Enhanced activity of AZD5582 and SM-164 in rabies virus glycoprotein-lactoferrin-liposomes to downregulate inhibitors of apoptosis proteins in glioblastoma.

Upregulated proliferation of neoplastic cells from suppressing apoptotic signals associated with the inhibitors of apoptosis proteins (IAP) makes difficult the achievement of therapeutic efficiency against glioblastoma multiforme. Studies in the last few years have witnessed a paradigm focusing on targeting IAP using its antagonists, such as Smac mimetics, to restrain tumor malignancy. A Smac mimetic compound needs to penetrate the blood-brain barrier (BBB), and must be internalized into cerebral tumor for improved chemotherapy. Rabies virus glycoprotein (RVG) and lactoferrin (Lf)-grafted liposomes were developed in this study to carry two IAP antagonists, AZD5582 and SM-164, across the BBB and to induce apoptosis in U87 MG and human brain cancer stem cells (HBCSCs). Liposomes modified with RVG slightly reduced BBB tightness and enhanced capability of AZD5582 and SM-164 for traversing the barrier because of their brain-targeting ability. Immunofluorescence and western-blot results revealed that AZD5582- and SM-164-encapsulated liposomes facilitated mutual curative intensity, effectively triggered apoptosis of U87 MG and HBCSCs, reduced the expression of cellular IAP 1 (cIAP1) and X-linked IAP (XIAP), and enhanced the expression of caspase-3. Hence, RGV-Lf-liposomes carrying AZD5582 and SM-164 can be promising formulations to activate apoptosis of U87 MG and HBCSCs, and this functionalized drug delivery system targeting cIAP and XIAP is a potential strategy to cure glioblastoma in clinical cancer management.

Rescuing cholinergic neurons from apoptotic degeneration by targeting of serotonin modulator-and apolipoprotein E-conjugated liposomes to the hippocampus.

ß-Amyloid (Aß)-targeting liposomes (LIP) with surface serotonin modulator (SM) and apolipoprotein E (ApoE) were utilized to facilitate the delivery of nerve growth factor (NGF) across the blood-brain barrier (BBB) for neuroprotection in the hippocampus. The therapeutic efficacy of SM- and ApoE-grafted LIP carrying NGF (NGF-SM-ApoE-LIP) was assessed by an in vitro Alzheimer's disease (AD) model of degenerated SK-N-MC cells and an in vivo AD model of Aß-insulted Wistar rats. The experimental evidences revealed that the modified SM and ApoE on the surface of LIP increased the permeation of NGF across the BBB without serious damage to structural integrity of tight junction. When compared with free NGF, NGF-SM-ApoE-LIP upregulated the expression of phosphorylated neurotrophic tyrosine kinase receptor type 1 on cholinergic neurons and significantly improved their survival. In addition, NGF-SM-ApoE-LIP could reduce the secretion of acetylcholinesterase and malondialdehyde and rescue hippocampal neurons from apoptosis in rat brains. The synergistic effect of SM and ApoE is promising in the induction of NGF to inhibit the neurotoxicity of Aß and NGF-SM-ApoE-LIP can be a potent antiapoptotic pharmacotherapy for clinical care of patients with AD.