Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Nanomedicine (Lond). 2012 Mar;7(3):335-52. doi: 10.2217/nnm.11.104.
This study tests the hypothesis that DNA intercalation and electrophilic interactions can be exploited to noncovalently assemble doxorubicin in a viral protein nanoparticle designed to target and penetrate tumor cells through ligand-directed delivery. We further test whether this new paradigm of doxorubicin targeting shows therapeutic efficacy and safety in vitro and in vivo.
MATERIALS & METHODS: We tested serum stability, tumor targeting and therapeutic efficacy in vitro and in vivo using biochemical, microscopy and cytotoxicity assays.
Self-assembly formed approximately 10-nm diameter serum-stable nanoparticles that can target and ablate HER2+ tumors at >10× lower dose compared with untargeted doxorubicin, while sparing the heart after intravenous delivery. The targeted nanoparticle tested here allows doxorubicin potency to remain unaltered during assembly, transport and release into target cells,while avoiding peripheral tissue damage and enabling lower, and thus safer, drug dose for tumor killing.
This nanoparticle may be an improved alternative to chemical conjugates and signal-blocking antibodies for tumor-targeted treatment.
本研究旨在验证以下假设，即通过设计靶向肿瘤细胞的配体导向递送来非共价组装多柔比星进入病毒蛋白纳米颗粒，利用 DNA 插入和亲电相互作用可以实现多柔比星的靶向传递。我们进一步测试了这种新的多柔比星靶向模式在体外和体内的治疗效果和安全性。
我们使用生化、显微镜和细胞毒性测定法，在体外和体内测试了血清稳定性、肿瘤靶向性和治疗效果。
自组装形成了约 10nm 直径的血清稳定纳米颗粒，与未靶向的多柔比星相比，其靶向和消融 HER2+肿瘤的剂量降低了 10 倍以上，而在静脉给药后，对心脏的损伤则更小。本研究中测试的靶向纳米颗粒可以在组装、运输和释放到靶细胞的过程中保持多柔比星的效力不变，从而避免了外周组织损伤，并使肿瘤杀伤所需的药物剂量更低，从而更安全。
与化学偶联物和信号阻断抗体相比，这种纳米颗粒可能是一种更优的肿瘤靶向治疗替代物。
