State Key Laboratory of Natural Medicines and Department of Pharmaceutics, China Pharmaceutical University, Nanjing, 210009, China.
Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Adv Healthc Mater. 2017 Apr;6(8). doi: 10.1002/adhm.201600693. Epub 2017 Feb 10.
The ability to escape endo/lysosomal trafficking is critically important to prevent entrapment of nanomedicines in lysosomes and to achieve maximum therapeutic efficacy of drugs delivered to cells through endocytosis. In this study, a novel pH-sensitive chitosan carrier with the ability to reverse its charge during endo/lysosomal trafficking is developed as a way of improving lysosomal disruption. N-Arginine-N-octyl chitosan (AOCS) is synthesized by grafting l-arginine onto carboxymethyl chitosan. The AOCS is used to modify the surface of nanostructured lipid carriers (NLC) to prepare pH-sensitive charge-reversal lysosomolytic nanocarriers (ANLC). The ANLC is loaded with 10-hydroxycamptothecin (HCPT). The results show that ANLC is able to reverse surface zeta potential from negative to positive at lysosomal pH, which contributes to improved release of encapsulated drugs into cytoplasm. The lysosomolytic capability of ANLC is confirmed by confocal microscopy and transmission electron microscopy. In vitro studies demonstrate that the anticancer activity of HCPT-loaded ANLC is improved when compared with HCPT-NLC and free HCPT. In vivo pharmacokinetics and tissue distribution analysis show improved delivery of HCPT-ANLC to subcutaneous Heps mouse liver tumors and greatly improved antitumor activity. The results present ANLC as a promising drug delivery carrier for improved antitumor therapy.
逃避内体/溶酶体运输的能力对于防止纳米药物被溶酶体困住以及实现通过内吞作用递送到细胞的药物的最大治疗效果至关重要。在这项研究中，开发了一种具有在内体/溶酶体运输过程中改变其电荷的能力的新型 pH 敏感壳聚糖载体，作为改善溶酶体破坏的一种方法。N-精氨酸-N-辛基壳聚糖（AOCS）是通过将 l-精氨酸接枝到羧甲基壳聚糖上合成的。将 AOCS 用于修饰纳米结构化脂质载体（NLC）的表面，以制备 pH 敏感的电荷反转溶酶体裂解纳米载体（ANLC）。将 10-羟基喜树碱（HCPT）装载到 ANLC 中。结果表明，ANLC 能够在溶酶体 pH 下将表面 ζ 电位从负变为正，有助于将包封的药物更有效地释放到细胞质中。通过共聚焦显微镜和透射电子显微镜证实了 ANLC 的溶酶体裂解能力。体外研究表明，与 HCPT-NLC 和游离 HCPT 相比，负载 HCPT 的 ANLC 的抗癌活性得到了提高。体内药代动力学和组织分布分析表明，HCPT-ANLC 递送到皮下 Heps 小鼠肝癌中的递送得到了改善，并且抗肿瘤活性大大提高。结果表明，ANLC 作为一种有前途的药物递送载体，可用于改善抗肿瘤治疗。
