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.

中文翻译：

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钙交联制备脂质体凝胶诱导DOX长期释放提高抗肿瘤效果

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。通过脂质体（Lipos）递送DOX可以改善体内血液循环时间并减少毒副作用，但药物在肿瘤中的蓄积往往不足以有效治疗。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，证明其与传统脂质体相比具有卓越的长期释放能力。通过利用这种增强的长期释放，我们可以增强肿瘤内的药物积累，最终提高抗肿瘤功效。本研究中采用薄膜分散法制备脂质。我们利用谷胱甘肽明胶（GSH-GG）的离子响应性在Lipos外部形成凝胶，并将在Lipos外部涂覆GSH-GG的纳米颗粒命名为Lipos@GSH-GG。 Lipos@GSH-GG的平均尺寸约为342.9 nm，负电荷为-25.6 mV。体外实验表明，与传统Lipos相比，Lipos@GSH-GG表现出优异的生物相容性和较慢的药物释放速度。进一步的细胞摄取和细胞毒性分析表明，与Lipos负载DOX（DOX&Lipos）相比，Lipos@GSH-GG负载DOX（DOX&Lipos@GSH-GG）表现出优异的长期释放效果和更低的毒副作用。此外，关于Lipos@GSH-GG体内长期释放效果和荷瘤小鼠体内肿瘤积聚的研究结果表明，与Lipos相比，它表现出优异的长期释放能力，并在肿瘤内实现了更大的药物积累。体内抗肿瘤功效实验表明，DOX&Lipos@GSH-GG 表现出优于 DOX&Lipos 的抗肿瘤功效。我们的研究强调Lipos@GSH-GG作为一种有前途的纳米载体，具有通过长期释放效应提高疗效和安全性的潜力，并可能为未来有效的抗肿瘤治疗提供一种替代方法。