Dual receptor-specific peptides modified liposomes as VEGF siRNA vector for tumor-targeting therapy

Area of Science:

• Oncology
• Nanotechnology
• Molecular Biology

Background:

• Tumor angiogenesis, driven by vascular endothelial growth factor (VEGF), is crucial for tumor growth and metastasis.
• VEGF-targeting small interfering RNA (siRNA) therapies are under development for anti-angiogenic cancer treatment.
• Effective delivery of siRNA to tumor cells remains a challenge in cancer therapy.

Purpose of the Study:

• To design and evaluate dual-modified liposomes (At-Lp) for targeted delivery of VEGF siRNA to brain tumors.
• To assess the in vitro and in vivo efficacy of At-Lp loaded with VEGF siRNA in inhibiting glioblastoma growth and angiogenesis.
• To investigate the targeting mechanisms and safety profile of the dual-modified liposomes.

Main Methods:

• Liposomes were dual-modified with Angiopep and tLyP-1 peptides for targeting low-density lipoprotein receptor (LRP) and neuropilin-1 receptor (NRP-1).
• VEGF siRNA-loaded At-Lp were tested for cellular uptake, gene silencing, and anti-tumor effects in U87 MG glioblastoma cells and orthotopic xenograft models.
• Mechanisms of cellular internalization, including enhanced permeability and retention (EPR) effect and receptor-mediated endocytosis, were studied.
• In vivo studies assessed tumor growth inhibition, anti-angiogenesis, VEGF expression, apoptosis, and systemic toxicity in nude mice.

Main Results:

• At-Lp demonstrated significantly enhanced cellular uptake (2-fold) and VEGF expression down-regulation in U87 MG cells compared to control liposomes.
• Internalization involved EPR effect and receptor-mediated endocytosis, followed by efficient endosomal escape of siRNA.
• In vivo, At-Lp significantly inhibited tumor growth, reduced angiogenesis, suppressed VEGF expression, and induced apoptosis in U87 MG glioblastomas.
• No significant systemic toxicity or innate immune response was observed after in vivo application.

Conclusions:

• Dual-modified liposomes (At-Lp) provide an effective platform for targeted delivery of VEGF siRNA for brain tumor therapy.
• The combination of Angiopep and tLyP-1 peptides enhances tumor targeting, cellular uptake, and therapeutic efficacy.
• This approach shows promise for developing novel anti-angiogenic cancer treatments with improved safety and effectiveness.