Glucose and Triphenylphosphonium Co-Modified Redox-Sensitive Liposomes to Synergistically Treat Glioma with Doxorubicin and Lonidamine.
Yao PengJiaqi LuRu LiYi ZhaoLi HaiLi GuoYong WuPublished in: ACS applied materials & interfaces (2021)
Glioma is one of the most lethal and complex tumors, and thus, an effective drug delivery system must selectively target the tumor sites and release its cargos in a controlled manner. For the first time, we combined chemotherapeutic agent doxorubicin (DOX) and chemosensitizer lonidamine (LND) to synergistically treat glioma. We also designed and prepared multitargeted redox-sensitive liposomes (Lip-SPG) co-modified with glucose and triphenylphosphonium (TPP) to effectively deliver DOX and LND for anti-glioma therapy. The anti-glioma evaluation shows that DOX and LND have a synergistic effect and Lip-SPG could further enhance their cooperation. In vitro, Lip-SPG could increase the cellular uptake and mitochondrial uptake on bEnd.3 cells and C6 cells with multitargeting ability on the brain, tumor, and mitochondria mediated by glucose and TPP. Lip-SPG can also escape from lysosomes before entering the mitochondria. The anti-glioma efficacy in vitro shows that Lip-SPG can inhibit tumor cell proliferation and induce apoptosis. In addition, Lip-SPG have a remarkable interference to mitochondria, such as reducing intracellular ATP production, inducing ROS generation, and promoting mitochondrial membrane potential depolarization. Furthermore, in vivo, the introduction of PEGylation via glutathione-sensitive disulfide bonds endows Lip-SPG with favorable pharmacokinetic properties, brain targeting ability, low toxicity to normal tissues, and great anti-glioma efficacy with the survival time extended from 19 to 39 days. In conclusion, Lip-SPG are an effective delivery system for synergistically treating glioma with DOX and LND.
Keyphrases
- oxidative stress
- cell death
- cell cycle arrest
- induced apoptosis
- drug delivery
- cell proliferation
- reactive oxygen species
- endoplasmic reticulum stress
- cancer therapy
- dna damage
- signaling pathway
- type diabetes
- adipose tissue
- cell cycle
- mesenchymal stem cells
- blood glucose
- blood brain barrier
- functional connectivity
- drug release
- human health