疗结合起来, 对荷脑胶质瘤的小鼠进行生存期实验, 结果表明缺氧敏感型脂质体相较于游离DOX来说能够延长小鼠生存周期(缺氧敏感型脂质体: 47天; 游离DOX: 44.5天), 而结合辐射治疗后, 生存周期进一步延长到65.5天。此外, 由Fe3O4组成的磁性脂质体也成为一类具有潜力的载体。Wang等[45]用聚乳酸聚乙醇酸共聚物(PLGA)、Fe3O4和聚谷氨酸等设计了一种载多柔比星的磁性脂质体-壳核纳米球PLGA/多功能聚合物脂质体(multifunctional polymer liposomes, MPLs), 将RGD和TAT修饰在表面分别起靶向和穿膜作用, RGD是一段靶向肿瘤新生血管表面αvβ3和αvβ5凝集素的三肽(Arg-Gly-Asp)[46], 该递送系统同时实现了化学药物与基因药物的共载, 提高了DOX的脑靶向性, 相较于单修饰组和无Fe3O4装载组, PLGA/MPLs组对胶质瘤的疗效有所提高。与表面单修饰的PLGA/PL-RGD与PLGA/PL-TAT组相比, PLGA/MPL组在C6细胞上的摄取转染率相对较高, 提示多功能脂质体能够提高细胞对药物的摄取能力。

3.3 胶束

将双亲性的高分子聚合物分散在水中, 当浓度超过临界胶束浓度(critical micelle concentration, CMC)可以自组装形成胶束, 粒径在10~100 nm, 以胶束作为药物的载体可以提高EPR效应, 对胶束表面进行修饰后, 亦可以实现主动靶向作用, 继而减少胶束递送系统与无关组织的作用。根据药物的性质不同, 将会被装载在胶束的不同位置处:疏水性药物倾向于聚集在疏水性内核, 而亲水性药物在亲水性外壳中。药物和胶束的结合方式多样, 包括疏水作用力、共价键和交联作用[47, 48]

黏蛋白1 (MUC1)受体是一类由两个亚单元组成的高表达于肿瘤细胞表面的异源二聚体蛋白, 是肿瘤治疗的一个重要靶点。为了提高DOX在乳腺癌组织的浓度, 并减少DOX用量, Charbgoo等[49]设计了一种基于MUCI适配体的靶向性DNA胶束DOX-KLA肽-anti MUCI-M。他们将胆甾醇基修饰的MUC1适配体单链DNA和由促凋亡KLA阳离子肽修饰的双链DNA混合, 在水溶液中自组装成混合胶束, 实现对DOX和KLA的共载, DOX和KLA肽共递送能够减少DOX用量, 减轻其毒副作用。这种靶向胶束在体外的释放行为和体内的抗肿瘤活性都显示出较好的结果。游离DOX与该胶束对高表达MUCI的MCF-7细胞IC50值分别为2.5和1 μmol·L-1; DOX-MUCI-M、KLA-anti MUCI-M、DOX-KLA-anti MUC1-M对MCF-7细胞的凋亡及坏死诱导率分别为18.5%、23.6%和28.3%, 这说明建立的DNA胶束对高表达MUCI蛋白的癌细胞抑制效果更好; 对荷C26肿瘤的小鼠静脉注射相同浓度(5 mg·kg-1)的游离DOX和DNA胶束观察药物体内抗肿瘤效果, 以瘤体积小于2 cm3为标准, DOX组于26天有2/3小鼠死亡, 而DNA胶束组在治疗的30天中小鼠都存活并达到了治疗标准, 提示新设计的胶束提高了抗肿瘤效果。非离子型表面活性剂Pluronic也被应用到了胶束制备中, Li等[50]将Pluronic F68与高分子材料PEG、聚己内酯(PCL)和PLGA混合形成聚合物混合胶束装载米托蒽醌, 这类胶束能够通过光敏剂提高激活活性氧(ROS)的水平, 利用光动力治疗克服乳腺癌对米托蒽醌等药物的多药耐药性。在体外耐药性MCF-7细胞毒实验中, 有光刺激时, 相同浓度(20 μmol·L-1)的游离米托蒽醌组和胶束组对细胞生存抑制率分别为11%和60%;撤去光刺激后, 胶束组的细胞生存抑制率降低至43%, 这些结果表明胶束在结合光刺激时可以发挥最大的肿瘤抑制能力。

普通胶束在体内存在着循环稳定性差或在病理部位释药慢的问题, 研究环境响应型胶束对于提高胶束的循环稳定性及智能释药性有着重要意义[51, 52]。Quader等[46]将表柔比星和聚合物胶束材料聚乙二醇-b-聚-β-苄基天冬酰胺(PEG-b-PBLA-Ac)共聚物通过酸敏感腙键连接, 并对胶束表面进行cRGD修饰, 继而制备载表柔比星的靶向性酸敏感聚合物胶束, 研究表明, 该递送系统具有极强的深入恶性肿瘤(如脑胶质瘤)组织的能力; 该pH敏感胶束能够通过提高表柔比星的脑靶向性解决表柔比星血脑屏障透过效率低的问题。值得一提的是, Maiti等[13]设计了一种简单但智能的还原环境响应型胶束[聚乙二醇-b-聚2-甲基丙烯酰氧基乙基, 5-(1, 2-二硫-3-基)戊酸] (PEG-b-PLAHEMA), 该嵌段共聚物上的LAHEMA部分可以对还原剂GSH做出响应而发生结构变化以提高药物的肿瘤靶向性, DOX和维拉帕米作为模型药物装载在胶束中。孵育24 h后, 一种该智能双载胶束BCP23CCM对产生多药耐药性的MDA-MB-231细胞的IC50为0.959 2 μmol·L-1, 远低于单载DOX胶束BCP23CCM (2.9 μmol·L-1)和游离DOX (14.75 μmol·L-1)。这提示, 维拉帕米作为一种P-gp抑制剂, 与DOX的共载能够通过克服DOX的耐药性, 减少药物的外排而提高药效。

3.4 树状大分子

聚酰胺(PAMAM)是一类低毒, 无免疫原性的阳离子高分子材料, PAMAM树状大分子在递送基因药物和化学药物上都显示一定的潜力。其材料正电荷赋予递送系统质子海绵效应, 继而发挥溶酶体逃逸功能[53, 54]。然而, PAMAM表面高度正电荷会产生细胞毒性而阻碍其使用, Han等[53]将透明质酸(HA)包载于PAMAM表面, 一方面中和了一部分正电荷; 另一方面对CD44高表达的细胞具有靶向作用, 共载DOX和靶向主要穹窿蛋白(MVP)的siRNA。PAMAM-HA组对耐药MCF-7细胞的IC50值为11.3 μmol·L-1, 远低于游离DOX的IC50值48.5 μmol·L-1; 同时, PAMAM-HA组的体内生物利用度(4.79 h·μg·mL-1)和平均滞留时间(21.8 h)高于PAMAM组(0.98 h·μg·mL-1, 3.1 h); 而HA修饰的树状大分子会提高siRNA的细胞转染效率。上述结果表明, 该树状大分子对DOX耐受的MCF-7细胞具有耐受逆转作用, 是一个非常有效的、用于化学药物和基因药物共载的载体。

除了PAMAM树状大分子, 基于DNA的树状大分子也有良好的载药能力。Taghdisi等[55]设计了一种以三磷酸腺苷(ATP)适配体为树状大分子构建块, 连接MUCI适配体和AS1411适配体的载表柔比星双靶向型DNA树状大分子, 以解决表柔比星靶向性差的问题, 该载体在富含ATP的溶酶体环境中裂解释放出药物。DNA树状大分子具有良好的稳定性、单层分散性和多孔性等优点。

3.5 凝胶

纳米凝胶作为一种载体, 相较于其他传统载体, 具有更好的生物相容性、更高的载药空间、更强的稳定性及更有效的细胞摄取效率等优点[56]。在特定的环境下(如pH变化、酶降解等)纳米凝胶会吸水膨胀, 缓慢释放药物[57]。Wang等[57]基于PAMAM树状大分子设计了一种装载DOX的交联纳米凝胶, 在PAMAM表面修饰生物黏附短肽和酶敏感肽, PAMAM的树枝在NaIO4的作用下发生交联形成酶敏感的纳米凝胶。该体系对肿瘤组织中高表达的中性粒细胞弹性蛋白酶敏感, 能够提高DOX的稳定性、穿过血脑屏障的效率及肿瘤靶向效率。

原位凝胶具有在低温下呈流动状, 在胶凝转变温度以上时黏度增加形成半固体状物质的特点。因此, 原位凝胶具有在体内形成药物储库缓慢释放药物的能力。为了减轻BLM A6在使用中因半衰期短、清除率高而多次重复、大剂量给药产生的毒副作用, Ding等[11]采用Pluronic F127为基质, 与包载BLM A6的阴离子脂质体共同形成原位凝胶。研究表明, Pluronic F127是一类重要的温敏型胶体, 阴离子磷脂二棕榈酰磷脂酰甘油(DPPG)的加入可以提高凝胶间的凝胶强度, 从而增加原位凝胶的稳定性, 减少药物的泄露。该递送系统将Pluronic F127的温敏性质和脂质体的缓释能力结合起来, 体外释放结果表明, 在阴离子脂质体原位凝胶系统、原位凝胶系统和BLM A6溶液中, 阴离子脂质体原位凝胶系统的释药速度最慢, 在4 h时释放51%, 远低于原位凝胶系统(78%)和BLM A6溶液(90%), 在48 h时, 阴离子脂质体凝胶递送系统释放了83% BLM A6, 其余二者均几乎完全释药; 体内滞留实验表明, 阴离子脂质体原位凝胶系统在注射部位的滞留时间远长于BLM A6溶液, 可以监测到注射7天后, 而BLM A6溶液在注射24 h后注射部位已经检测不到药物信号。

3.6 无机材料纳米粒

金纳米粒、多孔硅纳米粒、Fe3O4磁性纳米粒和碳纳米管等含无机材料的纳米递送系统因材料对化学物质和高温的强耐受性、高载药能力、内外表面易修饰性和体外低毒性[58, 59]等优点, 被广泛应用于药物递送载体的研究中。Yang等[60]设计了一种基于多能干细胞(iPS)的装载MMC的靶向型金纳米粒CXCR4-AuNP/SiO2。iPS具有较好的肿瘤倾向性, 将化学药物装入iPS内可以提高其在肿瘤部位的聚集。但iPS在肝脏、肾脏、脾脏和肺等组织的聚集会产生畸形瘤继而阻止iPS的临床应用, 而DOX能够压制iPS的浸润迁移, 从而解决该问题。CXCR4是一类表达于iPS表面具有靶向肿瘤细胞基质细胞衍生因子1 (SDF1)受体功能的蛋白。他们在过去的研究中提出将CXCR4连接在AuNP/SiO2表面能够增加iPS对纳米粒的摄取[61]。同时, 金纳米粒具有对光刺激敏感并将光刺激转换为热能的性质, 能够应用到光动力治疗中。给予光刺激后, 体内生存率实验表明, 相较于游离的MMC, AuNP/SiO2和MMC-CXCR4-AuNP/SiO2治疗组的荷瘤小鼠生存周期更长(三者分别为5、8和10天)。Meng等[62]用PEI-PEG共聚物修饰多孔硅纳米粒, 共载DOX和靶向P-gp的siRNA, 在治疗乳腺癌上发挥着协同作用, siRNA在靶部位可以定向下调P-gp的表达而减少化学药物的排出, 诱导细胞凋亡的能力有所提高。多孔硅纳米粒作为一种新型的载体, 具有粒径孔径可控性, 降解产物无毒副作用[59]等特点, 可以对药物起到控释和靶向作用。

3.7 超声微泡

超声微泡是一类由白蛋白、碳水化合物或脂质组成的壳包围着气体内核(通常是空气、氮气或全氟化碳)组成的药物递送载体, 已经被用作超声造影剂和血液流动示踪剂[63]。超声微泡作为药物载体, 被注射到体内后, 在靶组织给予一定强度的超声照射, 微泡将破裂释放出药物, 可以显著促进药物吸收, 提高药效。超声微泡作为一种新型的药物定位释放载体, 为疾病治疗提供了无创、简便和高效的新方法[64]

Chapius等[63]以BLM A5生物素-PEG共聚物为材料制备了超声微泡。超声微泡以共聚物为外壳, 生物素和PEG作为基本骨架, 共价结合模型药物。在MCF-7体外模型中观察到微泡能够黏附在细胞表面, 提示该微泡具有细胞黏附选择性。Luo等[65]设计了一种装载pH敏感且双靶向型DOX前药的微泡递送系统, DOX与琥珀酸肝素通过pH敏感腙键连接, 表面修饰FA靶头和cRGD靶头, 以生物素作为微泡壳的基本材料, 制备前药-微泡复合物(DPMC)。该递送系统能够提高DOX的肿瘤靶向性, 相较于游离的DOX和DOX前药, DPMC对MCF-7细胞的细胞毒作用更强(IC50分别为310.35、217.43和120.23 ng·mL-1); 体内实验中, 结合超声照射后DPMC组瘤重量显著低于PBS组、游离DOX组和DMPC组。上述结果说明, 结合超声微泡与酸敏感靶向型前药的治疗策略具有一定的优越性。

3.8 其他纳米粒

由阳离子载体形成的纳米粒可以提高药物跨膜效率, 同时也能实现化学药物和基因药物的共载。Chang等[66]将米托蒽醌和在生理条件下带正电荷的十六碳烯酸共价结合成二米托蒽醌和单米托蒽醌产物, 二者以1:1摩尔比混合形成阳离子纳米粒, 同时用以固缩靶向髓细胞白血病1基因(Mcl-1)的siRNA (siMcl-1), Mcl-1是Bcl-2家族中的重要成员, 具有抵御凋亡的能力, 因此通过下调Mcl-1的表达可以减弱肿瘤细胞的耐药性及增加肿瘤细胞对化学药物的敏感性而更好地抑制肿瘤发展。共载策略能够克服肿瘤对米托蒽醌等多药耐药性, 阳离子载体提高了药物进入细胞的能力, 并依托其提高的靶向性减少化学药物的用量、减轻毒副作用, 该纳米粒表现出很强抑制肿瘤生长的能力, 当荷瘤小鼠给药20天后, 共载纳米粒组相较于未治疗组的肿瘤抑制率增加了83.4%, 而游离米托蒽醌组相较于未治疗组的肿瘤抑制率增加55.4%。Taghavi等[67]用PLGA、壳聚糖(CS)为材料制备了阳离子纳米粒, 通过在纳米粒表面修饰5TR1 DNA适配体实现对MUCI受体的靶向功能, 制得包载表柔比星的5TR1 aptamer-CS-PLGA靶向型阳离子纳米粒。相较于非靶向性型和游离型药物, 该靶向纳米粒在C26结肠癌小鼠体内实验中表现出了更好的肿瘤抑制作用。

聚合物脂质纳米粒是一类由脂质内核和聚合物外壳组成的壳-核结构, 同时具有脂质体和纳米粒的理化特征, 因而具有更好的生物相容性和稳定性[68]。基于此, Li等[12]设计了一种由FA作为靶头, 以MMC的磷脂复合物为内核, PEG-DSPE作为外壳形成的聚合物脂质纳米粒, 磷脂复合物作为MMC的一种前药形式, 大豆油与药物通过静电作用、氢键和范德华力结合成对pH敏感的大豆油磷脂酰胆碱复合物(SPC)。该纳米粒有以下优点: ①极好地解决了强亲水的MMC的纳米粒包封问题; ②通过靶向作用提高了药物在肿瘤部位的聚集; ③ SPC的pH敏感性进一步增加了药物在肿瘤部位的浓度; ④ PEG修饰可以实现长循环功能。

近年来, 在研的载抗肿瘤抗生素的聚合物-药物偶联物递送系统、部分新型抗肿瘤抗生素脂质体递送系统和其他处于基础研究阶段的纳米粒总结于表 3[8, 9, 11-13, 36-39, 43-46, 49, 50, 53-60, 62, 63, 65-67, 69-102]

Table 3 New antitumor antibiotic drugs in the basic research stage. HA: Hyaluronic acid; β-CD: β-Cyclodextrin; ITA: Itraconazolel; PEI: Poly(ethyleneimine); RGD: Arg-Gly-Asp; AHGDM: Aminohexylgeldanamycin; HPMA: N-(2-Hydroxypropyl) methacrylamide; Glut: Glutaric acid; Lys: Lysine; Gly: Glycine; ppTAT: Matrix metalloproteinase (MMP2)-cleavable cell penetrating peptide; SMCC: Succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate; Bcl: B-cell lymphoma; ODN: Oligonucleotide; cAC10-SGGPEGGS: Anti CD30 antibody-serine-(glycine)2-proline-glutamic acid-(glycine)2-serine; LDM: Lidamycin; EGFR: Epidermal growth factor receptor; TIMP-2: Tissue inhibitor of metalloproteases; FA: Folic acid; NGR: Asparagine-glycine-arginine; DSPE: Distearoyl phosphoethanolamine; PC: Phosphocholine; ICG-ODA: A hydrophobically modified photosensitizer; Her2: Human epidermal growth factor receptor 2; H7K(R2)2: (Arginine)2-(histidine)7-methionine-(arginine)2 peptide; DOPE: Dioleoyl phosphoethanolamine; TAT: Tyrosine-glycine-arginine-(lysine)2-(arginine)2-glutamine-(arginine)3; PLGA: Poly (D, L-lactide-co-glycolide); GFP: Green fluorescent protein; OQPGA: Octadecyl-quaternized modified poly (g-glutamic acid); DPPC: Dipalmitoyl phosphatidylcholine; DSPC: Distearoyl phosphatidylcholine; MBHA: Rink amide p-methylbenzhydrylamine; DOPG: Dioleoyl phosphatidylglycerole; CA8: (Cholic acid)8; PBLA: Poly(β-benzyl-aspartamide); KLA: (Lysine-leucine-alanine-lysine-leucine-alanine-lysine)2; CS: Chitosan; PCL: Poly (ε-caprolactone); PLAHEMA: Poly 2-(metha-cryloyloxy) ethyl 5-(1, 2-dithiolan-3-yl) pentanoate; TPGS: D-α-tocopherol polyethylene 1000 succinate; PF: Pluronic F; PLL: Poly (L-lysine); PMPC: Poly (methacryloyloxyethyl phosphorylcholine); PLA: Polylactide; VIP: Vasocative intestinal peptide; SPA: Succinimidylpropionate; PAMAM: Poly(amido amine); MVP: Major vault protein; TPP: Sodium tripolyphosphate; BLM: Bleomycin; PECT: Poly (ε-caprolactone-co-1, 4, 8-trioxa [4.6] spiro-9-undecanone)-poly(ethyleneglycol)-poly (ε-caprolactone-co-1, 4, 8-trioxa [4.6] spiro-9-undecanone); DPPG: Dipalmitoyl phospha-tidylglycerol; CXCR4: Chemokine receptor; DC: Dendritic cell; FKBP: FK-506 binding protein 12; ELP: Elastin-like polypeptides; SP: Soybean phosphatidylcholine; LDL: Low density lipoprotein; mdr: Multi-drug resistence
4 展望

抗肿瘤抗生素作为一类化疗药物, 在多年的研究与临床应用中显示出较强的抗肿瘤活性和较宽的抗肿瘤谱。随着多种递送载体的发展, 抗肿瘤抗生素各种剂型的合理应用可以在一定程度上克服其固有缺陷, 如药物溶解性差、选择性低、毒性高和半衰期短等。智能递送系统的发展, 使药物具有可控的释药性能, 多种递送形式的出现能够让设计者依据药物的特性选用合适的策略以达到疗效最大化。此外, 一些载体也赋予化学药物与基因药物共载策略, 二者协同作用在一定程度上具有逆转肿瘤耐药性的潜能。然而, 任何一个全身给药系统都无法达到将药物全部递送到靶部位, 抗肿瘤抗生素制剂的发展仍然要克服许多障碍。现如今, 理想的递送载体应该是简单、安全、低毒、稳定和具有高转染效率的; 在此基础上, 选择恰当的修饰策略并控制药物释放是一个难题; 对于共载而言, 合适的药物组成及药物比例也是未来需要深入探讨的问题; 新型ADC策略依然面临着单抗和药物偶联后出现与抗原结合力下降和靶向效果减弱的问题。与此同时, 建立一个更有效的体外评估系统用于预测递送系统的体内行为对制剂的发展有着极大的推动作用。相信, 未来的研究会更加关注上述问题, 重视药物的性质与体内环境特征, 充分地发挥抗肿瘤抗生素的潜能。

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