School of Pharmacy, Changzhou University, Changzhou 213164, China.
School of Physics, Shandong University, Jinan 250100, China.
Mol Pharm. 2024 May 6;21(5):2394-2405. doi: 10.1021/acs.molpharmaceut.3c01200. Epub 2024 Apr 22.
Doxorubicin (DOX) is one of the most commonly used anticancer drugs; however, its clinical application is greatly limited due to its toxicity and chemotherapy resistance. The delivery of DOX by liposomes (Lipos) can improve the blood circulation time in vivo and reduce toxic side effects, but the drug's accumulation in the tumor is often insufficient for effective treatment. In this study, we present a calcium cross-linked liposome gel for the encapsulation of DOX, demonstrating its superior long-term release capabilities compared to conventional Lipos. By leveraging this enhanced long-term release, we can enhance drug accumulation within tumors, ultimately leading to improved antitumor efficacy. Lipos were prepared using the thin-film dispersion method in this study. We utilized the ion-responsiveness of glutathione-gelatin (GSH-GG) to form the gel outside the Lipos and named the nanoparticles coated with GSH-GG on the outside of Lipos as Lipos@GSH-GG. The average size of Lipos@GSH-GG was around 342.9 nm, with a negative charge of -25.6 mV. The in vitro experiments revealed that Lipos@GSH-GG exhibited excellent biocompatibility and slower drug release compared to conventional Lipos. Further analysis of cellular uptake and cytotoxicity demonstrated that Lipos@GSH-GG loading DOX (DOX&Lipos@GSH-GG) exhibited superior long-term release effects and lower toxic side effects compared to Lipos loading DOX (DOX&Lipos). Additionally, the findings regarding the long-term release effect in vivo and the tumor accumulation within tumor-bearing mice of Lipos@GSH-GG suggested that, compared to Lipos, it demonstrated superior long-term release capabilities and achieved greater drug accumulation within tumors. In vivo antitumor efficacy experiments showed that DOX&Lipos@GSH-GG demonstrated superior antitumor efficacy to DOX&Lipos. Our study highlights Lipos@GSH-GG as a promising nanocarrier with the potential to enhance efficacy and safety by means of long-term release effects and may offer an alternative approach for effective antitumor therapy in the future.
阿霉素（DOX）是最常用的抗癌药物之一；然而，由于其毒性和化疗耐药性，其临床应用受到极大限制。脂质体（Lipos）递送 DOX 可以改善体内血液循环时间并减少毒副作用，但药物在肿瘤中的积累往往不足以进行有效治疗。在这项研究中，我们提出了一种用于封装 DOX 的钙交联脂质体凝胶，证明其与传统 Lipos 相比具有优越的长期释放能力。通过利用这种增强的长期释放，我们可以增加肿瘤内的药物积累，最终提高抗肿瘤疗效。Lipos 是在本研究中通过薄膜分散法制备的。我们利用谷胱甘肽-明胶（GSH-GG）的离子响应性在 Lipos 外形成凝胶，并将在 Lipos 外包裹 GSH-GG 的纳米颗粒命名为 Lipos@GSH-GG。Lipos@GSH-GG 的平均粒径约为 342.9nm，带负电荷为-25.6mV。体外实验表明，与传统 Lipos 相比，Lipos@GSH-GG 具有良好的生物相容性和更缓慢的药物释放。进一步分析细胞摄取和细胞毒性表明，与 Lipos 加载 DOX（DOX&Lipos@GSH-GG）相比，Lipos@GSH-GG 加载 DOX（DOX&Lipos@GSH-GG）具有优越的长期释放效果和更低的毒副作用。此外，关于 Lipos@GSH-GG 在荷瘤小鼠体内的长期释放效果和肿瘤内积累的体内研究结果表明，与 Lipos 相比，它具有优越的长期释放能力，并在肿瘤内实现了更大的药物积累。体内抗肿瘤疗效实验表明，DOX&Lipos@GSH-GG 比 DOX&Lipos 具有更好的抗肿瘤疗效。我们的研究强调了 Lipos@GSH-GG 作为一种有前途的纳米载体，通过长期释放效果可以提高疗效和安全性，并可能为未来有效的抗肿瘤治疗提供一种替代方法。
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