Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, 215123, China; College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.
Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, 215123, China.
Acta Biomater. 2022 Jun;145:200-209. doi: 10.1016/j.actbio.2022.04.016. Epub 2022 Apr 14.
Gemcitabine (GEM) is among the most used chemotherapies for advanced malignancies including non-small cell lung cancer. The clinical efficacy of GEM is, however, downplayed by its poor bioavailability, short half-life, drug resistance, and dose-limiting toxicities (e.g. myelosuppression). In spite of many approaches exploited to improve the efficacy and safety of GEM, limited success was achieved. The short A6 peptide (sequence: Ac-KPSSPPEE-NH) is clinically validated for specific binding to CD44 on metastatic tumors. Here, we designed a robust and CD44-specific GEM nanotherapeutics by encapsulating hydrophobic phosphorylated gemcitabine prodrug (HPG) into the core of A6 peptide-functionalized disulfide-crosslinked micelles (A6-mHPG), which exhibited reduction-triggered HPG release and specific targetability to CD44 overexpressing tumor cells. Interestingly, A6 greatly enhanced the internalization and inhibitory activity of micellar HPG (mHPG) in CD44 positive A549 cells, and increased its accumulation in A549 cancerous lung, leading to potent repression of orthotopic tumor growth, depleted toxicity, and marked survival benefits compared to free HPG and mHPG (median survival time: 59 days versus 30 and 45 days, respectively). The targeted delivery of gemcitabine prodrug with disulfide-crosslinked biodegradable micelles appears to be a highly appealing strategy to boost gemcitabine therapy for advance tumors. STATEMENT OF SIGNIFICANCE: Gemcitabine (GEM) though widely used in clinics for treating advanced tumors is associated with poor bioavailability, short half-life and dose-limiting toxicities. Development of clinically translatable GEM formulations to improve its anti-tumor efficacy and safety is of great interest. Here, we report on CD44-targeting GEM nanotherapeutics obtained by encapsulating hydrophobic phosphorylated GEM prodrug (HPG), a single isomer of NUC-1031, into A6 peptide-functionalized disulfide-crosslinked micelles (A6-mHPG). A6-mHPG demonstrates stability against degradation, enhanced internalization and inhibition toward CD44 cells, and increased accumulation in A549 lung tumor xenografts, leading to potent repression of orthotopic tumor growth, depleted toxicity and marked survival benefits. The targeted delivery of GEM prodrug using A6-mHPG is a highly appealing strategy to GEM cancer therapy.
吉西他滨（GEM）是包括非小细胞肺癌在内的晚期恶性肿瘤最常用的化疗药物之一。然而，由于其生物利用度差、半衰期短、耐药性和剂量限制性毒性（如骨髓抑制），GEM 的临床疗效受到了影响。尽管已经尝试了许多方法来提高 GEM 的疗效和安全性，但收效甚微。短肽 A6（序列：Ac-KPSSPPEE-NH）已在临床上验证可特异性结合转移瘤上的 CD44。在这里，我们通过将疏水性磷酸化吉西他滨前药（HPG）包封到 A6 肽功能化的二硫键交联胶束（A6-mHPG）的核心中，设计了一种强大且特异性针对 CD44 的 GEM 纳米治疗药物，该药物在还原触发下释放 HPG，并特异性靶向过表达 CD44 的肿瘤细胞。有趣的是，A6 显著增强了 CD44 阳性 A549 细胞中胶束 HPG（mHPG）的内化和抑制活性，并增加了其在 A549 肺癌中的积累，从而导致原位肿瘤生长受到强烈抑制，毒性降低，与游离 HPG 和 mHPG 相比，生存获益显著（中位生存时间：59 天与 30 天和 45 天相比）。用二硫键交联可生物降解胶束传递吉西他滨前药似乎是一种很有吸引力的策略，可以增强吉西他滨治疗晚期肿瘤的疗效。
意义声明：吉西他滨（GEM）虽然在临床上广泛用于治疗晚期肿瘤，但存在生物利用度差、半衰期短和剂量限制性毒性等问题。开发可转化为临床应用的 GEM 制剂以提高其抗肿瘤疗效和安全性具有重要意义。在这里，我们报告了通过将疏水性磷酸化吉西他滨前药（HPG）（NUC-1031 的单一异构体）包封到 A6 肽功能化的二硫键交联胶束（A6-mHPG）中获得的 CD44 靶向 GEM 纳米治疗药物。A6-mHPG 对降解具有稳定性，增强了对 CD44 细胞的内化和抑制作用，并增加了在 A549 肺癌异种移植瘤中的积累，从而导致原位肿瘤生长受到强烈抑制，毒性降低，生存获益显著。使用 A6-mHPG 靶向递送 GEM 前药是一种很有吸引力的 GEM 癌症治疗策略。
