Surface Modified Glucose-Derived, Blood–Brain Barrier-Crossing Nanospheres Dually Targets Macrophage and Cancer Cells for Effective In Situ Anti-Glioma Effect

Glucose-derived carbon nanospheres (CSP), uniquely derived by hydrothermal condensation process, inherently cross blood–brain-barrier (BBB) but distribute all over the brain. Albeit its potential to treat glioma as an effective drug delivery system, it is challenging to restrict drug-associated CSP within the glioma region and reduce non-specific side effects. Incidentally, gliomas moderately express sigma receptors (SR). Earlier, a cationic lipid-conjugated neuropsychotic drug, haloperidol (H8) is developed with SR-targetability and anticancer effect but with zero BBB-crossing ability. In this study, the CSP surface is modified with H8 (CH8 nano-conjugate) and dual targeting is achieved within glioma-tumor microenvironment: 1) glioma cells and 2) pro-proliferative M2 tumor-associated macrophages (TAM), as both express SR. CH8-treatment increases the survivability of orthotopic glioma-tumor bearing mice and significantly reduces tumor burden in the glioma-subcutaneous model. Further CH8-surface is modified by combining the brain tumor drug, carmustine (CH8-CRM). CH8-CRM nano-conjugate selectively enhances the survivability of orthotopic glioma-carrying mice and reduces tumor aggressiveness significantly in comparison to other treatment groups. Lysates from CH8-CRM-treated tumor show upregulation of cleaved-caspase 3, p53, but downregulation of pAkt. The combination treatment pronouncedly enhances the anti-glioma effect of H8. Conclusively, CH8-mediated dual-targeting via SR within orthotopic glioma-associated mice exemplifies the repurposing of neuropsychotic drugs for treating glioma.