药学学报

Synergy strategy	Advantage	Disadvantage
Relieving tumor hypoxia	Red blood cells and hemoglobin carry O₂^[3-12]	Good biocompatibility, high in vivo stability, long systemic circulation. Drug delivery system^[86]	The micrometer sizes of red blood cells^[13]; the instability of oxyhemoglobin; low efficiency
	Perfluorocarbon dissolves O₂^[16-24]	Higher oxygen capacity and longer ¹O₂ lifetime^[87]	Release oxygen by diffusion through the oxygen concentration gradient with a low efficiency
	Decompose H₂O₂ to O₂^[27-33]	A higher level of H₂O₂ in the tumor than normal tissues	Catalase instability
	Split H₂O to O₂^[41-45]	The abundance of H₂O in biological tissues	Water-splitting materials with poor response to visible light and near-infrared^[88]
	MnO₂ catalyzes H₂O₂ to O₂^[46-48]	Good bio-compatibility; be used as the catalyzer for decompositing H₂O₂ to produce O₂	Its potential risks, long-term toxicity, cellular uptake mechanisms and metabolic pathways are still unclear^[89]
	Mild heating promotes oxygen supply^[50-60]	Low invasiveness, high specificity	Low photothermal conversion efficiency^[90], normal cell damage caused by hyperthermia and inflammatory reactions
	Chemical drugs regulate the normalization of microvessels^{[30, 61-65]}	Induction of vascular normalization, increasing tumor oxygen supply and drug concentration	Overdose will cause serious vascular degeneration. Be difficult to grasp the dosage
	Regulate HIF-1 to reduce hypoxia^[66-70]	Alleviating tumor hypoxia to a certain extent	The relief effect of hypoxia is limited, the regulation of HIF-1 less controllable
	Inhibit mitochondrial respiration^[71-73]	Reducing endogenous oxygen consumption^[71]	Be limited to the low oxygen content in the tumor tissue
Utilizing tumor hypoxia	Control drug release by hypoxia^[74-78]	Fully utilize tumor hypoxia and the hypoxia side effect of PDT and realize synergistic treatment	Be limited to the complexity of the tumor microenvironment and the heterogeneity caused by individual differences
	Activate hypoxic activation drugs by hypoxic^[79-81]	Improving the target ability, reducing the side effects, and realizing synergistic treatment	Be limited to the complexity of microenvironment and the heterogeneity caused by individual differences
Avoiding tumor hypoxia	Constructe oxygen- independent PDT^[82-85]	Without oxygen participation, getting rid of the dependence on O₂	The study of oxygen-independent PDT is still in the primary stage

Synergy strategy	Advantage	Disadvantage
Relieving tumor hypoxia	Red blood cells and hemoglobin carry O₂^[3-12]	Good biocompatibility, high in vivo stability, long systemic circulation. Drug delivery system^[86]	The micrometer sizes of red blood cells^[13]; the instability of oxyhemoglobin; low efficiency
	Perfluorocarbon dissolves O₂^[16-24]	Higher oxygen capacity and longer ¹O₂ lifetime^[87]	Release oxygen by diffusion through the oxygen concentration gradient with a low efficiency
	Decompose H₂O₂ to O₂^[27-33]	A higher level of H₂O₂ in the tumor than normal tissues	Catalase instability
	Split H₂O to O₂^[41-45]	The abundance of H₂O in biological tissues	Water-splitting materials with poor response to visible light and near-infrared^[88]
	MnO₂ catalyzes H₂O₂ to O₂^[46-48]	Good bio-compatibility; be used as the catalyzer for decompositing H₂O₂ to produce O₂	Its potential risks, long-term toxicity, cellular uptake mechanisms and metabolic pathways are still unclear^[89]
	Mild heating promotes oxygen supply^[50-60]	Low invasiveness, high specificity	Low photothermal conversion efficiency^[90], normal cell damage caused by hyperthermia and inflammatory reactions
	Chemical drugs regulate the normalization of microvessels^{[30, 61-65]}	Induction of vascular normalization, increasing tumor oxygen supply and drug concentration	Overdose will cause serious vascular degeneration. Be difficult to grasp the dosage
	Regulate HIF-1 to reduce hypoxia^[66-70]	Alleviating tumor hypoxia to a certain extent	The relief effect of hypoxia is limited, the regulation of HIF-1 less controllable
	Inhibit mitochondrial respiration^[71-73]	Reducing endogenous oxygen consumption^[71]	Be limited to the low oxygen content in the tumor tissue
Utilizing tumor hypoxia	Control drug release by hypoxia^[74-78]	Fully utilize tumor hypoxia and the hypoxia side effect of PDT and realize synergistic treatment	Be limited to the complexity of the tumor microenvironment and the heterogeneity caused by individual differences
	Activate hypoxic activation drugs by hypoxic^[79-81]	Improving the target ability, reducing the side effects, and realizing synergistic treatment	Be limited to the complexity of microenvironment and the heterogeneity caused by individual differences
Avoiding tumor hypoxia	Constructe oxygen- independent PDT^[82-85]	Without oxygen participation, getting rid of the dependence on O₂	The study of oxygen-independent PDT is still in the primary stage

基于肿瘤乏氧增效光动力治疗的研究进展

PDF下载

尹小杰 , 王晓倩 , 张凤玲 ^*

药学学报 | 综述 2020,55(11): 2618-2627

收起

药学学报 | 综述 2020, 55(11): 2618-2627

基于肿瘤乏氧增效光动力治疗的研究进展

全屏

尹小杰, 王晓倩, 张凤玲^*

作者信息

浙江中医药大学药学院, 浙江杭州 310053

通讯作者:

*张凤玲, Tel/Fax:86-571-61768163, E-mail:windring0@163.com

Advances in photodynamic therapy based on tumor hypoxia

Xiao-jie YIN, Xiao-qian WANG, Feng-ling ZHANG^*

Affiliations

School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou 310053, China

出版时间: 2020-11-12 doi: 10.16438/j.0513-4870.2020-0507

文章导航

摘要

收起

光动力治疗（PDT）由于其微创、高效和较高的选择性，且能够诱导抗肿瘤免疫响应等独特的优点而受到广泛关注。但其治疗过程严重依赖于治疗部位的氧含量，而恶性肿瘤中广泛存在乏氧现象，因而严重限制了其疗效。此外，PDT介导的氧消耗加剧了肿瘤乏氧，进一步降低了其治疗效果。近年来，许多研究致力于克服该问题，本文总结了基于肿瘤乏氧增效PDT的各种策略，探讨了这些策略的优缺点，分析了PDT治疗肿瘤的主要挑战和未来方向，以期为光动力治疗肿瘤的深入研究提供参考。

关键词

光动力治疗 / 肿瘤 / 乏氧 / 氧气运输 / 复氧 / 联合治疗

Abstract

收起

Photodynamic therapy (PDT) has attracted wide attention due to its unique advantages such as minimal invasiveness, high efficiency and high selectivity, and its ability to induce anti-tumor immune response. However, the treatment process is heavily dependent on the oxygen content of the treatment site, and the widespread oxygen deficiency in malignant tumors severely limits its efficacy. In addition, PDT-mediated oxygen depletion exacerbates tumor hypoxia, which further reduces its therapeutic effect. In recent years, many researches have been devoted to overcoming this problem. This paper summarized various strategies based on tumor hypoxic PDT in recent years, discussing the advantages and disadvantages of these strategies, and analyzing the main challenges and future directions of PDT in the treatment of tumors, so as to provide references for the in-depth study of photodynamic therapy of tumors.

Key words

photodynamic therapy / tumor / hypoxia / oxygen delivery / reoxygenation / combination therapy

引用本文

尹小杰, 王晓倩, 张凤玲. 基于肿瘤乏氧增效光动力治疗的研究进展. 药学学报, 2020 , 55 (11) : 2618 -2627 . DOI: 10.16438/j.0513-4870.2020-0507

Xiao-jie YIN, Xiao-qian WANG, Feng-ling ZHANG. Advances in photodynamic therapy based on tumor hypoxia[J]. Acta Pharmaceutica Sinica, 2020 , 55 (11) : 2618 -2627 . DOI: 10.16438/j.0513-4870.2020-0507

正文

收起

大量研究证实, 恶性肿瘤中广泛存在乏氧现象(pO₂ ≤ 2.5 mmHg), 乏氧是多数实体瘤的固有特征, 严重的肿瘤乏氧会导致肿瘤非手术治疗的疗效明显下降, 甚至导致肿瘤转移及产生耐药性, 因而乏氧已成为肿瘤治疗中的一大难题。

光动力治疗(photodynamic therapy, PDT)是一种治疗恶性肿瘤的新型疗法, 其作用原理是将光敏剂注射到体内, 利用特定波长的光照射光敏剂, 被激发的光敏剂分子与周围组织中的氧气作用生成细胞毒性物质-活性氧, 从而杀死肿瘤细胞。现已被临床应用于治疗各种肿瘤, 如乳腺癌和甲状腺癌^[1]等。与传统的手术切除复发率高^[2]、化疗易诱导全身性不良反应相比, PDT具有微创、高效和较高的选择性, 且能够诱导抗肿瘤免疫响应等独特的优点。而恶性肿瘤中广泛存在乏氧的现象, 一方面肿瘤乏氧严重限制了PDT效果, 致使PDT治疗不彻底, 使肿瘤存在复发的可能; 另一方面, 由于PDT过程会不断消耗组织氧, 造成肿瘤部位乏氧加剧, 最终可能导致肿瘤的转移及耐药性的产生。

近年来, 人们对肿瘤乏氧所导致的PDT疗效有限及PDT不良预后问题进行了大量的研究。本文简述了近年来克服或利用肿瘤乏氧以增强PDT疗效的研究进展, 以期为肿瘤光动力治疗提供参考和新的研究思路。

1 现有的克服或利用肿瘤乏氧增效PDT的方法

收起

现有的克服或利用肿瘤乏氧增效PDT的方法可以大致分为3类:增强氧供给策略, 即通过直接或间接方法, 在PDT之前或过程中提高肿瘤组织中O₂含量; 利用肿瘤乏氧加剧增效PDT; 构建非氧依赖型PDT治疗模式。

1.1 增强氧供给策略

1.1.1 直接增强氧供给

1.1.1.1 红细胞携氧

在人体内, 红细胞中的血红蛋白将氧从肺运送到其他组织。因此, 将红细胞或血红蛋白及类血红蛋白分子作为光敏剂的运输载体, 可以向肿瘤组织传送足够的氧, 补充氧消耗, 从而克服肿瘤乏氧对PDT的限制。基于这一假设, 红细胞被用于PDT持续供氧研究^[3-7]。Wang等^[4]将红细胞作为运输载体, 将原卟啉(PpIX)包封于其中, 包封了原卟啉的红细胞能够被肿瘤细胞快速摄取, 光照后, 在红细胞的持续供氧下, 原卟啉产生更好的PDT治疗效果。Shi等^[5]通过层层自组装技术, 将具有血红蛋白装载能力的Fe³⁺纳米粒装载上氧合血红蛋白作为人造红细胞的核, 而透明质酸包裹上光敏剂作为红细胞的细胞膜, 设计出一种人造红细胞, 该人造红细胞到达肿瘤部位后, 细胞膜中的透明质酸, 在透明质酸酶的作用下被降解, 释放出氧气, 从而增效PDT, 如图 1。

在一些研究中, 血红蛋白(Hb)分子也被用作单独的氧载体来改善肿瘤乏氧状况^{[6, 8-12]}。Wang等^[9]合成了Hb共轭三嵌段共聚物, 并将其自组装成封装了光敏剂酞菁锌(ZnPc)的胶束。结果证明, 相比于没有Hb的胶束, 该胶束在HeLa细胞中能够产生更多的活性氧。Jiang等^[12]在共轭聚合物纳米粒(CNPs)表面通过共价连接上Hb, Hb既作为化学发光体系鲁米诺-过氧化氢(H₂O₂)的催化剂, 又作为氧的载体。鲁米诺在H₂O₂和Hb存在时发出蓝光, 并将能量转移给CNPs, CNPs被激发从而敏化Hb携带的氧气产生活性氧, 达到杀死肿瘤细胞的目的。

红细胞具有良好的生物相容性, 体内稳定性高, 体循环时间长, 且红细胞去核后可负载各种药物或功能纳米材料, 以上研究表明红细胞或Hb的携氧系统是补充PDT过程中消耗氧气的有效途径。但红细胞尺寸过大(微米级别), 限制了其血管扩散能力, 因而很难到达肿瘤, 且由于这一特点, 也使得基于配体-受体结合的肿瘤靶向PDT难以实现^[13]。因此用Hb代替红细胞, 但Hb携氧量有限, 1个Hb只能携带4个O₂, 且所携带的O₂容易在一些低氧组织中释放(如静脉中), 因而对PDT增效有限; 并且Hb在低氧环境中不稳定, 循环半衰期短。因而部分研究利用透明质酸或脂质体保护Hb克服其不稳定的缺点。

1.1.1.2 全氟化碳(perfluocarbon, PFC)纳米材料携氧

PFC是一类人工合成的有机分子, 由碳和氟原子组成, 其结构中氟的高电负性赋予PFC极好的氧亲和力^[14]。该类化合物由于具有溶解相当容量氧气的能力及良好的生物相容性而被作为血液代用品, 在临床上应用于创伤、失血性休克和贫血等方面^{[15, 16]}。受此启发, PFC被用于为PDT持续供氧的研究^[16-24]。Cheng等^[17]制备了一种将PFC包封于核内, 近红外光敏剂(IR780)均匀分散在脂质单层内部的乳化液, 利用PFC的高亲氧能力增强IR780的PDT效果。Yuan等^[24]设计了一种负载近红外光敏剂BODIPY的PFC多肽纳米粒, 在乏氧肿瘤环境中的治疗机制见图 2, 该纳米粒具有更高的氧摄取能力, 也具有更强的PDT效果。

尽管PFC具有强O₂亲和力, 且¹O₂在其中的寿命要比水中或细胞环境中长, 有利于¹O₂扩散的优点, 由于肿瘤内氧含量低, 使得PFC所能溶解的氧量很少, 其吸附的O₂通过简单扩散释放率也很低, 因而对PDT增效有限。目前, 可以利用PFC与红细胞结合, 提高携氧量, 或利用近红外光或超声释放其携带的氧气, 从而提高治疗效果。其他能够增强PFC携氧量, 提高其氧气释放率的方法也值得进一步探索。

1.1.1.3 H₂O₂分解供氧

在生物体内, 过氧化氢酶通过催化H₂O₂分解生成O₂和H₂O来保护细胞免受氧化损伤。此外, 研究发现, 与正常细胞相比, 癌细胞中H₂O₂含量普遍较高, 这可能与癌细胞的异常增殖、转移、血管生成和DNA损伤有关^{[25, 26]}。有学者提出并证明了同时递送过氧化氢酶和光敏剂, 并利用过氧化氢酶催化分解肿瘤组织中过量的H₂O₂, 可以实现原位供氧, 增强PDT治疗效果^[27-33]。Chen等^[27]开发了一种H₂O₂激活型、α_vβ₃整合素靶向的纳米粒, 该体系以生物相容的聚合物PLGA为载体, 同时包覆光敏剂亚甲基蓝和过氧化氢酶, 并在载体表面修饰环肽肿瘤靶向配体c(RGDfK) (一种高效选择性环肽类抑制剂)。该纳米粒在c(RGDfK)的作用下能特异性地被α_vβ₃整合素高表达的肿瘤细胞摄取后, 细胞内高水平的H₂O₂迅速渗入纳米粒内部并在过氧化氢酶的催化下分解产生氧, 大量的氧使纳米粒内压强骤增从而导致壳层破裂并释放出亚甲基蓝。在近红外激光照射下, 亚甲基蓝的光敏性被激活, 产生大量具有细胞毒性的活性氧, 引发肿瘤细胞凋亡。该体系实现了对肿瘤的自供氧、高选择性的光动力治疗。

天然的过氧化氢酶能够高效催化H₂O₂分解原位产生氧, 但制造成本高、生产复杂、不稳定和苛刻的催化条件限制了其广泛使用^[34]。随着纳米技术的快速发展, 具有内在酶活性的纳米材料因其稳定性好^[35]、制备简单等优点而受到关注, 如金纳米团簇^{[36, 37]}和铂纳米酶等^{[38, 39]}。因此, 除了过氧化氢酶, 金纳米团簇和铂纳米酶等都被用于PDT相关系统催化H₂O₂向氧的转化^[36-40], 用于对抗癌细胞的乏氧, 而其他新型的纳米酶结构也值得进一步探索。

1.1.1.4 H₂O分解供氧

绿色植物中的叶绿体吸收光能, 并将光能转化为水, 高效地产生大量的氧气。受到这一自然现象的启发, 研究人员创新性地利用无机、有机或混合材料制成的水分解纳米复合材料用于PDT持续供氧的研究^[41-45]。Zheng等^[42]将能够裂解水的纳米材料碳氮化合物C₃N₄应用于提高PDT治疗效果, 首先用碳点(carbon dots)修饰C₃N₄, 再将PpIX-PEG-RGD吸附在C₃N₄上, 其中PpIX为光敏剂, 能利用O₂产生活性氧; 靶向Argi-Gly-Asp(RGD)的聚合物具有靶向作用; 聚乙二醇(PEG)起到连接PpIX和RGD的作用。经碳点修饰后, C₃N₄能够吸收红光(630 nm)裂解H₂O产生O₂, 随后PpIX将一部分O₂转化为活性氧。这种材料不仅能够提高肿瘤中O₂水平以提高PDT疗效, 还能够降低肿瘤扩散的风险。Jiang等^[43]报道了一种红细胞膜包被的氧化石墨炔纳米片, 在近红外光照射下, 该纳米片良好的肿瘤富集及其优异的光催化水分解产生氧, 缓解了肿瘤扩散型乏氧; 与此同时, 其光热转化功能有效扩张肿瘤血管, 增强血液灌注, 从而有效克服了灌注型乏氧。该纳米片同时改善扩散型乏氧与灌注型乏氧, 显著提高了肿瘤PDT效果。Li等^[44]设计了一种集光动力治疗、光热治疗和多模式成像于一体的FeS₂@C-PEG纳米结构(200 nm), 在近红外光照射下, 该纳米材料可将H₂O氧化, 产生O₂, 从而减轻肿瘤乏氧并增效PDT。Li等^[45]设计了双光子激发的纳米复合材料(FCRH), 首次使用氮化碳(Fe-C₃N₄)激发双光子辐射引发H₂O分解, 介导产生O₂。

水是生物体内最丰富的材料, 与以往的产氧材料相比, 以水为来源将为体内产氧提供无限材料。因此在缺氧微环境下, 利用H₂O产生O₂, 是一种有前景的方法。但各类水分解材料对可见光和近红外的响应较差, 催化效率有待提高。

1.1.1.5 氧化锰(MnO₂)分解供氧

最近, 作为创新材料MnO₂得到了广泛的关注, 它可以在肿瘤的微酸环境中和过量的H₂O₂作用下产生O₂, 其降解原理可用以下反应表示。

(1)${{\rm{Mn}}{{\rm{O}}_2} + 2{{\rm{H}}^ + } \to {\rm{M}}{{\rm{n}}^{2 + }} + {{\rm{H}}_{\rm{2}}}{\rm{O}} + 1/2{{\rm{O}}_2} \uparrow }$

(2)${{\rm{Mn}}{{\rm{O}}_{\rm{2}}} + {{\rm{H}}_{\rm{2}}}{{\rm{O}}_{\rm{2}}} + {\rm{2}}{{\rm{H}}^ + } \to {\rm{M}}{{\rm{n}}^{2 + }} + 2{{\rm{H}}_{\rm{2}}}{\rm{O}} + {{\rm{O}}_{\rm{2}}} \uparrow }$

基于此, 研究人员利用各种组成不同的MnO₂材料作为光敏剂的载体, 为光动力治疗提供O₂ ^[46-48]。Fan等^[46]设计了基于上转换纳米探针(UCSMs)的智能MnO₂纳米片, 该纳米材料可同时pH响应和H₂O₂响应, 实现高分辨率上转换发光成像和氧生成, 协助PDT。当MnO₂在酸性条件下被分解, UCSMs将恢复被淬灭上转换发光从而进行诊断, 同时, MnO₂分解所产生O₂可以显著促进PDT疗效。Zhao等^[47]开发了一种基于氮杂-BODIPY/MnO₂新型纳米复合材料。该纳米材料中MnO₂可产生热量并催化内源性H₂O₂产生O₂, 以提高PDT效率。

尽管MnO₂生物相容性好, 既可作为药物载体, 又可催化H₂O₂分解产O₂, 但其潜在的风险、长期毒性、细胞摄取机制和代谢途径尚不清楚。在保持其治疗效果的前提下, 应充分重视降低或减少其在生物体内的毒性, 结合生物可降解材料^[49], 加速其生物降解性, 从而促进MnO₂在PDT领域的应用。

氧载体(Hb和PFC)可以通过向肿瘤内加载额外的氧分子来增加肿瘤内O₂。氧发生器(MnO₂和过氧化氢酶)可以催化肿瘤中过表达的H₂O₂生成O₂, 因为肿瘤中H₂O₂含量高于正常组织。尽管这些策略前景看好, 但仍存在载氧率低、漏氧快和H₂O₂有限表达等缺陷。因此, 开发克服氧限制的新型作用机制非常必要。

1.1.2 间接提高氧供给

PDT过程中肿瘤血管的异常和血管的闭合共同降低了肿瘤的供氧量, 从而影响PDT的疗效。因此, 改善肿瘤血管异常化和避免血管闭合是改善肿瘤组织乏氧状况的有效途径。基于以上认知, 许多研究小组致力于通过改变肿瘤微环境, 间接提高肿瘤氧供给, 从而提高PDT疗效。

研究表明, 通过温和加热(约43 ℃)提高局部温度会导致肿瘤血流量增加从而提高肿瘤内氧水平^[50-52]。因此, 利用温和光热对肿瘤进行预热处理是减少乏氧、增效PDT的有效方法。基于此原理, 光热疗法(photothermal therapy, PTT)被广泛用于肿瘤热疗^[53-60]。Zhang等^[57]将具有高热转化率的金纳米片(GNS)用作PTT的核心, 其外壳由负载Ce6光敏剂的介孔二氧化硅组成。结果表明, 相较于单一PDT和PTT, 联合使用PTT, 减轻了乏氧并增加了PDT效果。Zhu等^[58]构建了基于牛血清白蛋白(BSA)、磺胺类药物(SAs)和铁卟啉纳米级金属有机骨架(NMOFs, 图 3), 可用于协同PDT和PTT。体外活性氧检测和光热温度检测结果表明, 该BSA/SAs-NMOF纳米平台可以在肿瘤细胞中表现出更好的PDT效果。Liu等^[59]将生物相容性铜铁氧体纳米球(CFNs), 经直接电子转移和光增强的Fenton反应后, 在650 nm激光辐照下生成活性氧, 并且该纳米球暴露于808 nm激光时具有高的光热转换效率, 从而显著提高PDT效果。Feng等^[60]制备了含有光敏剂己胺偶联氯(e6)和光热剂3'-四甲基吲哚并花青碘化物(DiR)的脂质体体系。在此体系中, 通过785 nm激光激发DiR, 可产生温和的光热效应, 同时使用660 nm激光激发光敏剂。结果表明, 该方法可显著改善肿瘤内血流, 使肿瘤乏氧减轻, 从而产生更好的PDT效果。虽然以上研究表明可有效改善肿瘤内血流, 使肿瘤乏氧减轻, 但光热转换效率低、由热疗引起的正常细胞损伤和炎性反应可能导致包括肿瘤复发和治疗抗性等不良反应仍有待解决。

除了使用温和加热来暂时改善肿瘤内血流, 化学药物(紫杉烷、吉西他滨和顺铂等)最近被用于调节肿瘤微血管系统的混乱结构, 使血液灌注率更高, 从而提高肿瘤内氧含量^{[30, 61-65]}。Wang等^[64]开发了一种交联了光敏剂(THPP)和肿瘤治疗前药(顺铂)的共价有机聚合物, 用于癌症联合治疗。将该聚合物静脉注射4T1荷瘤小鼠体内后, 顺铂能显著降低血管内皮生长因子的表达, 使血管恢复正常, 缓解肿瘤乏氧, PDT疗效随之提高。Yang等^[65]使用肝素, 增强抗凝血酶Ⅲ的活性, 减轻血管内凝血和血栓形成, 从而增强PDT效果。但是, 用这些抑制剂调节血管异常状态和预防血管闭合是暂时的, 导致氧供给量有限, PDT效果受到限制。利用化学药物诱导血管正常化, 可更有效地供氧和给药, 但用药过量反而会使血管退化严重, 阻碍O₂和药物运输, 且血管正常化只能持续一定时间, 故化学药物的用药量和作用时间的控制仍需进一步探索。

在肿瘤微环境中其他异常, 如过表达缺氧诱导因子(HIF-1)和存在致密的细胞外基质, 均为导致肿瘤乏氧的重要原因^[66-70]。因此, 通过降低肿瘤组织中HIF-1的水平减轻乏氧, 是提高PDT效果的有效方法。Chen等^[69]开发了以茴香酰胺为靶点的脂质磷酸钙纳米粒(LCP), 将HIF-1αsiRNA (siRNA, HIF-1α的干扰RNA)输送至SAS细胞(人舌鳞状细胞癌贴壁细胞)和SCC4细胞(鳞状细胞癌)中, 然后给予PDT。结果表明, 由于RNA的干扰作用, HIF-1α表达被有效降低, 且联合疗法比单独的HIF-1α siRNA或PDT更有效, 实现增效PDT。Liu等^[70]通过疏水性光敏剂Ce6和雷帕霉素(RAP)自组装形成了双药物纳米核, RAP的持续释放抑制了HIF-1α表达, 从而缓解了肿瘤乏氧, 实现增效PDT。降低肿瘤组织中HIF-1水平可一定程度缓解肿瘤乏氧状况, 对提高PDT有一定作用, 但缓解乏氧效果有限, 因而对PDT增效有限, 且肿瘤微环境的复杂性对该方法的影响也需进一步探索。

最近研究发现, 抑制肿瘤细胞线粒体呼吸和减少内源性氧消耗取得了新进展^[71-73]。Mai等^[71]以血小板膜(PM)作为纳米载体, 包封二甲双胍(Met)和光敏剂IR780 (PM-IR780-Met NP), Met的引入可抑制线粒体呼吸从而降低肿瘤耗氧量, 缓解肿瘤乏氧, 实现增效PDT的目的。Yang等^[73]将IR780和Met包装在PEG-PCL脂质体中。Met可以直接抑制线粒体电子传输链, 从而有效地抑制细胞呼吸。减少内源性氧消耗的这一概念提供了新的方式, 解决了乏氧限制PDT效果的重要难题。尽管抑制肿瘤细胞线粒体呼吸可减少内源性氧消耗, 间接促使肿瘤氧含量提高, 但受限于肿瘤组织本身氧含量低的状况, 其对提高肿瘤中氧含量效果有限。结合其他提高肿瘤组织氧含量的方法(PFC为载体)或许是解决上述问题的有效方法。

1.2 利用肿瘤乏氧加剧增效PDT

与其他侧重于缓解肿瘤乏氧的方法不同, 也有研究变劣势为优势, 巧妙利用光动力反应加剧的肿瘤乏氧, 释放其他治疗药物或活化生物还原药, 实现联合治疗。

1.2.1 利用乏氧加剧控制药物释放

研究表明, 硝基基团、醌、脂族氮氧化物和芳族氮氧化物等均为乏氧敏感结构。将光敏剂和具有乏氧敏感结构的药物载体相结合, 光动力反应加剧了肿瘤乏氧, 活化乏氧敏感结构, 进而促进了药物的释放, 整个治疗可以被认为是一种自反馈过程, 提高了治疗效果^[74-78]。Qian等^[76]报道了2-硝基咪唑(NI)缀合, 含二噻吩-苯并三唑的聚合物(NI-CP), 通过复乳法将多柔比星(DOX)封装成核壳(DOX/NI-CP)结构。肿瘤区域富集了DOX/NI-CP纳米粒后, 近红外光光敏剂(二噻吩-苯并三唑)产生高水平的细胞毒性活性氧和更严重的肿瘤组织乏氧状态, 从而触发疏水性NI基团被生物还原形成亲水性2-氨基咪唑类化合物, 导致纳米粒塌陷并释放DOX, 最终发挥DOX和PDT的协同抗癌作用。Wang等^[77]将PDT与缺氧反应性化疗(简称为Ce6-PEG-Azo-PCL)相结合研发了一种乏氧响应性输送系统。在该纳米系统中, 光敏剂Ce6在照射过程中持续消耗氧, 进一步放大肿瘤的缺氧状况, 并触发肿瘤部位乏氧响应性偶氮苯的分解, 从而释放负载的DOX, 实现了PDT和化疗的协同治疗, 增强了PDT效果。Zhang等^[78]将低氧响应药物递送系统与PDT整合在一起, 构建了一种新型偶氮苯(偶氮)纳米载体(CPs-CPT-Ce6 NPs), 该载体负载了光敏剂Ce6和化疗药物喜树碱(CPT), 通过PDT增强肿瘤区域的乏氧状态, 从而激活乏氧响应, 释放CPT, 实现PDT与化疗的结合。且体外和体内研究均证实该载药系统可以增效PDT。

1.2.2 乏氧加剧激活生物还原药

近年来, 针对乏氧引起的肿瘤生物学变化发展的生物还原药成为研究的热点。生物还原药是指“无毒”的前药在乏氧环境中被相关的还原酶还原激活为相应的细胞毒剂的一类制剂, 典型的生物还原药包括硝基咪唑类化合物、醌类化合物和氮氧化物等。目前已进入临床试验的该类药物有巴诺蒽醌(AQ4N)和替拉扎明(tirapazamine, TPZ)。将PDT同光敏剂与生物还原药联合使用, 利用PDT加剧的肿瘤乏氧活化生物还原药, 可起到联合治疗的作用^[79-81]。Liu等^[79]在PDT后, 瘤内直接注射生物还原前药TPZ, 利用PDT加剧的肿瘤乏氧活化TPZ, 达到PDT与生物还原药的协同治疗。Feng等^[80]制备了一种包裹了光敏剂Ce6和生物还原药AQ4N的脂质体, 在光照条件下, Ce6消耗瘤内氧并产生光动力效应, 加剧肿瘤乏氧, 肿瘤乏氧的加剧导致AQ4N活化, 产生细胞毒性, 从而进一步杀伤肿瘤细胞。Zhang等^[81]创新使用2-硝基咪唑衍生物共轭PEG制备了脂质体, 并在其中封装Ce6和低氧激活的前药TPZ。Ce6介导的PDT在激光照射下会引起缺氧导致脂质体分解并激活TPZ的抗肿瘤活性, 从而增强对癌细胞的杀伤力。体外和体内研究均表明, 与常规PDT相比, 该脂质体抗癌活性更高。

利用乏氧控制药物释放及激活乏氧响应药物都是充分利用了肿瘤本身的乏氧状况及PDT导致的肿瘤乏氧加剧, 在提高PDT靶向性的同时实现了协同治疗。然而, 面对肿瘤微环境的复杂性和个体差异引起的异质性, 该方法很多问题仍需进一步探讨和明晰。

1.3 构建非氧依赖型PDT

由于传统的PDT依靠氧产生具有细胞毒性的活性氧, 因而实体瘤的乏氧状态极大地限制了其疗效。而设计非氧依赖的新型光敏剂是克服这一限制的有效方法^[82-85]。Babii等^[82]开发了一种由二芳基乙烯衍生的拟肽, 在无氧条件下, 光照即可产生活性氧, 因此可以通过这种非氧依赖PDT进行肿瘤治疗。Han等^[84]设计了一种肿瘤pH响应性聚合物胶束。该胶束在808 nm近红外光辐射下产生高温, 同时诱导单线态氧供体(二苯基蒽内过氧化物, DPAE)的热裂解, 从而实现不需要氧参与即可产生大量PDT用单线态氧。该纳米体系将光热触发的非氧依赖PDT和PTT结合, 实现了有效的肿瘤消融, 且没有明显的毒副作用。Huang等^[85]设计报道了一种新型的聚合物单线态氧载体, 该聚合物由1, 4-二甲基萘的衍生物(DMN)、氮杂氟化硼二吡咯化物(B1)和水溶性PEG构成, 其中, DMN能与单线态氧反应生成过氧化物且在受热时释放出单线态氧, 实现了乏氧肿瘤内单线态氧的高效、可控释放, 成功抑制肿瘤的生长。目前, 非氧依赖的新型光敏剂仍较少见报道, 因而构建更多非氧依赖的新型光敏剂的研究仍需进一步开展。

综上所述, 3类基于肿瘤乏氧增效PDT的治疗策略:“克服乏氧”策略(增强氧供给策略)、“规避乏氧”策略(构建非氧依赖型PDT治疗模式)及“利用乏氧”策略(乏氧应激控释及乏氧激活乏氧响应药物)的优势和缺点见表 1^{[3-13, 16-24, 27-33, 41-45, 46-48, 50-90]}。

2 总结与展望

收起

实体瘤乏氧对PDT介导的癌症治疗是一个严峻挑战, 本文对克服PDT乏氧的各种策略进行了概述, 虽然所列的方法都被证明了具有提高肿瘤组织氧含量的能力, 但是肿瘤氧含量与PDT效率之间的精确相关性仍需要精密监测, 以便进一步合理设计PDT供氧载体, 提高其携氧能力。PDT还面临其他重要挑战, 如光的穿透有限和光敏剂对正常组织的毒性。因此, 需要开发智能和多功能的载体, 协同克服这些系统性障碍, 以获得最大抗癌效果, 还需要注意PDT诱导的肿瘤侵袭和转移等不良反应。此外, 为了满足临床应用, PDT载体需要满足生物相容性、生物降解性、简单、可控性和可重复性等要求。随着这些问题的解决, 利用或克服乏氧的系统将为PDT开辟一条新的途径。

作者贡献:尹小杰负责整理文献并撰写文章初稿; 王晓倩负责绘图、制作表格; 张凤玲负责文章设计、把握文章方向以及稿件修改。

利益冲突:所有作者均声明不存在利益冲突。

基金

收起

国家自然科学基金资助项目(81803346)

参考文献

收起

文献

收起

参考文献引证文献

排序方式：

[1]

Muhanna

, Chan

HHL

, Townson

et al . Photodynamic therapy enables tumor-specific ablation in preclinical models of thyroid cancer[J]. Endocr Relat Cancer, 2020, 27: 41-53. http://www.researchgate.net/publication/337379343_Photodynamic_therapy_enables_tumor_specific_ablation_in_preclinical_models_of_thyroid_cancer

https://doi.org/10.1530/ERC-19-0258

[2]

Wang

, Wu

. Clinical application of photodynamic therapy in respiratory tract tumors[J]. Mod Pract Med (现代实用医学), 2020, 32: 7-8.

[3]

Liu

, Liu

, Zou

et al . Aggressive man-made red blood cells for hypoxia-resistant photodynamic therapy[J]. Adv Mater, 2018, 30: 1802006. http://onlinelibrary.wiley.com/doi/10.1002/adma.201802006

https://doi.org/10.1002/adma.201802006

[4]

Wang

, Shi

, Yang

et al . Versatile RBC-derived vesicles as nanoparticle vector of photosensitizers for photodynamic therapy[J]. Nanoscale, 2013, 5: 416-421. http://europepmc.org/abstract/med/23187860

https://doi.org/10.1039/C2NR32506C

[5]

Shi

, Zhan

, Yan

et al . Oxyhemoglobin nano-recruiter preparation and its application in biomimetic red blood cells to relieve tumor hypoxia and enhance photodynamic therapy activity[J]. J Mater Chem B, 2020, 8: 534-545. http://pubs.rsc.org/en/content/articlelanding/2020/tb/c8tb02430h

https://doi.org/10.1039/C8TB02430H

[6]

Tang

, Zhen

, Wang

et al . Red blood cell-facilitated photodynamic therapy for cancer treatment[J]. Adv Funct Mater, 2016, 26: 1757-1768. http://onlinelibrary.wiley.com/doi/10.1002/adfm.201504803

https://doi.org/10.1002/adfm.201504803

[7]

Liu

, Li

, Ruan

et al . Polypeptide-based artificial erythrocytes conjugated with near infrared photosensitizers for imaging-guided photodynamic therapy[J]. J Mater Sci, 2018, 53: 9368-9381. http://link.springer.com/10.1007/s10853-018-2276-6

https://doi.org/10.1007/s10853-018-2276-6

[8]

Wang

, Li

, Yao

et al . Orthogonal near-infrared upconversion co-regulated site-specific O₂ delivery and photodynamic therapy for hypoxia tumor by using red blood cell microcarriers[J]. Biomaterials, 2017, 125: 90-100. http://europepmc.org/abstract/MED/28235648

https://doi.org/10.1016/j.biomaterials.2017.02.017

[9]

Wang

, Yuan

, Chen

et al . Synthesis of hemoglobin conjugated polymeric micelle:a ZnPc carrier with oxygen self-compensating ability for photodynamic therapy[J]. Biomacromolecules, 2015, 16: 2693-2700. http://dx.doi.org/10.1021/acs.biomac.5b00571

https://doi.org/10.1021/acs.biomac.5b00571

[10]

Luo

, Zheng

, Zhao

et al . Self-monitoring artificial red cells with sufficient oxygen supply for enhanced photodynamic therapy[J]. Sci Rep, 2016, 6: 23393. http://europepmc.org/articles/PMC4796897/

https://doi.org/10.1038/srep23393

[11]

, Cui

, Bu

et al . A photosensitizer loaded hemoglobin-polymer conjugate as a nanocarrier for enhanced photodynamic therapy[J]. J Mater Chem B, 2018, 6: 1825-1833. http://smartsearch.nstl.gov.cn/paper_detail.html?id=1125a0f660d5e76f0be0a73ecab60fce

https://doi.org/10.1039/C7TB03109B

[12]

Jiang

, Bai

, Liu

et al . Luminescent, oxygen-supplying, hemoglobin-linked conjugated polymer nanoparticles for photodynamic therapy[J]. Angew Chem Int Ed Engl, 2019, 58: 10660-10665. http://onlinelibrary.wiley.com/doi/10.1002/ange.201905884

https://doi.org/10.1002/anie.201905884

[13]

Wang

, Sun

, Cheng

et al . Multifunctional theranostic red blood cells for magnetic-field-enhanced in vivo combination therapy of cancer[J]. Adv Mater, 2014, 26: 4794-4802. http://www.ncbi.nlm.nih.gov/pubmed/24838472

https://doi.org/10.1002/adma.201400158

[14]

Kaneda

, Caruthers

, Lanza

et al . Perfluorocarbon nanoemulsions for quantitative molecular imaging and targeted therapeutics[J]. Ann Biomed Eng, 2009, 37: 1922-1933. http://europepmc.org/abstract/MED/19184435

https://doi.org/10.1007/s10439-009-9643-z

[15]

Chen

, Pan

, Lanza

et al . Perfluorocarbon nanoparticles for physiological and molecular imaging and therapy[J]. Adv Chronic Kidney Dis, 2013, 20: 466-478. http://europepmc.org/articles/PMC4074885/

https://doi.org/10.1053/j.ackd.2013.08.004

[16]

Song

, Feng

, Liang

et al . Ultrasound triggered tumor oxygenation with oxygen-shuttle nanoperfluorocarbon to overcome hypoxia-associated resistance in cancer therapies[J]. Nano Lett, 2016, 16: 6145-6153. http://pubs.acs.org/doi/10.1021/acs.nanolett.6b02365

https://doi.org/10.1021/acs.nanolett.6b02365

[17]

Cheng

, Cheng

, Jiang

et al . Perfluorocarbon nanoparticles enhance reactive oxygen levels and tumour growth inhibition in photodynamic therapy[J]. Nat Commun, 2015, 6: 8785. http://www.nature.com/articles/ncomms9785

https://doi.org/10.1038/ncomms9785

[18]

Que

, Liu

, Tan

et al . Enhancing photodynamic therapy efficacy by using fluorinated nanoplatform[J]. ACS Macro Lett, 2016, 5: 168-173. http://pubs.acs.org/doi/10.1021/acsmacrolett.5b00935

https://doi.org/10.1021/acsmacrolett.5b00935

[19]

Song

, Ji

, Liang

et al . TaOx decorated perfluorocarbon nanodroplets as oxygen reservoirs to overcome tumor hypoxia and enhance cancer radiotherapy[J]. Biomaterials, 2017, 112: 257-263. http://www.ncbi.nlm.nih.gov/pubmed/27768978

https://doi.org/10.1016/j.biomaterials.2016.10.020

[20]

Song

, Liang

, Yi

et al . Perfluorocarbon-loaded hollow Bi₂Se₃ nanoparticles for timely supply of oxygen under near-infrared light to enhance the radiotherapy of cancer[J]. Adv Mate, 2016, 28: 2716-2723. http://dx.doi.org/10.1002/adma.201504617

https://doi.org/10.1002/adma.201504617

[21]

Spahn

. Blood substitutes artificial oxygen carriers:perfluorocarbon emulsions[J]. Critical Care, 1999, 3: R93. http://www.springerlink.com/content/e50102lv0t21701x/

https://doi.org/10.1186/cc364

[22]

Day

, Estabrook

, Logan

et al . Fluorous photosensitizers enhance photodynamic therapy with perfluorocarbon nanoemulsions[J]. Chem Commun, 2017, 53: 13043-13046. http://www.ncbi.nlm.nih.gov/pubmed/29164187

https://doi.org/10.1039/C7CC07038A

[23]

Wang

, Liu

, You

et al . All-in-one theranostic nanoplatform based on hollow MoS(x) for photothermally-maneuvered oxygen self-enriched photodynamic therapy[J]. Theranostics, 2018, 8: 955-971. http://europepmc.org/articles/PMC5817104/

https://doi.org/10.7150/thno.22325

[24]

Yuan

, Ruan

, Jiang

et al . Oxygen self-sufficient fluorinated polypeptide nanoparticles for NIR imaging-guided enhanced photodynamic therapy[J]. J Mater Chem B, 2018, 6: 2323-2331. http://smartsearch.nstl.gov.cn/paper_detail.html?id=d46f9ee3c5f75d0c9c3d511916c8d9ec

https://doi.org/10.1039/C8TB00493E

[25]

López-Lázaro

. Dual role of hydrogen peroxide in cancer:possible relevance to cancer chemoprevention and therapy[J]. Cancer Lett, 2007, 252: 1-8. http://europepmc.org/abstract/med/17150302

https://doi.org/10.1016/j.canlet.2006.10.029

[26]

Lippert

, Van de Bittner

, Chang

. Boronate oxidation as a bioorthogonal reaction approach for studying the chemistry of hydrogen peroxide in living systems[J]. Acc Chem Res, 2011, 44: 793-804. http://europepmc.org/articles/PMC3178007/

https://doi.org/10.1021/ar200126t

[27]

Chen

, Tian

, He

et al . H₂O₂-activatable and O₂-evolving nanoparticles for highly efficient and selective photodynamic therapy against hypoxic tumor cells[J]. J Am Chem Soc, 2015, 137: 1539-1547. http://europepmc.org/abstract/med/25574812

https://doi.org/10.1021/ja511420n

[28]

Cheng

, Zhu

, Li

et al . An O₂ self-sufficient biomimetic nanoplatform for highly specific and efficient photodynamic therapy[J]. Adv Funct Mater, 2016, 26: 7847-7860. http://dx.doi.org/10.1002/adfm.201603212

https://doi.org/10.1002/adfm.201603212

[29]

, Cheng

, Xie

et al . Cancer cell membrane camouflaged cascade bioreactor for cancer targeted starvation and photodynamic therapy[J]. ACS Nano, 2017, 11: 7006-7018. http://www.ncbi.nlm.nih.gov/pubmed/28665106

https://doi.org/10.1021/acsnano.7b02533

[30]

Chen

, Chen

, Liang

et al . Drug-induced co-assembly of albumin/catalase as smart nano-theranostics for deep intra-tumoral penetration, hypoxia relieve, and synergistic combination therapy[J]. J Control Release, 2017, 263: 79-89. http://www.sciencedirect.com/science/article/pii/S0168365916312020

https://doi.org/10.1016/j.jconrel.2016.11.006

[31]

Tang

, Yang

, Yin

et al . Investigating the optimal size of anticancer nanomedicine[J]. Proc Natl Acad Sci U S A, 2014, 111: 15344-15349. http://europepmc.org/abstract/MED/25316794

https://doi.org/10.1073/pnas.1411499111

[32]

Zhang

, Shen

, Zhang

et al . A multifunctional nanocomposite for luminescence resonance energy transfer-guided synergistic monitoring and therapy under single near infrared light[J]. Chem Commun, 2016, 52: 4880-4883. http://www.ncbi.nlm.nih.gov/pubmed/26912095

https://doi.org/10.1039/C6CC00010J

[33]

, Cong

, He

et al . Tumor hypoxia relief overcomes multidrug resistance and immune inhibition for self-enhanced photodynamic therapy[J]. Chem Eng J, 2019, 375: 122079. http://www.sciencedirect.com/science/article/pii/S1385894719314731

https://doi.org/10.1016/j.cej.2019.122079

[34]

Zhang

, Li

, Wu

et al . Recent progress in the design fabrication of metal-organic frameworks-based nanozymes and their applications to sensing and cancer therapy[J]. Bionsens Bioelectron, 2019, 137: 178-198. http://www.sciencedirect.com/science/article/pii/S0956566319303525

https://doi.org/10.1016/j.bios.2019.04.061

[35]

Shang

, Liu

, Wang

et al . Enzyme mimic nanomaterials and their biomedical applications[J]. ChemBioChem, 2020. DOI:10.1002/cbic.202000123.

https://doi.org/10.1002/cbic.202000123

[36]

Dan

, Hu

, Ge

et al . Ultrasmall theranostic nanozymes to modulate tumor hypoxia for augmenting photodynamic therapy and radiotherapy[J]. Biomater Sci, 2020, 8: 973-987. http://pubs.rsc.org/en/content/articlepdf/2020/bm/c9bm01742a

https://doi.org/10.1039/C9BM01742A

[37]

Liu

, Wu

, Liu

et al . Self-supplying O₂ through the catalase-like activity of gold nanoclusters for photodynamic therapy against hypoxic cancer cells[J]. Small, 2017, 13: 1700278. http://dx.doi.org/10.1002/smll.201700278

https://doi.org/10.1002/smll.201700278

[38]

Gao

, Li

, Zhang

et al . Biomimetic platinum nanozyme immobilized on 2D metal-organic frameworks for mitochondrion-targeting and oxygen self-supply photodynamic therapy[J]. ACS Appl Mater Inter, 2020, 12: 1963-1972. http://www.ncbi.nlm.nih.gov/pubmed/31873002

https://doi.org/10.1021/acsami.9b14958

[39]

, Zhu

, Tang

et al . Au nanoparticles with enzyme-mimicking activity-ornamented ZIF-8 for highly efficient photodynamic therapy[J]. Biomater Sci, 2019, 7: 2740-2748. http://www.researchgate.net/publication/332198676_Au_Nanoparticles_with_Enzyme-Mimicking_Activities_Ornamented_ZIF-8_for_Highly_Efficient_Photodynamic_Therapy

https://doi.org/10.1039/C9BM00333A

[40]

Zhang

, Wang

, Liu

et al . Nanozyme decorated metal-organic frameworks for enhanced photodynamic therapy[J]. ACS Nano, 2018, 12: 651-661. http://www.ncbi.nlm.nih.gov/pubmed/29290107

https://doi.org/10.1021/acsnano.7b07746

[41]

, Sheng

, Gao

et al . Activatable albumin-photosensitizer nanoassemblies for triple-modal imaging and thermal-modulated photodynamic therapy of cancer[J]. Biomaterials, 2016, 93: 10-19. http://www.irgrid.ac.cn/handle/1471x/1169448?mode=full&submit_simple=Show+full+item+record

https://doi.org/10.1016/j.biomaterials.2016.03.037

[42]

Zheng

, Li

et al . Carbon-dot-decorated carbon nitride nanoparticles for enhanced photodynamic therapy against hypoxic tumor via water splitting[J]. ACS Nano, 2016, 10: 8715-8722. http://www.ncbi.nlm.nih.gov/pubmed/27532320

https://doi.org/10.1021/acsnano.6b04156

[43]

Jiang

, Zhang

, Wang

et al . Tumor reoxygenation and blood perfusion enhanced photodynamic therapy using ultrathin graphdiyne oxide nanosheets[J]. Nano Lett, 2019, 19: 4060-4067. http://pubs.acs.org/doi/10.1021/acs.nanolett.9b01458

https://doi.org/10.1021/acs.nanolett.9b01458

[44]

, Lin

, Qu

. FeS₂@C-ICG-PEG nanostructure with intracellular O₂ generation for enhanced photo-dynamic/thermal therapy and imaging[J]. Biochem Eng J, 2020, 384: 123374. http://www.sciencedirect.com/science/article/pii/S1385894719327871

[45]

, Zhang

, Xie

et al . A two-photon excited O₂-evolving nanocomposite for efficient photodynamic therapy against hypoxic tumor[J]. Biomaterials, 2019, 194: 84-93. http://www.sciencedirect.com/science/article/pii/S0142961218308457

https://doi.org/10.1016/j.biomaterials.2018.12.017

[46]

Fan

, Bu

, Shen

et al . Intelligent MnO₂ nanosheets anchored with upconversion nanoprobes for concurrent pH-/H₂O₂-responsive UCL imaging and oxygen-elevated synergetic therapy[J]. Adv Mater, 2015, 27: 4155-4161. http://europepmc.org/abstract/MED/26058562

https://doi.org/10.1002/adma.201405141

[47]

Zhao

, Xie

, Guo

et al . Facile phototherapeutic nanoplatform by integrating a multifunctional polymer and MnO₂ for enhancing tumor synergistic therapy[J]. Adv Healthc Mater, 2019, 8: 1900414. http://onlinelibrary.wiley.com/doi/pdf/10.1002/adhm.201900414

https://doi.org/10.1002/adhm.201900414

[48]

Liu

, Pan

, Cao

et al . A tumor microenvironment responsive biodegradable CaCO₃/MnO₂-based nanoplatform for the enhanced photodynamic therapy and improved PD-L1 immunotherapy[J]. Theranostics, 2019, 9: 6867-6884. http://www.ncbi.nlm.nih.gov/pubmed/31660074

https://doi.org/10.7150/thno.37586

[49]

Luo

, Liu

, Yin

et al . Biodegradable micelles for two-photon photodynamic therapy in a mouse model of breast cancer[J]. Acta Pharm Sin (药学学报), 2019, 54: 927-936. http://en.cnki.com.cn/Article_en/CJFDTotal-YXXB201905021.htm

[50]

Song

, Rhee

, Levitt

. Effect of hyperthermia on hypoxic cell fraction in tumor[J]. Int J Radiat Oncol, 1982, 8: 851-856. http://europepmc.org/abstract/med/7107420

https://doi.org/10.1016/0360-3016(82)90088-8

[51]

Chen

, Chen

, Shapiro

et al . Sequencing of combined hyperthermia and photodynamic therapy[J]. Radiat Res, 1996, 146: 293-297. http://europepmc.org/abstract/MED/8752307

https://doi.org/10.2307/3579459

[52]

Brizel

, Scully

, Harrelson

et al . Radiation therapy and hyperthermia improve the oxygenation of human soft tissue sarcomas[J]. Cancer Res, 1996, 56: 5347-5350. http://www.ncbi.nlm.nih.gov/pubmed/8968082

[53]

Jin

, Lovell

, Chen

et al . Ablation of hypoxic tumors with dose-equivalent photothermal, but not photodynamic, therapy using a nanostructured porphyrin assembly[J]. ACS Nano, 2013, 7: 2541-2550. http://europepmc.org/articles/PMC3610399

https://doi.org/10.1021/nn3058642

[54]

Jaque

, Martínez

Maestro L

, del

Rosal B

et al . Nanoparticles for photothermal therapies[J]. Nanoscale, 2014, 6: 9494-9530. http://www.ncbi.nlm.nih.gov/pubmed/25030381

https://doi.org/10.1039/C4NR00708E

[55]

Chen

, Xu

, Liang

et al . Photothermal therapy with immune-adjuvant nanoparticles together with checkpoint blockade for effective cancer immunotherapy[J]. Nat Commun, 2016, 7: 13193. http://www.ncbi.nlm.nih.gov/pubmed/27767031

https://doi.org/10.1038/ncomms13193

[56]

, Peng

, Zheng

et al . New application of phthalocyanine molecules:from photodynamic therapy to photothermal therapy by means of structural regulation rather than formation of aggregates[J]. Chem Sci, 2018, 9: 2098-2104. http://pubs.rsc.org/en/content/articlehtml/2018/SC/C7SC05115H

https://doi.org/10.1039/C7SC05115H

[57]

Zhang

, Yang

, Wei

et al . Intelligent gold nanostars for in vivo CT imaging and catalase-enhanced synergistic photodynamic & photothermal tumor therapy[J]. Theranostics, 2019, 9: 5424-5442.

https://doi.org/10.7150/thno.33015

[58]

Zhu

, Liu

, Yang

et al . Albumin/sulfonamide stabilized iron porphyrin metal organic framework nanocomposites:targeting tumor hypoxia by carbonic anhydrase Ⅸ inhibition and T1-T2 dual mode MRI guided photodynamic/photothermal therapy[J]. J Mater Chem B, 2018, 6: 265-276. http://www.ncbi.nlm.nih.gov/pubmed/32254169

https://doi.org/10.1039/C7TB02818K

[59]

Liu

, Zhen

, Jin

et al . All-in-one theranostic nanoagent with enhanced reactive oxygen species generation and modulating tumor microenvironment ability for effective tumor eradication[J]. ACS Nano, 2018, 12: 4886-4893. http://www.ncbi.nlm.nih.gov/pubmed/29727164

https://doi.org/10.1021/acsnano.8b01893

[60]

Feng

, Tao

, Dong

et al . Near-infrared light activation of quenched liposomal Ce6 for synergistic cancer phototherapy with effective skin protection[J]. Biomaterials, 2017, 127: 13-24. http://europepmc.org/abstract/MED/28279918

https://doi.org/10.1016/j.biomaterials.2016.11.027

[61]

Jain

. Normalization of tumor vasculature:an emerging concept in antiangiogenic therapy[J]. Science, 2005, 307: 58-62. http://jb.oxfordjournals.org/cgi/ijlink?linkType=ABST&journalCode=sci&resid=307/5706/58

https://doi.org/10.1126/science.1104819

[62]

Cham

KKY

, Baker

JHE

, Takhar

et al . Metronomic gemcitabine suppresses tumour growth, improves perfusion, and reduces hypoxia in human pancreatic ductal adenocarcinoma[J]. Br J Cancer, 2010, 103: 52-60. http://www.biomedcentral.com/pubmed/20531411

https://doi.org/10.1038/sj.bjc.6605727

[63]

Mpekris

, Baish

, Stylianopoulos

et al . Role of vascular normalization in benefit from metronomic chemotherapy[J]. Proc Natl Acad Sci U S A, 2017, 114: 1994-1999. http://www.ncbi.nlm.nih.gov/pubmed/28174262

https://doi.org/10.1073/pnas.1700340114

[64]

Wang

, Zhu

, Feng

et al . Nanoscale covalent organic polymers as a biodegradable nanomedicine for chemotherapy-enhanced photodynamic therapy of cancer[J]. Nano Res, 2018, 11: 3244-3257. http://link.springer.com/10.1007/s12274-017-1858-y

https://doi.org/10.1007/s12274-017-1858-y

[65]

Yang

, Wei

, Xing

et al . Increasing the efficiency of photodynamic therapy by improved light delivery and oxygen supply using an anticoagulant in a solid tumor model[J]. Laser Surg Med, 2010, 42: 671-679. http://onlinelibrary.wiley.com/doi/10.1002/lsm.20951/abstract

https://doi.org/10.1002/lsm.20951

[66]

Jahanban-Esfahlan

, de la Guardia

, Ahmadi

et al . Modulating tumor hypoxia by nanomedicine for effective cancer therapy[J]. J Cell Physiol, 2018, 233: 2019-2031. http://www.ncbi.nlm.nih.gov/pubmed/28198007

https://doi.org/10.1002/jcp.25859

[67]

Broekgaarden

, Weijer

, Krekorian

et al . Inhibition of hypoxia-inducible factor 1 with acriflavine sensitizes hypoxic tumor cells to photodynamic therapy with zinc phthalocyanine-encapsulating cationic liposomes[J]. Nano Res, 2016, 9: 1639-1662. http://dx.doi.org/10.1007/s12274-016-1059-0

https://doi.org/10.1007/s12274-016-1059-0

[68]

Gong

, Chao

, Xiang

et al . Hyaluronidase to enhance nanoparticle-based photodynamic tumor therapy[J]. Nano Lett, 2016, 16: 2512-2521. http://www.ncbi.nlm.nih.gov/pubmed/27022664

https://doi.org/10.1021/acs.nanolett.6b00068

[69]

Chen

, Lecaros

RLG

, Tseng

et al . Nanoparticle delivery of HIF1α siRNA combined with photodynamic therapy as a potential treatment strategy for head-and-neck cancer[J]. Cancer Lett, 2015, 359: 65-74. http://pubmedcentralcanada.ca/pmcc/articles/PMC5010227/

https://doi.org/10.1016/j.canlet.2014.12.052

[70]

Liu

, Xie

, Shi

et al . Oxygen-self-supplying and HIF-1α-inhibiting core-shell nanosystem for hypoxia-resistant photodynamic therapy[J]. ACS Appl Mater Inter, 2019, 11: 48261-48270. http://www.ncbi.nlm.nih.gov/pubmed/31763809

https://doi.org/10.1021/acsami.9b18112

[71]

Mai

, Zhang

, Fan

et al . Integration of immunogenic activation and immunosuppressive reversion using mitochondrial-respiration-inhibited platelet-mimicking nanoparticles[J]. Biomaterials, 2020, 232: 119699. http://www.sciencedirect.com/science/article/pii/S0142961219308178

https://doi.org/10.1016/j.biomaterials.2019.119699

[72]

Zhao

, Zheng

, Chen

et al . Self-delivery nanomedicine for O₂-economized photodynamic tumor therapy[J]. Nano Lett, 2020, 20: 2062-2071. http://www.researchgate.net/publication/339495802_Self-Delivery_Nanomedicine_for_O2-Economized_Photodynamic_Tumor_Therapy

https://doi.org/10.1021/acs.nanolett.0c00047

[73]

Yang

, Wang

, Liu

et al . Defeating relapsed and refractory malignancies through a nano-enabled mitochondria-mediated respiratory inhibition and damage pathway[J]. Biomaterials, 2020, 229: 119580. http://www.sciencedirect.com/science/article/pii/s0142961219306799

https://doi.org/10.1016/j.biomaterials.2019.119580

[74]

Park

, Bae

, Na

. A highly tumor-specific light-triggerable drug carrier responds to hypoxic tumor conditions for effective tumor treatment[J]. Biomaterials, 2016, 77: 227-234. http://www.sciencedirect.com/science/article/pii/S0142961215009102

https://doi.org/10.1016/j.biomaterials.2015.11.014

[75]

Kim

, Lee

, Na

. Light-controlled reactive oxygen species (ROS)-producible polymeric micelles with simultaneous drug-release triggering and endo/lysosomal escape[J]. Chem Commun, 2016, 52: 2839-2842. http://pubs.rsc.org/en/content/articlepdf/2016/cc/c5cc09239f

https://doi.org/10.1039/C5CC09239F

[76]

Qian

, Yu

, Chen

et al . Light-activated hypoxia-responsive nanocarriers for enhanced anticancer therapy[J]. Adv Mater, 2016, 28: 3313-3320. http://www.zhangqiaokeyan.com/academic-journal-foreign-pmc_detail_thesis/040005456499.html

https://doi.org/10.1002/adma.201505869

[77]

Wang

, Lin

, Ma

et al . Light-iduced hypoxia-triggered living nanocarriers for synergistic cancer therapy[J]. ACS Appl Mater Inter, 2018, 10: 19398-19407. http://europepmc.org/abstract/MED/29781276

https://doi.org/10.1021/acsami.8b03506

[78]

Zhang

, Wu

, Li

et al . Light-enhanced hypoxia-response of conjugated polymer nanocarrier for successive synergistic photodynamic and chemo-therapy[J]. ACS Appl Mater Inter, 2018, 10: 21909-21919. http://europepmc.org/abstract/MED/29882654

https://doi.org/10.1021/acsami.8b06491

[79]

Liu

, Liu

, Bu

et al . Hypoxia induced by upconversion-based photodynamic therapy:towards highly effective synergistic bioreductive therapy in tumors[J]. Angew Chem Int Ed Engl, 2015, 54: 8105-8109.

https://doi.org/10.1002/anie.201500478

[80]

Feng

, Cheng

, Dong

et al . Theranostic liposomes with hypoxia-activated prodrug to effectively destruct hypoxic tumors post-photodynamic therapy[J]. ACS Nano, 2017, 11: 927-937.

https://doi.org/10.1021/acsnano.6b07525

[81]

Zhang

, Zhang

, Meng

et al . Light-triggered theranostic liposomes for tumor diagnosis and combined photodynamic and hypoxia-activated prodrug therapy[J]. Biomaterials, 2018, 185: 301-309. http://www.ncbi.nlm.nih.gov/pubmed/30265899

https://doi.org/10.1016/j.biomaterials.2018.09.033

[82]

Babii

, Afonin

, Garmanchuk

et al . Direct photocontrol of peptidomimetics:an alternative to oxygen-dependent photodynamic cancer therapy[J]. Angew Chem Int Ed Engl, 2016, 55: 5493-5496. http://www.ncbi.nlm.nih.gov/pubmed/27028784

https://doi.org/10.1002/anie.201600506

[83]

Kolemen

, Ozdemir

, Lee

et al . Remote-controlled release of singlet oxygen by the plasmonic heating of endoperoxide-modified gold nanorods:towards a paradigm change in photodynamic therapy[J]. Angew Chem Int Ed Engl, 2016, 55: 3606-3610. http://www.ingentaconnect.com/content/bpl/anie/2016/00000055/00000011/art00015

https://doi.org/10.1002/anie.201510064

[84]

Han

, Chen

, Zhao

et al . Oxygen-independent combined photothermal/photodynamic therapy delivered by tumor acidity-responsive polymeric micelles[J]. J Control Release, 2018, 284: 15-25. http://www.sciencedirect.com/science/article/pii/S0168365918303559

https://doi.org/10.1016/j.jconrel.2018.06.012

[85]

Huang

, Zhao

, Yu

et al . De novo design of polymeric carrier to photothermally release singlet oxygen for hypoxic tumor treatment[J]. Research, 2019, 2019: 1-11. http://www.ncbi.nlm.nih.gov/pubmed/31549095

[86]

Zheng

, Zhao

, Chen

et al . Tumor microenvironment responsive biomimetic nanoparticles for photodynamic tumor therapy[J]. Acta Pharm Sin (药学学报), 2020, 55: 1672-1679.

[87]

, Yan

, Wang

et al . Perfluorocarbon-based O₂ nanocarrier for efficient photodynamic therapy[J]. J Mater Chem B, 2019, 7: 1116-1123. http://www.ncbi.nlm.nih.gov/pubmed/32254779

https://doi.org/10.1039/C8TB01844H

[88]

Yang

, Yang

, Sun

et al . Carbon-dot-decorated TiO₂ nanotubes toward photodynamic therapy based on water-splitting mechanism[J]. Adv Healthc Mater, 2018, 7: 1800042. http://www.ncbi.nlm.nih.gov/pubmed/29527835

https://doi.org/10.1002/adhm.201800042

[89]

Chen

, Cong

, Shen

et al . Biomedical application of manganese dioxide nanomaterials[J]. Nanotechnology, 2020, 31: 202001. http://www.researchgate.net/publication/338806984_Biomedical_Application_of_Manganese_Dioxide_Nanomaterials

https://doi.org/10.1088/1361-6528/ab6fe1

[90]

, Cheng

, Zhang

. Recent advances in nanomaterials for enhanced photothermal therapy of tumors[J]. Nanoscale, 2018, 10: 22657-22672. http://www.ncbi.nlm.nih.gov/pubmed/30500042

https://doi.org/10.1039/C8NR07627H

2020年第55卷第11期

PDF下载

107

引用本文

BibTeX

文章信息

doi: 10.16438/j.0513-4870.2020-0507

接收时间：2020-04-09
首发时间：2026-01-23
出版时间：2020-11-12

补充材料

相关文章

文章信息

作者

出版历史

收稿日期：2020-04-09
修回日期：2020-05-13

基金

国家自然科学基金资助项目(81803346)

作者信息

浙江中医药大学药学院, 浙江杭州 310053

通讯作者:

*张凤玲, Tel/Fax:86-571-61768163, E-mail:windring0@163.com

参考文献

分享链接

https://castjournals.cast.org.cn/joweb/yxxb/CN/10.16438/j.0513-4870.2020-0507

分享至

全文二维码

扫描看全文

引用本文

BibTeX

本文的引用情况

2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

关闭全屏

BibTeX
EndNote
RefWorks
TxT

Synergy strategy	Advantage	Disadvantage
Relieving tumor hypoxia	Red blood cells and hemoglobin carry O₂^[3-12]	Good biocompatibility, high in vivo stability, long systemic circulation. Drug delivery system^[86]	The micrometer sizes of red blood cells^[13]; the instability of oxyhemoglobin; low efficiency
	Perfluorocarbon dissolves O₂^[16-24]	Higher oxygen capacity and longer ¹O₂ lifetime^[87]	Release oxygen by diffusion through the oxygen concentration gradient with a low efficiency
	Decompose H₂O₂ to O₂^[27-33]	A higher level of H₂O₂ in the tumor than normal tissues	Catalase instability
	Split H₂O to O₂^[41-45]	The abundance of H₂O in biological tissues	Water-splitting materials with poor response to visible light and near-infrared^[88]
	MnO₂ catalyzes H₂O₂ to O₂^[46-48]	Good bio-compatibility; be used as the catalyzer for decompositing H₂O₂ to produce O₂	Its potential risks, long-term toxicity, cellular uptake mechanisms and metabolic pathways are still unclear^[89]
	Mild heating promotes oxygen supply^[50-60]	Low invasiveness, high specificity	Low photothermal conversion efficiency^[90], normal cell damage caused by hyperthermia and inflammatory reactions
	Chemical drugs regulate the normalization of microvessels^{[30, 61-65]}	Induction of vascular normalization, increasing tumor oxygen supply and drug concentration	Overdose will cause serious vascular degeneration. Be difficult to grasp the dosage
	Regulate HIF-1 to reduce hypoxia^[66-70]	Alleviating tumor hypoxia to a certain extent	The relief effect of hypoxia is limited, the regulation of HIF-1 less controllable
	Inhibit mitochondrial respiration^[71-73]	Reducing endogenous oxygen consumption^[71]	Be limited to the low oxygen content in the tumor tissue
Utilizing tumor hypoxia	Control drug release by hypoxia^[74-78]	Fully utilize tumor hypoxia and the hypoxia side effect of PDT and realize synergistic treatment	Be limited to the complexity of the tumor microenvironment and the heterogeneity caused by individual differences
	Activate hypoxic activation drugs by hypoxic^[79-81]	Improving the target ability, reducing the side effects, and realizing synergistic treatment	Be limited to the complexity of microenvironment and the heterogeneity caused by individual differences
Avoiding tumor hypoxia	Constructe oxygen- independent PDT^[82-85]	Without oxygen participation, getting rid of the dependence on O₂	The study of oxygen-independent PDT is still in the primary stage

Synergy strategy

Advantage

Disadvantage

Relieving tumor
hypoxia

Red blood cells and
hemoglobin carry O₂^[3-12]

Good biocompatibility, high in vivo stability,
long systemic circulation. Drug delivery
system^[86]

The micrometer sizes of red blood cells^[13];
the instability of oxyhemoglobin; low efficiency

Perfluorocarbon
dissolves O₂^[16-24]

Higher oxygen capacity and longer ¹O₂
lifetime^[87]

Release oxygen by diffusion through the oxygen
concentration gradient with a low efficiency

Decompose H₂O₂ to
O₂^[27-33]

A higher level of H₂O₂ in the tumor than
normal tissues

Catalase instability

Split H₂O to O₂^[41-45]

The abundance of H₂O in biological tissues

Water-splitting materials with poor response to
visible light and near-infrared^[88]

MnO₂ catalyzes H₂O₂ to
O₂^[46-48]

Good bio-compatibility; be used as the
catalyzer for decompositing H₂O₂ to
produce O₂

Its potential risks, long-term toxicity, cellular
uptake mechanisms and metabolic pathways
are still unclear^[89]

Mild heating promotes
oxygen supply^[50-60]

Low invasiveness, high specificity

Low photothermal conversion efficiency^[90],
normal cell damage caused by hyperthermia
and inflammatory reactions

Chemical drugs regulate
the normalization of
microvessels^{[30, 61-65]}

Induction of vascular normalization,
increasing tumor oxygen supply and
drug concentration

Overdose will cause serious vascular
degeneration. Be difficult to grasp the dosage

Regulate HIF-1 to reduce
hypoxia^[66-70]

Alleviating tumor hypoxia to a certain
extent

The relief effect of hypoxia is limited, the
regulation of HIF-1 less controllable

Inhibit mitochondrial
respiration^[71-73]

Reducing endogenous oxygen
consumption^[71]

Be limited to the low oxygen content in the
tumor tissue

Utilizing tumor
hypoxia

Control drug release by
hypoxia^[74-78]

Fully utilize tumor hypoxia and the hypoxia
side effect of PDT and realize synergistic
treatment

Be limited to the complexity of the tumor
microenvironment and the heterogeneity
caused by individual differences

Activate hypoxic activation
drugs by hypoxic^[79-81]

Improving the target ability, reducing the
side effects, and realizing synergistic
treatment

Be limited to the complexity of
microenvironment and the heterogeneity
caused by individual differences

Avoiding tumor
hypoxia

Constructe oxygen-
independent PDT^[82-85]

Without oxygen participation, getting rid of
the dependence on O₂

The study of oxygen-independent PDT is still
in the primary stage