Cancer nanomedicines: closing the translational gap.
Cancer nanomedicines: closing the translational gap.
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DOI：
10.1016/s0140-6736(14)61457-4
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发表时间：
2014-12-20
期刊：
影响因子：
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通讯作者：
Grodzinski P
中科院分区：
文献类型：
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作者：
Gabizon A;Bradbury M;Prabhakar U;Zamboni W;Libutti S;Grodzinski P
国际癌症研究机构1 2014年的更新令人沮丧地提醒人们，全球癌症造成的发病率和死亡率负担。许多癌症治疗药物都是小的疏水分子，其特点是水溶性差、生物降解快、非特异性生物分布和靶外毒性。因此，这些药物往往表现出有问题的剂量限制毒性，治疗指数狭窄，临床益处有限。这些缺点突显了替代药物输送系统的必要性，这些系统可以提供比传统制剂更好的优势，并克服这些障碍。治疗癌症的纳米药物使用纳米级药物释放系统(如脂质体、树枝状大分子、聚合物或无机颗粒；如图)，这些系统可以改善溶解性和药物动力学特征，保护治疗有效载荷免受过早降解，增强对疾病组织的药物释放，并控制药物释放速率，通常导致毒性降低。2、3它们还可以促进跨越生物屏障的运输，并克服耐药机制。4肿瘤新生血管的渗漏性质和缺乏有效的淋巴引流使系统注射的纳米药物在肿瘤组织中积聚和保留。这种增强的渗透性和滞留效应被认为是成功传递纳米配方药物的原因；4尽管这种效应在单个肿瘤内和不同类型的肿瘤中有多明显和均匀尚不清楚。还设计了纳米颗粒来询问不同癌症的分子特征，以探测特定的细胞表面和细胞内目标，并提供直接的活性读数。6、7原则上，纳米药物平台的多功能性可以实现积极的靶向和多靶点的方法、协同制剂的联合传递、治疗(即在同一纳米颗粒中联合传递治疗剂和诊断剂)以及依赖于癌症疫苗和人造抗原提呈细胞的抗原递送载体的有效免疫疗法的开发。8聚乙二醇化多柔比星(Doxil)、柔红霉素(DaunoXome)、阿糖胞苷(DepoCyt)、长春新碱(Marchibo)脂质体和白蛋白结合紫杉醇(Abraxane)是美国食品和药物管理局(FDA)批准的这类相对较新的药物中仅有的成员。9然而，其他几种纳米药物目前正在开发中，目的是提高一系列细胞毒性药物和生物制品的临床潜力。超过50种这样的纳米药物正在进行临床试验。9尽管纳米药物前景看好，但在它们进入主流癌症护理环境之前，需要克服实质性的障碍。2这些问题包括制造的技术挑战、开发成本高、修改制造标准和过程控制要求的条例，以及减轻由于定价和补偿而导致市场渗透率下降的高风险。单核巨噬细胞系统对纳米材料的非特异性摄取可能会阻碍治疗潜力或导致不必要的毒性。这些材料的表面电荷也可能潜在地影响体内的生物结果，因为它们倾向于结合一系列血浆蛋白。纳米药物对肿瘤的传递、它们的细胞内化和释放机制是复杂的，并且在肿瘤类型内和之间有所不同。5改善产品特性的分析和药理学方法，或监测纳米药物及其…的生物命运
The 2014 update from the International Agency for Research on Cancer1 is a sombre reminder of the burden of morbidity and mortality resulting from cancer worldwide. Many cancer therapeutics are small, hydrophobic molecules, characterised by poor water solubility, rapid biodegradation, non-specific biodistribution, and offtarget toxicities. As a result, these agents often show problematic dose-limiting toxicities, narrow therapeutic indices, and provide limited clinical benefit. These shortcomings underscore the need for alternative drug delivery systems that can offer advantages over traditional formulations and overcome such obstacles. Nanomedicines in cancer use nanometre-scale drug delivery systems (eg, liposomes, dendrimers, polymers, or inorganic particles; figure) that can improve solubility and drug pharmacokinetic profiles, protect therapeutic payloads from premature degradation, enhance drug delivery to diseased tissue, and control rates of drug release, often resulting in reduced toxicities. 2, 3 They can also enhance transport across biological barriers and overcome drug-resistance mechanisms. 4 The leaky nature of the tumour neovasculature and the lack of effective lymphatic drainage allow systemically injected nanomedicines to accumulate and be retained in tumour tissues. This enhanced permeability and retention effect is believed to be responsible for the successful delivery of nano-formulated drugs; 4 although how pronounced and homogeneous this effect is within individual tumours and across different tumour types is unclear. 5 Nanoparticles have also been designed to interrogate the molecular signatures of different cancers to probe specific cell-surface and intracellular targets, and to provide direct activity readouts. 6, 7 In principle, the versatility of nanomedicine platforms could allow active targeted and multi-targeted approaches, codelivery of synergistic agents, theranostics (ie, codelivery of a therapeutic and a diagnostic agent in the same nanoparticle), and development of effective immunotherapies relying on antigen delivery vehicles for cancer vaccines and artificial antigen-presenting cells. 8 PEGylated liposomal doxorubicin (Doxil), liposomal daunorubicin (DaunoXome), liposomal cytarabine (DepoCyt), liposomal vincristine (Marqibo), and albumin-bound paclitaxel (Abraxane) are the only US Food and Drug Administration-approved members of this relatively new class of drugs. 9 However, several other nanomedicines are currently in development with the aim of increasing the clinical potential of a broad range of cytotoxic drugs and biologicals. More than 50 of such nanomedicines are in clinical trials. 9 Despite the promise of nanomedicines, substantial obstacles need to be overcome before they can enter mainstream cancer-care settings. 2 These problems include the technical challenges of manufacturing, the high cost of development, modification of regulations on manufacturing standards and process control requirements, and mitigation of the high risk of reduced market penetration as a consequence of pricing and reimbursement. Non-specific uptake of nanomaterials by the mononuclear phagocyte system might hinder therapeutic potential or result in unwanted toxicities. Surface charges of these materials could also potentially affect biological outcomes in the body given their tendency to bind a range of plasma proteins. The delivery of nanomedicines to tumours, their cellular internalisation, and mechanisms of release are complex and vary within and among tumour types. 5 Analytical and pharmacological methods to improve product characterisation, or monitor the biological fate of nanomedicines and their …