Kuhn Paul M, Russo Gabriella C, Crawford Ashleigh J, Venkatraman Aditya, Yang Nanlan, Starich Bartholomew A, Schneiderman Zachary, Wu Pei-Hsun, Vo Thi, Wirtz Denis, Kokkoli Efrosini
Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
Johns Hopkins Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA.
Pharmaceutics. 2024 Jul 25;16(8):981. doi: 10.3390/pharmaceutics16080981.
Effectively utilizing MEK inhibitors in the clinic remains challenging due to off-target toxicity and lack of predictive biomarkers. Recent findings propose E-cadherin, a breast cancer diagnostic indicator, as a predictor of MEK inhibitor success. To address MEK inhibitor toxicity, traditional methodologies have systemically delivered nanoparticles, which require frequent, high-dose injections. Here, we present a different approach, employing a thermosensitive, biodegradable hydrogel with functionalized liposomes for local, sustained release of MEK inhibitor PD0325901 and doxorubicin. The poly(δ-valerolactone--lactide)--poly(ethylene-glycol)--poly(δ-valerolactone--lactide) triblock co-polymer gels at physiological temperature and has an optimal degradation time in vivo. Liposomes were functionalized with PR_b, a biomimetic peptide targeting the αβ integrin receptor, which is overexpressed in E-cadherin-positive triple negative breast cancer (TNBC). In various TNBC models, the hydrogel-liposome system delivered via local injection reduced tumor progression and improved animal survival without toxic side effects. Our work presents the first demonstration of local, sustained delivery of MEK inhibitors to E-cadherin-positive tumors alongside traditional chemotherapeutics, offering a safe and promising therapeutic strategy.
由于脱靶毒性和缺乏预测性生物标志物，在临床上有效利用MEK抑制剂仍然具有挑战性。最近的研究结果提出，作为乳腺癌诊断指标的E-钙黏蛋白可作为MEK抑制剂疗效的预测指标。为了解决MEK抑制剂的毒性问题，传统方法通过全身递送纳米颗粒，这需要频繁进行高剂量注射。在此，我们提出一种不同的方法，采用一种热敏性、可生物降解的水凝胶与功能化脂质体相结合，用于局部持续释放MEK抑制剂PD0325901和阿霉素。聚（δ-戊内酯-丙交酯）-聚（乙二醇）-聚（δ-戊内酯-丙交酯）三嵌段共聚物在生理温度下形成凝胶，且在体内具有最佳降解时间。脂质体用PR_b进行功能化，PR_b是一种靶向αβ整合素受体的仿生肽，该受体在E-钙黏蛋白阳性三阴性乳腺癌（TNBC）中过表达。在各种TNBC模型中，通过局部注射递送的水凝胶-脂质体系统可减少肿瘤进展并提高动物存活率，且无毒性副作用。我们的工作首次证明了在传统化疗药物的基础上，可将MEK抑制剂局部持续递送至E-钙黏蛋白阳性肿瘤，提供了一种安全且有前景的治疗策略。
