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Dual-targeting immunoliposomes using angiopep-2 and CD133 antibody for glioblastoma stem cells
Jung Seok Kim1, Dae Hwan Shin2, Jin-Seok Kim1
1Research Center for Cell Fate Control (RCCFC), Drug Information Research Institute (DIRI), College of Pharmacy, Sookmyung Women's University, Seoul 04310, Republic of Korea.
Abstract:
Glioblastoma stem cells (GSCs), which are identified as subpopulation of CD133+/ALDH1+, are known to show resistance to the most of chemotherapy and radiation therapy, leading to the recurrence of tumor in glioblastoma multiforme (GBM) patients. Also, delivery of temozolomide (TMZ), a mainline treatment of GBM, to the GBM site is hampered by various barriers including the blood-brain barrier (BBB). A dual-targeting immunoliposome encapsulating TMZ (Dual-LP-TMZ) was developed by using angiopep-2 (An2) and anti-CD133 monoclonal antibody (CD133 mAb) for BBB transcytosis and specific delivery to GSCs, respectively. The size, zeta potential and drug encapsulation efficiency of Dual-LP-TMZ were 203.4nm in diameter, -1.6mV and 99.2%, respectively. The in vitro cytotoxicity of Dual-LP-TMZ against U87MG GSCs was increased by 425- and 181-folds when compared with that of free TMZ and non-targeted TMZ liposome (LP-TMZ) (10.3μM vs. 4380μM and 1869μM in IC50, respectively). Apoptosis and anti-migration ability of Dual-LP-TMZ in U87MG GSCs were also significantly enhanced comparing with those of free TMZ or LP-TMZ. In vivo study clearly showed a significant reduction in tumor size after intravenous administrations of Dual-LP-TMZ to the orthotopically-implanted brain tumor mice when compared with free TMZ or LP-TMZ. Increased life span (ILS) and median survival time (MST) of tumor-bearing mice were also increased when treated with Dual-LP-TMZ (211.2% in ILS and 49.2days in MST) than with free TMZ (0% in ILS and 23.3day in MST). These data indicate that conjugation of both An2 peptide and CD133 mAb to TMZ-encapsulating liposome is very effective in delivering the TMZ to GSCs via BBB, suggesting a potential use of Dual-LP-TMZ as a therapeutic modality for GBM.
Insights
This study developed a dual-targeting immunoliposome encapsulating temozolomide (TMZ) to overcome glioblastoma stem cell resistance and the blood-brain barrier. The novel Dual-LP-TMZ significantly improved treatment efficacy in preclinical models, offering a promising therapeutic strategy for glioblastoma multiforme.
Area of Science:
- Nanomedicine
- Oncology
- Biotechnology
Background:
- Glioblastoma stem cells (GSCs) exhibit resistance to standard therapies, leading to tumor recurrence.
- Temozolomide (TMZ) delivery to glioblastoma (GBM) is limited by the blood-brain barrier (BBB).
Purpose of the Study:
- To develop a dual-targeting immunoliposome (Dual-LP-TMZ) for enhanced TMZ delivery to GSCs across the BBB.
- To evaluate the in vitro and in vivo efficacy of Dual-LP-TMZ against GBM.
Main Methods:
- Conjugation of angiopep-2 (An2) and anti-CD133 monoclonal antibody (CD133 mAb) to TMZ-loaded liposomes.
- In vitro cytotoxicity, apoptosis, and anti-migration assays using U87MG GSCs.
- In vivo studies in orthotopically implanted GBM mouse models to assess tumor reduction, increased lifespan (ILS), and median survival time (MST).
Main Results:
- Dual-LP-TMZ demonstrated superior in vitro cytotoxicity against GSCs compared to free TMZ and non-targeted liposomes.
- Significant enhancement in apoptosis and anti-migration effects was observed with Dual-LP-TMZ.
- In vivo administration of Dual-LP-TMZ resulted in substantial tumor size reduction, improved ILS (211.2%), and prolonged MST (49.2 days) in tumor-bearing mice.
Conclusions:
- Dual-LP-TMZ effectively targets GSCs and penetrates the BBB, enhancing TMZ's therapeutic potential.
- This dual-targeting strategy represents a promising approach for overcoming GBM treatment resistance and improving patient outcomes.
