ICGM, Univ. Montpellier, CNRS, ENSCM, Montpellier, France.
Institut des Biomolécules Max Mousseron, UMR5247, Université de Montpellier, CNRS, ENSCM, Faculté de Pharmacie, 15 Avenue Charles Flahault, 34093, Montpellier, Cedex 05, France.
J Mater Chem B. 2020 Feb 19;8(7):1472-1480. doi: 10.1039/c9tb02225b.
Herein hybrid silica nanoparticles have been engineered to direct the sequential delivery of multiple chemotherapeutic drugs in response to external stimuli such as variations in pH. The nanocarriers consist of conventional MCM-41-type nanoparticles, which have been functionalised with an organic ligand (or stalk) grafted onto the external surface. The stalk is designed to "recognise" a complementary molecule, which serves as a "cap" to block the pores of the nanoparticles. First, camptothecin is introduced into the pores by diffusion prior to capping the pore apertures via molecular recognition. The cap, which is a derivative of 5-fluorouracil, serves as a second cytotoxic drug for synergistic chemotherapy. In vitro tests revealed that negligible release of the drugs occurred at pH 7.4, thus avoiding toxic side effects in the blood stream. In contrast, the stalk/cap complex is destabilised within the endolysosomal compartment (pH 5.5) of cancer cells, where release of the drugs was demonstrated. Furthermore, this environmentally responsive system exhibited a synergistic effect of the two drugs, where the pH-triggered release of the cytotoxic cap followed by diffusion-controlled release of the drug cargo within the pores led to essentially complete elimination of breast cancer cells.
在此，我们设计了一种杂化二氧化硅纳米粒子，使其能够对外界刺激（如 pH 值变化）做出响应，从而顺序递输送达多种化疗药物。这些纳米载体由传统的 MCM-41 型纳米粒子组成，其外表面接枝有有机配体（或“茎干”）。该“茎干”旨在“识别”互补分子，作为“盖子”来阻塞纳米粒子的孔道。首先，通过扩散将喜树碱引入孔道中，然后通过分子识别封闭孔道的开口。作为第二种细胞毒性药物的“盖子”是 5-氟尿嘧啶的衍生物，用于协同化疗。体外测试表明，在 pH 值为 7.4 时，药物几乎没有释放，从而避免了血液中的毒副作用。相比之下，在癌细胞的内溶酶体区室（pH 值为 5.5）中，“茎干/盖子”复合物不稳定，药物被释放。此外，这种环境响应系统表现出两种药物的协同作用，即细胞毒性盖子在 pH 触发下释放，随后药物货物在孔道内扩散控制释放，导致乳腺癌细胞基本上被完全消除。
