State Key Laboratory of Natural Medicines, Department of Pharmaceutics, School of Pharmacy , China Pharmaceutical University , Nanjing 210009 , China.
Department of Chemical Engineering, 313 Snell Engineering Center , Northeastern University , 360 Huntington Avenue , Boston , Massachusetts 02115 , United States.
ACS Appl Mater Interfaces. 2018 Dec 19;10(50):43411-43428. doi: 10.1021/acsami.8b15147. Epub 2018 Dec 7.
Glioblastoma multiforme is the most devastating malignant brain tumor in adults. Even with the standard care of therapy, the prognosis remains dismal due to tumor heterogeneity, tumor infiltration, and, more importantly, the restrictive nature of the blood-brain barrier (BBB). To overcome the challenge of effectively delivering therapeutic cargo into the brain, herein a "smart", multifunctional polymeric micelle was developed using a cholesterol-conjugated polyoxyethylene sorbitol oleate. A cell-penetrating peptide, arginine-glycine repeats (RG), was incorporated into the micelles to improve cellular uptake, while a pH-sensitive masking sequence, histidine-glutamic acid repeats (HE), was introduced for charge shielding to minimize nonspecific binding and uptake at physiological pH. Results demonstrated that (RG)- and (HE)-modified mixed micelles were optimized using this strategy to effectively mask the cationic charges of the activated cell-penetrating peptide (RG) at physiological pH, i.e., limiting internalization, and were selectively triggered in response to a mildly acidic microenvironment in vitro based on a charge reversal mechanism. In vivo results further confirmed that such micelles preferentially accumulated in both brain and tumor tissues in both xenograft and orthotropic glioma mouse models. Furthermore, micelles significantly inhibited tumor growth with limited toxicity to peripheral tissues. The combination of BBB penetration, tumor targeting, potent efficacy, and high tolerance of these micelles strongly suggests that they could be a promising candidate for safe and effective drug delivery to the brain.
多形性胶质母细胞瘤是成人中最具破坏性的恶性脑肿瘤。即使采用标准的治疗方法，由于肿瘤异质性、肿瘤浸润以及更重要的血脑屏障（BBB）的限制，预后仍然不佳。为了克服有效将治疗性载药递送到大脑中的挑战，本文开发了一种“智能”多功能聚合物胶束，使用胆固醇缀合的聚氧乙烯山梨糖醇油酸酯。将细胞穿透肽，精氨酸-甘氨酸重复序列（RG），掺入胶束中以提高细胞摄取率，而将 pH 敏感掩蔽序列，组氨酸-谷氨酸重复序列（HE）引入到胶束中以进行电荷屏蔽，以最大程度地减少在生理 pH 值下的非特异性结合和摄取。结果表明，（RG）-和（HE）-修饰的混合胶束通过该策略进行了优化，以在生理 pH 值下有效地掩蔽激活的细胞穿透肽（RG）的正电荷，即限制内化，并且基于电荷反转机制在体外对轻度酸性微环境进行选择性触发。体内结果进一步证实，这些胶束在异种移植和原位胶质母细胞瘤小鼠模型中均优先在大脑和肿瘤组织中积累。此外，胶束显著抑制了肿瘤生长，对周围组织的毒性有限。这些胶束的 BBB 穿透、肿瘤靶向、强大的功效和高耐受性的结合强烈表明，它们可能是一种有前途的安全有效递送至大脑的药物载体候选物。
