Department of Biophysics, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 610054, PR China.
Department of Biophysics, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 610054, PR China.
Acta Biomater. 2022 Sep 15;150:391-401. doi: 10.1016/j.actbio.2022.07.044. Epub 2022 Jul 30.
Tumor microenvironment (TME)-oriented nanomedicine emerges as an efficient routine to greatly improve the efficiency of cancer treatment. The typical feature of hypoxia in TME remains as the main obstacle of many therapeutics like photodynamic therapy. Herein, a specific two-dimensional (2D) phototheranostics (GO-MnO@tLyP-1/Ce6, denoted as GMtC) with the function of oxygen self-producing and tumor barrier-breaking was detailed by integrating the nanoenzyme MnO colloids, tumor homing-penetrating peptide tLyP-1 and photosensitizer chlorin e6 (Ce6) to tackle the hypoxic tumors. GMtC was capable to accumulate into the inner of murine mammary 4T1 tumor spheroids (and the depth could be as far as 90 µm) and to relieve the hypoxia state by catalytic decomposition of endogenous HO to oxygen, which subsequently enhanced the yield of cytotoxic singlet oxygen under laser irradiation. In vivo dual-modal imaging of magnetic resonance and biofluorescence demonstrated the targeted accumulation and distribution of GMtC in tumor regions, thus facilitating the tumor hypoxia alleviation. Notably, GMtC achieved the highest photodynamic anticancer efficiency against 4T1 tumors without obvious systemic toxicity compared with the non-penetrating and no oxygen-generating counterparts. This study suggests the great promise of GMtC as an endogenous TME-responsive and exogenous laser-triggered theranostic platform against the solid hypoxic tumors. STATEMENT OF SIGNIFICANCE: The hostile tumor hypoxia not only induces the tumor angiogenesis, invasiveness and irreversible metastasis, but also inherently impairs the efficiency of many therapeutic modalities like photodynamic therapy (PDT). Though numerous hypoxia-alleviating strategies based on nanomedicine have been proposed, little attention is paid to the hypoxia-specific transportation barriers. This study develops a type of 2D phototheranostics GMtC against hypoxic solid tumors by integrating the function of tumor homing-penetrating and in situ oxygen-generating. GMtC displays outstanding performance in tumor deep penetration to hypoxia center and generating abundant oxygen in responsive to tumor microenvironment, thus exerting the highest efficiency of PDT against 4T1 mammary tumor. GMtC can be a potent theranostics to treat the solid hypoxic tumors.
肿瘤微环境（TME）导向的纳米医学作为一种提高癌症治疗效率的有效方法而出现。TME 中的缺氧典型特征仍然是许多治疗方法（如光动力疗法）的主要障碍。在此，通过整合纳米酶 MnO 胶体、肿瘤归巢穿透肽 tLyP-1 和光敏剂氯代叶绿素 e6（Ce6），详细设计了一种具有产氧和肿瘤屏障破坏功能的特定二维（2D）光热治疗（GO-MnO@tLyP-1/Ce6，记为 GMtC），以解决缺氧肿瘤问题。GMtC 能够聚集到鼠源性乳腺癌 4T1 肿瘤球体的内部（深度可达 90 µm），并通过催化分解内源性 HO 产生氧气来缓解缺氧状态，随后在激光照射下增强细胞毒性单线态氧的产量。磁共振和生物荧光双模态体内成像证明了 GMtC 在肿瘤区域的靶向积累和分布，从而促进了肿瘤缺氧的缓解。值得注意的是，与非穿透性和非产氧性对照相比，GMtC 对 4T1 肿瘤的光动力抗癌效率最高，且没有明显的全身毒性。这项研究表明，GMtC 作为一种内源性 TME 反应性和外源性激光触发的治疗平台，具有治疗实体缺氧肿瘤的巨大潜力。
恶劣的肿瘤缺氧不仅诱导肿瘤血管生成、侵袭和不可逆转的转移，而且还固有地损害许多治疗方式（如光动力疗法（PDT））的效率。尽管已经提出了许多基于纳米医学的缓解缺氧策略，但很少关注缺氧特异性的运输屏障。本研究通过整合肿瘤归巢穿透和原位产氧功能，开发了一种针对缺氧实体肿瘤的 2D 光热治疗 GMtC。GMtC 在肿瘤深部穿透缺氧中心和响应肿瘤微环境产生丰富氧气方面表现出出色的性能，从而对 4T1 乳腺癌发挥最高效的 PDT 作用。GMtC 可以成为治疗实体缺氧肿瘤的有效治疗方法。
