School of Biomedical Engineering and Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Southern Medical University, Guangzhou 510515, PR China.
School of Biomedical Engineering and Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Southern Medical University, Guangzhou 510515, PR China.
Acta Biomater. 2022 Oct 15;152:507-518. doi: 10.1016/j.actbio.2022.08.045. Epub 2022 Aug 25.
As a first studied and generally accepted programmed cell death regulator, Bcl-2 has been identified to overexpress in many types of cancer promoting tumor proliferation and progression. Herein, inspired by drug self-delivery systems, a self-assembled nanomedicine (designated as GosCe) was designed based on the hydrophobic interaction between chlorin e6 (Ce6) and gossypol (Gos). Without extra carriers, GosCe exhibited high drug loading rates, favorable size distribution, and a long-term stability at aqueous phase. More importantly, GosCe could be internalized by tumor cells more effectively than free Ce6, which brought about its multiple toxicity. Upon intravenous injection, GosCe preferred to accumulate in tumor site through enhanced permeability and retention (EPR) effect. After cellular internalization, Gos contributed to increasing the lethality of Ce6-guided photodynamic therapy (PDT) by down-regulating Bcl-2 protein expression and inducing endoplasmic reticulum (ER) stress. Both in vitro and in vivo investigations indicated that the Gos-assisted PDT greatly inhibit cell proliferation and tumor growth. This study might shed light on developing carrier free nanomedicine for PDT-based synergistic tumor therapy. STATEMENT OF SIGNIFICANCE: Metabolic abnormalities of tumor cells create defensive microenvironments which induce a therapeutic resistance against photodynamic therapy (PDT). Among which, the upregulated B-cell lymphoma (Bcl-2) in tumors could inhibit the PDT-induced cell apoptosis. In this work, a self-delivery nanomedicine (GosCe) was developed based on a Bcl-2 inhibitor and photosensitizer through intermolecular interactions, which had favorable size distribution, high drug contents and improved drug delivery efficiency. Importantly, GosCe increased the PDT efficacy by Bcl-2 inhibition and endoplasmic reticulum stress elevation. Thus, GosCe greatly inhibited the tumor growth while caused a reduced side effect in vivo. This carrier free nanomedicine with tumor microenvironment regulation would advance the development of photodynamic nanoplatform in tumor treatment.
作为第一个被研究并被普遍认可的程序性细胞死亡调控因子，Bcl-2 在许多类型的癌症中被发现过度表达，促进肿瘤增殖和进展。在此，受药物自递送系统的启发，我们设计了一种基于氯乙（Ce6）和棉酚（Gos）之间的疏水相互作用的自组装纳米药物（命名为 GosCe）。在没有额外载体的情况下，GosCe 表现出高载药量、有利的粒径分布和在水相中的长期稳定性。更重要的是，GosCe 比游离的 Ce6 更能有效地被肿瘤细胞内化，从而产生多种毒性。静脉注射后，GosCe 通过增强的通透性和保留（EPR）效应优先积聚在肿瘤部位。进入细胞后，Gos 通过下调 Bcl-2 蛋白表达和诱导内质网（ER）应激，有助于增加 Ce6 引导的光动力疗法（PDT）的致死率。体外和体内研究均表明，Gos 辅助 PDT 能显著抑制细胞增殖和肿瘤生长。这项研究为开发用于 PDT 协同肿瘤治疗的无载体纳米药物提供了新的思路。
肿瘤细胞的代谢异常会产生防御性的微环境，从而导致光动力疗法（PDT）产生治疗抵抗。其中，肿瘤中上调的 B 细胞淋巴瘤（Bcl-2）可以抑制 PDT 诱导的细胞凋亡。在这项工作中，我们基于分子间相互作用，开发了一种自递送纳米药物（GosCe），它由 Bcl-2 抑制剂和光敏剂组成，具有良好的粒径分布、高载药量和改善的药物递送效率。重要的是，GosCe 通过 Bcl-2 抑制和内质网应激增加来提高 PDT 疗效。因此，GosCe 大大抑制了肿瘤生长，同时在体内降低了副作用。这种具有肿瘤微环境调节功能的无载体纳米药物将推进肿瘤治疗中光动力纳米平台的发展。
