TY - JOUR
T1 - Targeted liposomes for combined delivery of artesunate and temozolomide to resistant glioblastoma
AU - Ismail, Muhammad
AU - Yang, Wen
AU - Li, Yanfei
AU - Chai, Tianran
AU - Zhang, Dongya
AU - Du, Qiuli
AU - Muhammad, Pir
AU - Hanif, Sumaira
AU - Zheng, Meng
AU - Shi, Bingyang
PY - 2022/8
Y1 - 2022/8
N2 - The effective treatment of glioblastoma (GBM) is a great challenge because of the blood-brain barrier (BBB) and the growing resistance to single-agent therapeutics. Targeted combined co-delivery of drugs could circumvent these challenges; however, the absence of more effective combination drug delivery strategies presents a potent barrier. Here, a unique combination ApoE-functionalized liposomal nanoplatform based on artesunate-phosphatidylcholine (ARTPC) encapsulated with temozolomide (ApoE-ARTPC@TMZ) was presented that can successfully co-deliver dual therapeutic agents to TMZ-resistant U251-TR GBM in vivo. Examination in vitro showed ART-mediated inhibition of DNA repair through the Wnt/β-catenin signaling cascade, which also improved GBM sensitivity to TMZ, resulting in enhanced synergistic DNA damage and induction of apoptosis. In assessing BBB permeation, the targeted liposomes were able to effectively traverse the BBB through low-density lipoprotein family receptors (LDLRs)-mediated transcytosis and achieved deep intracranial tumor penetration. More importantly, the targeted combination liposomes resulted in a significant decrease of U251-TR glioma burden in vivo that, in concert, substantially improved the survival of mice. Additionally, by lowering the effective dosage of TMZ, the combination liposomes reduced systemic TMZ-induced toxicity, highlighting the preclinical potential of this novel integrative strategy to deliver combination therapies to brain tumors.
AB - The effective treatment of glioblastoma (GBM) is a great challenge because of the blood-brain barrier (BBB) and the growing resistance to single-agent therapeutics. Targeted combined co-delivery of drugs could circumvent these challenges; however, the absence of more effective combination drug delivery strategies presents a potent barrier. Here, a unique combination ApoE-functionalized liposomal nanoplatform based on artesunate-phosphatidylcholine (ARTPC) encapsulated with temozolomide (ApoE-ARTPC@TMZ) was presented that can successfully co-deliver dual therapeutic agents to TMZ-resistant U251-TR GBM in vivo. Examination in vitro showed ART-mediated inhibition of DNA repair through the Wnt/β-catenin signaling cascade, which also improved GBM sensitivity to TMZ, resulting in enhanced synergistic DNA damage and induction of apoptosis. In assessing BBB permeation, the targeted liposomes were able to effectively traverse the BBB through low-density lipoprotein family receptors (LDLRs)-mediated transcytosis and achieved deep intracranial tumor penetration. More importantly, the targeted combination liposomes resulted in a significant decrease of U251-TR glioma burden in vivo that, in concert, substantially improved the survival of mice. Additionally, by lowering the effective dosage of TMZ, the combination liposomes reduced systemic TMZ-induced toxicity, highlighting the preclinical potential of this novel integrative strategy to deliver combination therapies to brain tumors.
KW - Artesunate-phosphatidylcholine
KW - Liposomes
KW - MGMT inhibition
KW - Resistant glioblastoma
KW - Synergistic therapy
UR - http://www.scopus.com/inward/record.url?scp=85131681479&partnerID=8YFLogxK
U2 - 10.1016/j.biomaterials.2022.121608
DO - 10.1016/j.biomaterials.2022.121608
M3 - Article
C2 - 35690021
AN - SCOPUS:85131681479
SN - 0142-9612
VL - 287
SP - 1
EP - 13
JO - Biomaterials
JF - Biomaterials
M1 - 121608
ER -