Combining Doxorubicin-Conjugated Polymeric Nanoparticles and 5-Aminolevulinic Acid for Enhancing Radiotherapy against Lung Cancer
Combining Doxorubicin-Conjugated Polymeric Nanoparticles and 5-Aminolevulinic Acid for Enhancing Radiotherapy against Lung Cancer
复制标题
结合阿霉素缀合的聚合物纳米颗粒和 5-氨基乙酰丙酸以增强肺癌放射治疗
DOI：
10.1021/acs.bioconjchem.2c00066
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发表时间：
2022-04-20
影响因子：
4.7
通讯作者：
Huang, Xinglu
中科院分区：
文献类型：
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作者：
Han, Jinghua;Yang, Wei;Huang, Xinglu
放疗（RT）与化疗同时进行可改善局部肺癌控制，但可能导致全身毒性。有一个未得到满足的临床需要的治疗，可以选择性地敏感癌细胞RT。在这里，我们探讨了放射增敏策略，结合阿霉素（DOX）封装的聚酰胺纳米粒子和5-氨基乙酰丙酸（5-ALA）。将DOX-聚酰胺纳米颗粒与NTSmut偶联，NTSmut是一种对1型神经降压素受体（NTSR 1）具有特异性的配体，用于肺癌靶向。DOX通过pH敏感的腙连接体偶联到聚合物主链上，这允许药物在酸性肿瘤微移动中的受控释放。同时，5-ALA在癌细胞的线粒体中积累，形成原卟啉（PpIX），放大RT诱导的氧化应激。当在H1299细胞中进行体外测试时，由于DOX和5-ALA的互补放射增敏作用，DOX封装的纳米颗粒与5-ALA结合增强了癌细胞杀伤。体内研究证实，相对于单独的RT，该组合改善了肿瘤抑制，而不会对正常组织造成毒性。总的来说，我们的研究提出了一种有效的和选择性的放射增敏方法。
Radiation therapy (RT) concurrent with chemotherapy improves local lung cancer control but may cause systemic toxicity. There is an unmet clinical need of treatments that can selectively sensitize cancer cells to RT. Herein, we explored a radiosensitizing strategy that combines doxorubicin (DOX)-encapsulated polyaspartamide nanoparticles and 5-aminolevulinic acid (5-ALA). The DOX-polyaspartamide nanoparticles were coupled with NTSmut, a ligand specific to neurotensin receptor type 1 (NTSR1), for lung cancer targeting. DOX was coupled to the polymer backbone through a pH-sensitive hydrazone linker, which allows for controlled release of the drug in an acidic tumor micromovement. Meanwhile, 5-ALA accumulates in the cancer cell's mitochondria, forming protoporphyrin (PpIX) that amplifies RT-induced oxidative stress. When tested in vitro in H1299 cells, DOX-encapsulated nanoparticles in conjugation with 5-ALA enhanced cancer cell killing owing to the complementary radiosensitizing effects of DOX and 5-ALA. In vivo studies confirmed that the combination improved tumor suppression relative to RT alone without causing toxicity to normal tissues. Overall, our study suggests an effective and selective radiosensitizing approach.