利用酸性肿瘤微环境开发新型肿瘤纳米诊疗技术

Exploiting acidic tumor microenvironment for the development of novel cancer nano-theranostics

图示：

用可分解的无机纳米材料构建的可开关纳米诊疗技术，用于酸性TME靶向癌症治疗。(a)制备HSA-MnO2-Ce6&Pt (HMCP)纳米颗粒的方案，以及(b)其肿瘤微环境响应分离，以使治疗性白蛋白复合物在肿瘤内有效渗透。(c)一种显示Ce6(Mn)@CaCO3-PEG的制备方案，以及(d)其酸性TME反应分离以增强磁共振成像和协同治疗癌症。©中国科学出版社

2017年6月30日，中国科学出版社

利用酸性肿瘤微环境开发新型肿瘤纳米治疗诊疗技术

用可分解的无机纳米材料构建的可开关纳米治疗诊疗技术，用于酸性肿瘤微环境（TME）靶向癌症治疗。(a)制备HSA-MnO2-Ce6&Pt (HMCP)纳米颗粒的方案，以及(b)其肿瘤微环境响应分离，以使治疗性白蛋白复合物在肿瘤内有效渗透。(c)一种显示Ce6(Mn)@CaCO3-PEG的制备方案，以及(d)其酸性TME反应分离以增强磁共振成像和协同治疗癌症。

癌症是全世界导致人类死亡的主要原因之一。目前主流的癌症治疗方式(如手术、化疗和放疗)治疗效果有限，部分原因是肿瘤生物学的复杂性和异质性。近几十年来，随着纳米技术的飞速发展，纳米医学作为一种有希望的个性化医学，在癌症诊断和治疗方面取得了越来越多的关注。

与正常细胞通过氧化磷酸化获得能量不同的是，肿瘤细胞通过适应肿瘤血管分布不均(也称为Warburg效应)导致的肿瘤氧供应不足，利用独立于氧的糖酵解产生能量来生存。通过这种致癌代谢，肿瘤细胞会产生大量的乳酸和过量的质子和二氧化碳，共同促进细胞外TME与pH的酸化，通常在6.5 - 6.8之间，导致肿瘤转移和治疗耐药性增加。

随着纳米技术的飞速发展，一些纳米材料的目录已被广泛探索，用于设计抗癌纳米治疗诊疗技术。在《国家科学评论》上发表的一篇新综述中，苏州东吴大学功能纳米与软材料研究所(FUNSOM)的联合作者冯良柱、董自良、陶丹磊、张一成和刘庄，摘要以酸性TME为靶点，介绍了新型多功能纳米治疗诊疗技术用于精密肿瘤纳米医学的新进展，并展望了未来酸性肿瘤微环境响应纳米治疗诊疗技术的发展方向。

“各种类型的pH响应纳米微探针已经被开发，以使在酸性的实体瘤内的信号放大。通过以酸性TME为靶点，具有极好的pH响应信号放大的智能成像纳米微探针有望实现更灵敏、更准确的肿瘤诊断“”。研究者指出。

“就纳米治疗而言，研究发现，酸性TME反应表面电荷反向、PEG电晕剥离和纳米颗粒大小收缩(或分解)会促进纳米颗粒在肿瘤内的有效积累、肿瘤内扩散和肿瘤细胞吸收，从而显著改善癌症治疗。”

因此，合理开发新型肿瘤靶向纳米治疗诊疗技术，其大小顺序从大到小，表面电荷从中性或略负向正反转，更有利于肿瘤靶向药物的高效传递。

科学家们还写道，“为了将那些有趣的智能pH反应纳米治疗药物从实验台转化到临床，这些纳米系统的配方应该相对简单、可靠，而且具有良好的生物相容性，因为目前开发的许多纳米治疗诊疗技术可能过于复杂，无法进行临床转化。”

更多信息:冯良柱等，《酸性肿瘤微环境:智能抗癌纳米治疗诊疗技术的目标》，《国家科学评论》(2017)。DOI:10.1093 / nsr / nwx062

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Exploiting acidic tumor microenvironment for the development of novel cancer nano-theranostics

June 30, 2017, Science China Press

 Exploiting acidic tumor microenvironment for the development of novel cancer nano-theranostics

Size switchable nano-theranostics constructed with decomposable inorganic nanomaterials for acidic TME targeted cancer therapy. (a) A scheme showing the preparation of HSA-MnO2-Ce6&Pt (HMCP) nanoparticles, and (b) their tumor microenvironment responsive dissociation to enable efficient intra-tumoral penetration of therapeutic albumin complexes. (c) A scheme showing the preparation of Ce6(Mn)@CaCO3-PEG, and (d) its acidic TME responsive dissociation for enhanced MR imaging and synergistic cancer therapy.

Cancer is one of leading causes of human mortality around the world. The current mainstream cancer treatment modalities (e.g. surgery, chemotherapy and radiotherapy) only show limited treatment outcomes, partly owing to the complexities and heterogeneity of tumor biology. In recent decades, with the rapid advance of nanotechnology, nanomedicine has attracted increasing attention as promising for personalized medicine to enable more efficient and reliable cancer diagnosis and treatment.

Unlike normal cells energized via oxidative phosphorylation, tumor cells utilize the energy produced from oxygen-independent glycolysis for survival by adapting to insufficient tumor oxygen supply resulting from the heterogeneously distributed tumor vasculatures (also known as the Warburg effect). Via such oncogenic metabolism, tumor cells would produce a large amount of lactate along with excess protons and carbon dioxide, which collectively contribute to enhanced acidification of the extracellular TME with pH, often in the range of 6.5 to 6.8, leading to increased tumor metastasis and treatment resistance.

With rapid advances in nanotechnology, several catalogs of nanomaterials have been widely explored for the design of cancer-targeted nano-theranostics. In a new overview published in the Beijing-based National Science Review, co-authors Liangzhu Feng, Ziliang Dong, Danlei Tao, Yicheng Zhang and Zhuang Liu at the Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University in Suzhou, China present new developments in the design of novel multifunctional nano-theranostics for precision cancer nanomedicine by targeting the acidic TME and outline the potential development directions of future acidic tumor microenvironment-responsive nano-theranostics.

"Various types of pH-responsive nanoprobes have been developed to enable great signal amplification under slightly reduced pH within solid tumors. By taking the acidic TME as the target, smart imaging nanoprobes with excellent pH-responsive signal amplification would be promising to enable more sensitive and accurate tumor diagnosis," they state in the published study.

"As far as nano-therapeutics are concerned, it has been found that the acidic TME responsive surface charge reverse, PEG corona detachment and size shrinkage (or decomposition) of nanoparticles would facilitate the efficient tumor accumulation, intra-tumoral diffusion and tumor cellular uptake of therapeutics, leading to significantly improved cancer treatment. Therefore, the rational development of novel cancer-targeted nano-theranostics with sequential patterns of size switch from large to small, and surface charge reverse from neutral or slightly negative to positive within the tumor, would be more preferred for efficient tumor-targeted drug delivery."

The scientists also write, "For the translation of those interesting smart pH-responsive nano-therapeutics from bench to bedside, the formulation of those nanoscale systems should be relatively simple, reliable and with great biocompatibility, since many of those currently developed nano-theranostics were may be too complicated for clinical translation."

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More information: Liangzhu Feng et al, The acidic tumor microenvironment: a target for smart cancer nano-theranostics, National Science Review (2017). DOI: 10.1093/nsr/nwx062

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