Instituto de Tecnología Química-UPV-CSIC, Av. Los Naranjos s/n, 46022 Valencia, Spain.
J Control Release. 2011 Dec 10;156(2):246-57. doi: 10.1016/j.jconrel.2011.06.039. Epub 2011 Jul 4.
Here we report the design, synthesis and biological evaluation of surface-modified silica nanoparticles (SNP) for the delivery of camptothecin (CPT). Drug has been covalently linked to the nanoparticle through an ester bond with the 20-hydroxy moiety, in order to stabilize its lactone ring and to avoid unspecific release of the drug. The obtained material is highly stable in plasma, with low release of the cargo at physiological pH. Cell internalization and in vitro efficacy assays demonstrated that nanoparticles carrying CPT (SNP-CPT) entered cells via endocytosis and the intracellular release of the cargo induced cell death with half maximal inhibitory concentration (IC₅₀) values and cell cycle distribution profiles similar to those observed for the naked drug. Further, in vivo biodistribution, therapeutic efficacy and biocompatibility of the SNP-CPT were evaluated in human colorectal cancer xenografts using in vivo fluorescence or bioluminescence optical imaging. In vivo tumor-accumulation and whole-body tissue distribution were carried out based on the acquisition of fluorescence emission of a fluorophore (Cy5.5) conjugated to the SNP-CPT, as well as by HPLC quantification of tissue CPT levels. The results showed that, although SNP-CPT tended to accumulate in organs of the reticulo-endothelial system, nanoparticles boost CPT concentration in tumor vs administration of the free drug. Accordingly, SNP-CPT treatment delayed the growth of subcutaneous tumors while significantly reducing the systemic toxicity associated with CPT administration. These results indicate that the SNP-CPT could be used as a robust drug delivery system for antitumoral treatments based on CPT.
在这里，我们报告了表面修饰的硅纳米粒子（SNP）的设计、合成和生物学评价，用于递送喜树碱（CPT）。药物通过酯键与纳米粒子共价连接，其中 20-羟基部分稳定了药物的内酯环，避免了药物的非特异性释放。所得材料在血浆中高度稳定，在生理 pH 值下药物的释放量低。细胞内化和体外功效测定表明，携带 CPT 的纳米粒子（SNP-CPT）通过内吞作用进入细胞，细胞内货物的释放诱导细胞死亡，其半数最大抑制浓度（IC₅₀）值和细胞周期分布与裸药观察到的相似。此外，在人结直肠癌细胞异种移植模型中，通过体内荧光或生物发光光学成像评估了 SNP-CPT 的体内分布、治疗效果和生物相容性。基于 SNP-CPT 上缀合的荧光团（Cy5.5）的荧光发射的获取，以及组织中 CPT 水平的 HPLC 定量，进行了体内肿瘤积聚和全身组织分布。结果表明，尽管 SNP-CPT 倾向于在网状内皮系统器官中积聚，但与给予游离药物相比，纳米粒子增加了肿瘤中的 CPT 浓度。因此，SNP-CPT 治疗延迟了皮下肿瘤的生长，同时显著降低了与 CPT 给药相关的全身毒性。这些结果表明，SNP-CPT 可用作基于 CPT 的抗肿瘤治疗的强大药物递送系统。
