Carbonic anhydrase IX-targeted H-APBC nanosystem combined with phototherapy facilitates the efficacy of PI3K/mTOR inhibitor and resists HIF-1α-dependent tumor hypoxia adaptation.
Carbonic anhydrase IX-targeted H-APBC nanosystem combined with phototherapy facilitates the efficacy of PI3K/mTOR inhibitor and resists HIF-1α-dependent tumor hypoxia adaptation.
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碳酸酐酶IX靶向H-APBC纳米系统联合光疗促进PI3K/mTOR抑制剂疗效并抵抗HIF-1α依赖性肿瘤缺氧适应
DOI：
10.1186/s12951-022-01394-w
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发表时间：
2022-04-12
影响因子：
10.2
通讯作者：
Dong C
中科院分区：
文献类型：
--
作者：
Liu J;Hu X;Feng L;Lin Y;Liang S;Zhu Z;Shi S;Dong C
缺氧和酸中毒等非冗余特性促进肿瘤代谢适应，限制抗癌治疗。肿瘤细胞适应缺氧的关键是缺氧诱导因子-1α (HIF-1α)的转录和稳定表达。磷酸化激活的致瘤信号PI3K/AKT/mTOR促进下游HIF-1α的产生以适应肿瘤缺氧。研究表明，酸有利于抑制mTOR信号。然而，碳酸酐酶IX （CAIX）在缺氧肿瘤细胞膜上过表达，具有ph调节作用，会减弱细胞内酸度，不利于mTOR抑制。本文设计了一种配备双PI3K/mTOR抑制剂Dactolisib （NVP-BEZ235, BEZ235）和CAIX抑制剂4‐（2‐氨基乙基）苯磺酰胺（ABS）的药物递送纳米平台，以减轻缺氧适应并改善乳腺癌治疗。ABS和PEG-NH2在中空聚多巴胺（HPDA）表面被成功修饰，而BEZ235和氯胺e6 （Ce6）在HPDA内部被有效负载，形成HPDA-ABS/PEG-BEZ235/Ce6 （H-APBC）纳米粒子。在酸性微环境下，H-APBC释放BEZ235可抑制PI3K/mTOR信号，抑制hif -1α依赖性肿瘤缺氧适应。更重要的是，修饰在H-APBC表面的ABS可以增加细胞内酸，增强对mTOR的抑制。纳米平台结合光疗，通过改变适应缺氧和细胞外酸中毒的微环境，抑制原位乳腺癌的生长，同时减少自发性肺转移和血管生成。综上所述，与游离的BEZ235和ABS相比，纳米平台具有显著的抗肿瘤效率，降低了BEZ235的缺氧适应性，减轻了BEZ235的非肿瘤毒性，解决了BEZ235溶解度弱导致的生物利用度限制。在线版本包含补充材料，可在10.1186/s12951-022-01394-w获得。
Non-redundant properties such as hypoxia and acidosis promote tumor metabolic adaptation and limit anti-cancer therapies. The key to the adaptation of tumor cells to hypoxia is the transcriptional and stable expression of hypoxia-inducible factor-1 alpha (HIF-1α). The phosphorylation-activated tumorigenic signal PI3K/AKT/mTOR advances the production of downstream HIF-1α to adapt to tumor hypoxia. Studies have elucidated that acid favors inhibition of mTOR signal. Nonetheless, carbonic anhydrase IX (CAIX), overexpressed on membranes of hypoxia tumor cells with pH-regulatory effects, attenuates intracellular acidity, which is unfavorable for mTOR inhibition. Herein, a drug delivery nanoplatform equipped with dual PI3K/mTOR inhibitor Dactolisib (NVP-BEZ235, BEZ235) and CAIX inhibitor 4‐(2‐aminoethyl) benzene sulfonamide (ABS) was designed to mitigate hypoxic adaptation and improve breast cancer treatment. ABS and PEG-NH2 were successfully modified on the surface of hollow polydopamine (HPDA), while BEZ235 and Chlorin e6 (Ce6) were effectively loaded with the interior of HPDA to form HPDA-ABS/PEG-BEZ235/Ce6 (H-APBC) nanoparticles. The release of BEZ235 from H-APBC in acid microenvironment could mitigate PI3K/mTOR signal and resist HIF-1α-dependent tumor hypoxia adaptation. More importantly, ABS modified on the surface of H-APBC could augment intracellular acids and enhances the mTOR inhibition. The nanoplatform combined with phototherapy inhibited orthotopic breast cancer growth while reducing spontaneous lung metastasis, angiogenesis, based on altering the microenvironment adapted to hypoxia and extracellular acidosis. Taken together, compared with free BEZ235 and ABS, the nanoplatform exhibited remarkable anti-tumor efficiency, reduced hypoxia adaptation, mitigated off-tumor toxicity of BEZ235 and solved the limited bioavailability of BEZ235 caused by weak solubility. The online version contains supplementary material available at 10.1186/s12951-022-01394-w.
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肿瘤微环境产生的酸度驱动局部侵袭。
影响因子：
11.2
作者：
Estrella V;Chen T;Lloyd M;Wojtkowiak J;Cornnell HH;Ibrahim-Hashim A;Bailey K;Balagurunathan Y;Rothberg JM;Sloane BF;Johnson J;Gatenby RA;Gillies RJ
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38.3
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4.7
作者：
Iommarini L;Porcelli AM;Gasparre G;Kurelac I
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影响因子：
4.7
作者：
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通讯作者：
Calorini, Lido
影响因子：
21.3
作者：
LaGory EL;Giaccia AJ
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Giaccia AJ