Lipid-Conjugated Reduced Haloperidol in Association with Glucose-Based Nanospheres: A Strategy for Glioma Treatment

Area of Science:

• Neuroscience
• Oncology
• Nanotechnology
• Drug Delivery

Background:

• Aggressive glioma has a poor prognosis, with both tumor cells and tumor-associated macrophages (TAMs) contributing to its progression.
• Targeting both glioma cells and TAMs is crucial for effective brain cancer treatment.
• The sigma receptor (SR) is overexpressed on both glioma cells and TAMs, making it a viable therapeutic target.

Purpose of the Study:

• To develop a novel nanodrug delivery system for targeting SR-expressing glioma cells and TAMs.
• To evaluate the efficacy of the developed nanoconjugate in preclinical brain cancer models.
• To investigate the mechanism of action, including TAM polarization and cytokine modulation.

Main Methods:

• Development of a cationic lipid-conjugated reduced haloperidol (±RHPC8) targeting the sigma receptor.
• Conjugation of ±RHPC8 to glucose-based carbon nanospheres (CSPs) for blood-brain barrier (BBB) penetration.
• Evaluation of ±RHPC8-CSP efficacy in orthotopic and subcutaneous mouse glioma models.
• Assessment of TAM uptake, polarization (M2 to M1), and cytokine expression (TGF-β, IL-10, VEGF).

Main Results:

• The ±RHPC8-CSP nanoconjugate successfully delivered the drug across the BBB and targeted SR-expressing glioma cells.
• Treatment with ±RHPC8-CSP significantly prolonged survival and regressed tumors in mouse models.
• ±RHPC8-CSP was effectively taken up by TAMs, inducing M1 polarization and reducing immunosuppressive cytokines.
• The nanoconjugate demonstrated a dual therapeutic effect on both glioma cells and TAMs.

Conclusions:

• The designed ±RHPC8-CSP nanoconjugate is a promising and effective nanodrug delivery system for brain cancer therapy.
• This approach offers a novel strategy for simultaneously targeting glioma cells and modulating the tumor microenvironment via TAMs.
• The BBB-crossing capability and dual-targeting mechanism highlight the potential of ±RHPC8-CSP for clinical translation in glioblastoma treatment.