Glycopolymers are synthetic macromolecules having pendant sugar moieties and widely utilized to target cancer cells. They are usually considered as a hydrophilic segment of amphiphilic block copolymers to fabricate micelles as drug carriers. A novel amphiphilic block copolymer, namely, poly(2-deoxy-2-methacrylamido-d-glucose-co-2-hydroxyethyl methacrylate)-b-poly(β-amino ester) [P(MAG-co-HEMA)-b-PBAE], with active cancer cell targeting potential and pH responsivity was prepared. Tetrazine end functional P(MAG-co-HEMA) and norbornene end functional PBAE blocks were separately synthesized through reversible addition fragmentation chain transfer polymerization and Michael addition-based poly-condensation, respectively, and followed by end-group transformation. Then, inverse electron demand Diels Alder reaction between the tetrazine and the norbornene groups was performed by simply mixing to obtain the amphiphilic block copolymer. After characterization of the block copolymer in terms of chemical structure, pH responsivity, and drug loading/releasing, pH-responsive micelles were obtained with or without doxorubicin (DOX), a model anticancer drug. The micelles exhibited a sharp protonated/deprotonated transition on tertiary amine groups around pH 6.75 and the pH-specific release of DOX below this value. Eventually, the drug delivery potential was evaluated by cytotoxicity assays on both the noncancerous human umbilical vein endothelial cell (HUVEC) cell line and glioblastoma cell line, U87-MG. While the DOX-loaded polymeric micelles were not toxic in noncancerous HUVEC cells, being toxic only to the cancer cells indicates that it is a potential specific cell targeting strategy in the treatment of cancer.

Anti-apoptotic members of the Bcl-2 family proteins play central roles in the regulation of cell death in glioblastoma (GBM), the most malignant type of brain tumor. Despite the advances in GBM treatment, there is still an urgent need for new therapeutic approaches. Here, we report a novel 4-thiazolidinone derivative BH3 mimetic, BAU-243 that binds to Bcl-2 with a high affinity. BAU-243 effectively reduced overall GBM cell proliferation including a subpopulation of cancer-initiating cells in contrast to the selective Bcl-2 inhibitor ABT-199. While ABT-199 successfully induces apoptosis in high BCL2-expressing neuroblastoma SHSY-5Y cells, BAU-243 triggered autophagic cell death rather than apoptosis in GBM A172 cells, indicated by the upregulation of BECN1, ATG5, and MAP1LC3B expression. Lc3b-II, a potent autophagy marker, was significantly upregulated following BAU-243 treatment. Moreover, BAU-243 significantly reduced tumor growth in vivo in orthotopic brain tumor models when compared to the vehicle group, and ABT-199 treated animals. To elucidate the molecular mechanisms of action of BAU-243, we performed computational modeling simulations that were consistent with in vitro results. Our results indicate that BAU-243 activates autophagic cell death by disrupting the Beclin 1:Bcl-2 complex and may serve as a potential small molecule for treating GBM.