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

Abstract 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.