Smart cancer nanomedicine 智慧型癌症纳米医学

Abstract

Nanomedicines are extensively employed incancer therapy. We here propose four strategic directions to improve nanomedicine translation and exploitation. (1) Patient stratification（成层，层理） has become common practice in oncology drug development. Accordingly, probes and protocols for patient stratification are urgently needed in cancer nanomedicine, to identify individuals suitable for inclusion in clinicaltrials. (2) Rational（合理的，理性的；有理数） drug selection is crucial for clinical and commercialsuccess. Opportunistic choices based on drug availability should be replaced byinvestments in modular (pro)drug and nanocarrier design. (3) Combination therapiesare the mainstay of clinical cancer care. Nanomedicines synergize withpharmacological and physical co-treatments, and should be increasinglyintegrated in multimodal combination therapy regimens. (4) Immunotherapy isrevolutionizing the treatment of cancer. Nanomedicines can modulate thebehaviour of myeloid(骨髓的) and lymphoid（淋巴的） cells, thereby empowering anticancer immunityand immunotherapy efficacy. Alone and especially together, these fourdirections will fuel and foster the development of successful cancernanomedicine therapies.

纳米药物广泛用于癌症治疗。我们在这里提出四个战略方向，以改善纳米医学的转化和开发。 （1）患者分层已经成为肿瘤药物开发中的普遍做法。因此，在癌症纳米医学中迫切需要用于患者分层的探针和方案，以鉴定适合纳入临床试验的个体。（2）合理的药物选择对于临床和商业成功至关重要。基于药物可得性的机会选择应被模块化（前）药物和纳米载体设计的投资所取代。（3）组合疗法是临床癌症治疗的主要手段。纳米药物与药理和物理共同治疗具有协同作用，应越来越多地整合到多模式联合治疗方案中。（4）免疫疗法正在彻底改变癌症的治疗方法。纳米药物可以调节髓样和淋巴样细胞的行为，从而增强抗癌免疫力和免疫治疗功效。这四个方向，尤其是一起，将推动并促进成功的癌症纳米医学疗法的发展。

Nanomedicine holds potential to improve anticancer therapy1. Traditionally, nanomedicines are used to modulate the biodistribution and the target site accumulation of systemically administered chemotherapeutic drugs, thereby improving the balance between their efficacy and toxicity. In preclinical settings, nanomedicines typically increase tumour growth inhibition and prolong survival as compared to non-formulated drugs, but in clinical practice, patients often only benefit from nanomedicines because of reduced or altered side effects2. Despite the recent approval of several nanomedicinal anticancer drugs, such as Onivyde (liposomal irinotecan) and Vyxeos (liposomal daunorubicin plus cytarabine), the success rate of clinical translation remains relatively low. In this context, the striking imbalance between the ever-increasing number of preclinical studies reporting the development of ever more complex nanomedicines on the one hand, and the relatively small number of nanomedicine products approved for clinical use on the other hand, has become the focus of intense debate3,4. Multiple biological, pharmaceutical and translational barriers contribute to this imbalance5. Biological barriers include tumour (and metastasis) perfusion, permeability and penetration, as well as delivery to and into target cells, endo/lysosomal escape, and appropriate intracellular processing and trafficking. Pharmaceutical barriers encompass both nanoformulation- and production-associated aspects. These range from a proper stability in the bloodstream, a beneficial biodistribution, an acceptable toxicity profile, and rational mechanisms for drug release, biodegradation and elimination, to issues related to intellectual property position, cost of goods, cost of manufacturing, upscaling and batch-to-batch reproducibility. In terms of clinical translation, the key challenge is to select the right drug and the right combination regimen, and to apply them in the right disease indication and the right patient population.