Research Progress of Osimertinib Supported by Nanodrug Delivery System Against Non-small Cell Lung Cancer
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摘要:
奥希替尼是不可逆的第三代表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI),用于治疗经典EGFR突变和T790M耐药突变的非小细胞肺癌(NSCLC)。然而,与其他EGFR-TKIs一样,奥希替尼不可避免地存在获得性耐药、水溶性差、肿瘤累积率低等问题,限制了其治疗效果。纳米递药系统可增加药物的溶解度和稳定性,延长药物血液循环时间,提高细胞摄取率,增加在肿瘤组织中的聚集改善药物耐药问题,已成为解决传统靶向药物弊端的有效手段。本文综述了第三代EGFR-TKI奥希替尼的作用机制,重点阐述了奥希替尼纳米递药系统抗NSCLC的研究进展,并对该领域面临的挑战和未来发展方向进行了展望。
Abstract:Osimertinib is an irreversible third representative epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) for the treatment of non-small cell lung cancer (NSCLC) with T790M resistance and classical EGFR mutations. However, the therapeutic effectiveness of osimertinib is limited by acquired drug-resistance, poor water solubility and low tumor accumulation rates. Nanodrug delivery systems can increase the solubility and stability of drugs, prolong the blood circulation time of drugs, improve the uptake rate of cells, promote drug accumulation in tumor tissues, and improve drug resistance. Thus, they are effective in overcoming the limitations of traditional targeted drugs. In this study, we reviewed the mechanism of action of the third-generation EGFR-TKI osimertinib, focused on research advances in osimertinib nanodrug delivery systems against NSCLC, and explored the challenges and future development direction in this field.
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Key words:
- NSCLC /
- Osimertinib /
- Nanodrug delivery system
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0 引言
肺癌是全球范围内最常见的恶性肿瘤之一,也是全球癌症相关死亡的主要原因之一,其中非小细胞肺癌(NSCLC)占肺癌总数的80%~85%[1],然而由于缺乏特异性的临床表现,大多数NSCLC患者在确诊时已处于晚期,严重影响患者预后[2]。
近年来,随着基因检测水平的不断提高,NSCLC进入精准化治疗时代。NSCLC最常见的驱动基因突变是表皮生长因子受体(EGFR)突变,针对这种突变,临床一线治疗会选用表皮生长因子受体-酪氨酸激酶抑制剂(EGFR-TKIs)。虽然一、二代EGFR-TKIs初始治疗反应良好,但是在9~12个月后会产生耐药[3-4],最常见的原因是产生EGFR-T790M突变。针对此类突变,FDA批准了奥希替尼作为替代治疗,但仍不可避免地再次出现获得性耐药[5]。此外奥希替尼还有溶解度低、肿瘤积聚效率低及不良反应多等缺点,限制了其进一步应用[6]。纳米递药系统可以将靶向治疗与其他治疗方法,如光疗、基因治疗、化疗等联合起来,缓解耐药;通过高渗透长滞留效(EPR)将药物靶向递送至肿瘤部位,增加药物在瘤内的蓄积,提高治疗效果,降低不良反应,此外还可以加入其他载体药物,提高药物的溶解度和化学稳定性,延长药物的血液循环时间,成为解决传统靶向药物弊端的有效手段[7-8]。目前纳米药物递送系统在癌症治疗中展现了巨大的潜力,本文就奥希替尼作用机制及其相关的纳米药物在NSCLC治疗方面的进展作简要综述。
1 奥希替尼作用机制
1.1 EGFR信号通路
EGFR是一个经典的跨膜蛋白,属于酪氨酸激酶型受体。正常情况下,EGFR处于结构紧凑的自抑制状态。当其与特异性配体结合时,会导致细胞内结构域受体同源或异二聚化,引起细胞内酪氨酸激酶结构域的磷酸化,进而激活下游磷酸肌醇-3/蛋白激酶B(PI3K/AKT)和丝裂原激活蛋白激酶(Ras/Raf/MEK/ERK)途径,促进肿瘤细胞的增殖、生存、侵袭及迁移等[9-11]。
1.2 EGFR基因突变
EGFR基因突变包括经典突变及少见突变[12]。经典突变包括19号外显子的缺失突变(19-del)和21号外显子的点突变(L858R),约占EGFR突变的85%~90%[13]。少见突变包括18号外显子的点突变(E709X、G719X)及缺失突变、19号外显子的插入突变、20号外显子的点突变(S768I)及插入突变、21号外显子的点突变(L861Q)、EGFR激酶结构域重复及复杂突变等[14-15],见图 1。研究表明,EGFR是NSCLC中最常发生突变的致癌基因,因此靶向突变的EGFR是有效抗NSCLC策略[16]。
1.3 奥希替尼的应用
奥希替尼是FDA批准的第一款第三代EGFR-TKI,用于治疗EGFR突变以及由于T790M耐药突变而对第一代EGFR-TKI耐药的患者[17]。但是绝大多数NSCLC患者在接受了10个月奥希替尼的二线治疗或18~20个月的一线治疗后依旧会产生耐药,疗效不佳[18]。由于肿瘤的异质性,奥希替尼出现耐药的机制复杂繁多,其中最常见分类为EGFR依赖性耐药及EGFR非依赖性耐药。EGFR依赖性耐药机制包括C797S突变、L718Q突变、G724S突变、T790M缺失及EGFR扩增等,其中以C797S突变最为常见[19-20];EGFR非依赖性耐药机制主要包括KRAS突变、MET扩增、HER2扩增、上皮间充质转化、PI3K旁路激活及PTEN缺失等[21-22]。为防止或者延缓奥希替尼耐药的出现,延长患者的生存期,开发安全高效的多机制、多方式递送系统或联合治疗策略具有重大意义。
2 纳米递药系统负载奥希替尼抗NSCLC
纳米药物递送系统是指纳米直径在1~1 000 nm之间、用于包封小分子纳米药物的系统[23]。通过纳米技术对药物进行包载,药物的稳定性和溶解度提升,环境响应地完成药物的释放,降低了药物对其他器官的毒副作用,提高了肿瘤细胞的药物生物利用度,缩小了给药频率及剂量[24-25]。相较于传统的药物,纳米药物递送载体在疗效、生物相容性、血液循环时间、靶向性等方面表现出明显的优势[26]。
近年来,纳米递药系统在NSCLC治疗方面取得了长足的进展,从化疗药物到靶向治疗药物,从单药到联合治疗,从一代EGFR-TKIs到三代EGFR-TKIs,从载体药物到无载体纳米药物,相关纳米递药系统研究层出不穷[27]。由于奥希替尼对T790M、19-del、L858R等EGFR突变的NSCLC显示出强大的抗肿瘤活性[28],相关的载体药物研究较多,在抗NSCLC治疗中展示了良好的效果[29]。一方面奥希替尼可以和其他治疗(如化疗、光疗、免疫治疗等)联合应用,多机制联用提高治疗效果缓解耐药[30-31];另一方面,奥希替尼相关纳米药物可以通过EPR效应被动靶向到肿瘤细胞,减少不良反应,肿瘤累积率更高,进一步提高了治疗效果[32-33]。基于此,关于奥希替尼相关的纳米药物在抗NSCLC方面研究不断深入。
2.1 递送奥希替尼的载体纳米递药系统
纳米载体具有改进物理化学性质、提高生物利用度,延长血液保留时间及增强治疗效果的作用,大量基于纳米载体的药物已研发并正在临床试验中[34]。用于递送纳米药物的载体包括介孔纳米载体、金纳米载体、碳纳米载体、量子点、脂质体、聚合物胶束、蛋白质纳米载体等[35]。目前用于递送奥希替尼的纳米载体有聚合物胶束、蛋白质载体及脂质体,其中聚合物载体纳米因其在改善药代动力学、增强疗效和生物安全性方面具有显著的优势,在递送奥希替尼方面应用广泛。
奥希替尼单次、长期和高剂量使用会引起耐药和不良反应[5],Hu等设计了一种延长药物持续作用时间并提高奥希替尼疗效的方法。该团队通过乳化和溶剂蒸发法制备无毒聚乳酸-羟基乙酸共聚物(PLGA)作为纳米颗粒包载奥希替尼(AZD 9291),并用低分子量甲壳低聚糖(COS)对纳米颗粒进行修饰,最终得到AZD-PLGA-COS NPs。结果表明,该纳米药物生物相容性良好、细胞摄取率较高、药物积累率高,可通过调节内源性蛋白表达来抑制细胞存活,促进细胞凋亡。此外,甲壳低聚糖抑制了PD-L1在H1975细胞中的表达,具有免疫抑制潜力,为靶向治疗联合免疫治疗提供了新策略,为开发更有效、更安全的临床治疗方法奠定了基础[30]。
壳聚糖作为药物载体可以稳定药物中的成分,促进药物吸收,延缓或控制药物的溶解速度,因其表面富有多糖链,能被细胞或组织特异性识别,可靶向投递药物至病灶部位贮存、释放[36-37]。为了改善游离奥希替尼溶解度差、吸收率低及口服生物利用度低等问题,Kumar等采用离子凝胶法制备了壳聚糖包被的奥希替尼纳米药物,可以在酸性环境下响应性的释放奥希替尼,结果显示该纳米颗粒药物释放速度缓慢、细胞毒性强、抑瘤效果明显,此外发现该纳米药物可通过降低NSCLC患者的耐药性和减少疾病复发来改善奥希替尼临床治疗效果[38]。
为了延缓奥希替尼耐药,联合其他药物治疗表现出明显的优势,MEK/ERK信号通路在调节肿瘤细胞增殖和存活中起着关键作用,MEK抑制剂对MEK/ERK信号通路的作用可以恢复奥希替尼耐药细胞的敏感性,在早期阶段进行干预,可以很好地延迟或消除获得性耐药性的出现[39-40]。司美替尼是一种MEK抑制剂,可以抑制MEK/ERK信号通路及下游信号通路的激活。Chen等通过薄膜分散法制备了共同递送奥希替尼和司美替尼的纳米颗粒制剂,首先通过活性氧响应接头将司美替尼与聚乙二醇偶联,生成两亲性的聚乙二醇-司鲁美替尼偶联物前药,在水溶液中自组装形成胶束纳米颗粒,最后通过非共价相互作用加载奥希替尼形成纳米药物。结果显示,形成的纳米药物可以靶向递送到肿瘤组织中,在高ROS环境下响应性的释放各药物,最大限度地减少正常组织中的药物暴露,可以同时抑制EGFR和ERK通路来克服奥希替尼耐药,从而有效地诱导奥希替尼耐药及NSCLC细胞的凋亡,表现出潜在的抗肿瘤效果[41]。
环孢素A作为化疗耐药的敏化剂已被广泛研究,可以逆转单药长期应用出现的耐药问题,多药联合疗法已被证明是一种很好的癌症治疗策略,可最大限度地提高治疗效果或克服耐药性[42-43]。基于此,Chen等通过透析法设计了具有pH/氧化还原级联响应和电荷反转共载环孢素A和奥希替尼的核壳纳米颗粒,结果显示纳米药物进入肿瘤细胞后成功释放环孢素A和奥希替尼,抑制耐药细胞生长,促进细胞凋亡,此外合成的纳米药物具有低毒、高摄取率和肿瘤微环境响应释放等特点。因此,形成的纳米颗粒可能是克服奥希替尼耐药性的有效且安全的选择[44]。
细胞膜生物相容性好且清除时间长,可阻止膜包被的纳米药物被巨噬细胞识别,从而降低免疫原性反应[45]。为了改善游离奥希替尼在体内治疗反应不充分,增强肿瘤部位的药物富集并减少全身不良反应,Xu团队开发了一种肿瘤细胞膜介导的同源和分子靶向药物的双靶向策略,该团队通过纳米沉淀法利用肿瘤细胞膜表面负载奥希替尼,获得了具有体内双重靶向抗肿瘤治疗的仿生纳米药物,研究显示仿生纳米药物优先积累在肿瘤组织中,表面黏附分子和肿瘤特异性结合蛋白介导增强癌细胞的摄取,仿生纳米药物显著增强对奥希替尼的反应,抑制肿瘤细胞的增殖,促进凋亡,这种仿生纳米颗粒的双靶向策略可以增强分子靶向给药能力,提高临床疗效[46]。
奥希替尼相关的载体纳米药物在治疗NSCLC方面展示了令人鼓舞的治疗效果,但目前载体纳米药物还没有实现临床应用。主要基于以下几个方面:第一,靶向药物可能与载体材料缺乏亲和力,导致药物过早泄漏[47];第二,过度使用的载体材料会限制载药效率[48];第三,合成纳米载体材料主要是外源性的,在体内诱导免疫应答或引起潜在的长期全身毒性[49];第四,尽管一些新型纳米递送系统取得了进展,但它们的制备技术及制备成本对于临床转化来说过于费力,限制了载体相关纳米递药系统更进一步的发展[50]。
2.2 递送奥希替尼的无载体纳米递药系统
随着无载体纳米递送系统的发展,无载体纳米递药系统受到了越来越多研究者的关注。无载体纳米递送系统主要通过简单、“绿色”的自组装策略,包括溶剂交换、反溶剂或纳米沉淀法来制备,是不使用惰性载体的纳米药物递送系统[51-52]。无载体纳米递送系统具有以下优势:第一,合成简便可重复,可以解决纳米药物制备的关键问题,包括质量控制(如合适的粒径、尺寸及稳定性等)、规模化生产和临床转化[53];第二,不需要或只需要少量的表面活性剂就可以提高无载体纳米药物胶体的稳定性[54];第三,无载体纳米药物既是载体又是货物,具有超高的载药量;第四,无载体纳米药物的共组装可以有效地共递送双药或多药,实现多模式联合治疗,有助于解决肿瘤转移和耐药等癌症治疗中最棘手的问题[55]。
近年来新兴的光热和光动力治疗也为解决奥希替尼耐药问题带来新思路。光热治疗是将光能转变为热能杀伤肿瘤细胞的一种无创性肿瘤治疗新方法[56];光动力治疗是在氧元素存在的情况下,利用特定波长的光激活光敏剂产生活性氧造成细胞损坏,引起肿瘤组织坏死的治疗方法[57]。吲哚菁绿是目前已获得批准用于光热和光动力治疗的药物,但其易聚集、降解快及可与血浆蛋白的非特异性结合,极大地限制了其作为光敏剂在癌症管理中的应用[58]。为了解决上述问题,Hu等通过自组装技术利用溶剂交换法构建了吲哚菁绿-奥希替尼无载体纳米药物。实验结果表明该纳米药物在肿瘤部位滞留时间更长、靶向性更强、热疗效果显著及活性氧生成能力更强,细胞死亡率比单独使用吲哚菁绿更高,具有抑制细胞增殖、促凋亡能力。因此具有制备过程简单、EGFR靶向能力、兼具光热及光动力效果及抑癌效果好等优点,在EGFR表达的NSCLC治疗中具有很大的临床应用潜力[59]。
奥希替尼相关纳米递药系统相关总结见表 1。由于奥希替尼批准上市时间不长,关于奥希替尼的无载体纳米药物的研究还不太深入,期待更多有效的关于奥希替尼相关的无载体纳米药物的研究改善奥希替尼单药应用产生诸多的问题,以实现更早的临床应用,为NSCLC患者带去福音。
表 1 奥希替尼相关纳米递药系统Table 1 Osimertinib-related nanodrug delivery systems3 总结与展望
肺癌仍是癌症死亡的主要原因之一,然而由于缺乏特异性临床表现,在确诊时大多患者已是晚期,失去手术机会,只能选择药物治疗,虽然靶向药物治疗效果显著,但是不可避免产生耐药。联合治疗有望解决靶向药物常见的耐药性问题,在协同抗肿瘤的同时降低不良反应。纳米药物递送系统因其独特的结构,具有药物可控释放、尺寸较小及肿瘤部位累积高、靶向性更强等优势,被认为是联合治疗的有效方式,但其也存在亟待解决的问题。为了促进纳米递药系统的发展,今后的研究将集中在以下几个方面:第一,虽然纳米药物递送系统可以提高药物在肿瘤的富集,但是肿瘤的累积率仍不高,开发具有分步或者共同靶向能力的纳米递药系统进一步增加纳米药物的通透性和滞留效应;第二,基于靶向治疗的联合治疗虽然取得了良好的治疗效果,但其具体的机制仍需要进一步的探索;第三,进一步提高基于靶向治疗的纳米药物递送系统的安全性,关注临床安全性、药物代谢动力学、及开展更深入的生物安全性研究。总之,只有解决上述问题,基于靶向治疗的纳米药物递送系统才能更好的应用于临床,期待纳米递药系统在NSCLC方面更多的研究和未来的应用,为临床治疗NSCLC治疗提供更有力的武器。
Competing interests: The authors declare that they have no competing interests.利益冲突声明:所有作者均声明不存在利益冲突。作者贡献:刘汝贵、赵瑞瑞:总结和归纳文献、文章撰写刘春朝、武晓:文章选题、指导、审校 -
表 1 奥希替尼相关纳米递药系统
Table 1 Osimertinib-related nanodrug delivery systems
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