Bioinspired Lipoproteins of Furoxans-Gemcitabine Preferentially Targets Glioblastoma and Overcomes Radiotherapy...

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Oncology

Background:

• Radiotherapy resistance is a major challenge in glioblastoma multiforme (GBM) treatment.
• Mechanisms include DNA repair, poor radical distribution, and limited radiosensitizer delivery.
• Upregulation of RAD51, scavenger receptor B type 1 (SR-B1), and C-C motif chemokine ligand 5 (CCL5) is observed in GBM.

Purpose of the Study:

• To design a novel radiosensitizer delivery system to overcome GBM radiotherapy resistance.
• To target GBM tumor sites preferentially and enhance therapeutic efficacy.
• To develop a reduction-sensitive nitric oxide (NO) donor conjugate of gemcitabine (NG) and encapsulate it in a CCL5 peptide-modified bioinspired lipoprotein (C-LNG).

Main Methods:

• Synthesis of a reduction-sensitive NO donor conjugate of gemcitabine (NG) as a radiosensitizer.
• Design of a CCL5 peptide-modified bioinspired lipoprotein system (C-LNG) for targeted delivery.
• Evaluation of C-LNG accumulation, drug release, and therapeutic efficacy in an orthotopic GBM mouse model.

Main Results:

• C-LNG preferentially accumulated at orthotopic GBM tumor sites with significant intratumor permeation.
• C-LNG responsively released gemcitabine and NO, generating peroxynitrite (ONOO-) upon X-ray radiation.
• Achieved 99.64% tumor growth inhibition and a 71.44% survival rate at 120 days in the GL261-induced orthotopic GBM model.

Conclusions:

• The rationally designed C-LNG system effectively targets GBM and overcomes radiotherapy resistance.
• This bioinspired lipoprotein system offers a promising strategy for GBM treatment.
• The combination of gemcitabine, NO, and targeted delivery enhances radiosensitization and therapeutic outcomes.