在这项工作中，开发了一种可注射的原位储库形成脂质溶致液晶（L3C）系统，用于在肿瘤内共同输送精确同步的化疗药物组合。开发的L3C系统由两亲性脂质和表面活性剂组成，包括单油酸甘油酯、磷脂酰胆碱、醋酸生育酚和d-α-生育酚聚乙二醇1000琥珀酸酯。由于其两亲性质，所开发的制剂可以同时共容纳疏水性和亲水性化疗部分。该研究通过设计体外联合化疗方案并分别使用阿霉素和紫杉醇作为模型亲水性和疏水性药物部分证明其体内翻译，从而提供了概念验证。确定了两种具有最大协同活性的化疗药物的同步组合，以预定的化学计量比共同加载到开发的 L3C 系统中，并在 BALB/c 小鼠的 4T1 乳腺肿瘤模型中评估其抗肿瘤功效。载药L3C制剂是一种低粘度可注射液体，具有层状相，在瘤内注射后转变为六角形中间相储库系统。载药储库系统以精确同步的比例在局部持续肿瘤内递送化疗药物组合超过一个月。结果表明，与不同步的联合化疗或通过传统静脉途径给药的同步但不协调的药物递送相比，通过开发的 L3C 系统将肿瘤暴露于精确同步的瘤内化疗组合可显着提高抗肿瘤活性并降低心脏毒性。这些发现证明了所开发的 L3C 系统在实现肿瘤内化疗组合同步共递送并提高联合化疗疗效方面的潜力。

In this work, an injectable in situ depot-forming lipidic lyotropic liquid crystal (L3C) system is developed to codeliver a precisely synchronized combination of chemotherapeutics intratumorally. The developed L3C system is composed of amphiphilic lipids and surfactants, including monoolein, phosphatidylcholine, tocopherol acetate, and d-α-tocopherol polyethylene glycol 1000 succinate. Owing to its amphiphilic nature, the developed formulation can coaccommodate both hydrophobic and hydrophilic chemotherapeutic moieties simultaneously. The study presents a proof of concept by designing a combination chemotherapy regimen in vitro and demonstrating its in vivo translation using doxorubicin and paclitaxel as model hydrophilic and hydrophobic drug moieties, respectively. The synchronized combination of the two chemotherapeutics with maximum synergistic activity was identified, coloaded in the developed L3C system at predefined stoichiometric ratios, and evaluated for antitumor efficacy in the 4T1 breast tumor model in BALB/c mice. The drug-loaded L3C formulation is a low-viscosity injectable fluid with a lamellar phase that transforms into a hexagonal mesophase depot system upon intratumoral injection. The drug-loaded depot system locally provides sustained intratumoral delivery of the chemotherapeutics combination at their precisely synchronized ratio for over a period of one month. Results demonstrate that the exposure of the tumor to the precisely synchronized intratumoral chemotherapeutics combination via the developed L3C system resulted in significantly higher antitumor activity and reduced cardiotoxicity compared to the unsynchronized combination chemotherapy or the synchronized but uncoordinated drug delivery administered by a conventional intravenous route. These findings demonstrate the potential of the developed L3C system for achieving synchronized codelivery of the chemotherapeutics combination intratumorally and improving the efficacy of combination chemotherapy.