Nano-Codelivery of Temozolomide and siPD-L1 to Reprogram the Drug-Resistant and Immunosuppressive Microenvironment in Orthotopic Glioblastoma

Abstract

Glioblastoma (GBM) is an invasive cancer with high mortality in central nervous system. Resistance to temozolomide (TMZ) and immunosuppressive microenvironment lead to low outcome of the standardized treatment for GBM. In this study, a 2-deoxy-d-glucose modified lipid polymer nanoparticle loaded with TMZ and siPD-L1 (TMZ/siPD-L1@GLPN/dsb) was prepared to reprogram the TMZ-resistant and immunosuppressive microenvironment in orthotopic GBM. TMZ/siPD-L1@GLPN/dsb simultaneously delivered a large amount of TMZ and siPD-L1 to the deep area of the orthotopic TMZ-resistant GBM tissue. By inhibiting PD-L1 protein expression, TMZ/siPD-L1@GLPN/dsb markedly augmented the percentage of CD3+CD8+IFN-γ+ cells (Teff cells) and reduced the percentage of CD4+CD25+FoxP3+ cells (Treg cells) in orthotopic TMZ-resistant GBM tissue, which enhanced T-cell mediated cytotoxicity on orthotopic TMZ-resistant GBM. Moreover, TMZ/siPD-L1@GLPN/dsb obviously augmented the sensitivity of orthotopic TMZ-resistant GBM to TMZ through decreasing the protein expression of O 6-methyl-guanine-DNA methyltransferase (MGMT) in TMZ-resistant GBM cells. Thus, TMZ/siPD-L1@GLPN/dsb markedly restrained the growth of orthotopic TMZ-resistant GBM and extended the survival time of orthotopic GBM rats through reversing a TMZ-resistant and immunosuppressive microenvironment. TMZ/siPD-L1@GLPN/dsb shows potential application to treat orthotopic TMZ-resistant GBM.

Reducing Chemo-/Radioresistance to Boost the Therapeutic Efficacy against Temozolomide-Resistant Glioblastoma

“…It has been known that the Wnt/β-catenin signaling pathway is overactivated in glioma tissues . Pharmacologically or genetically inhibiting Wnt activity is an effective way to downregulate MGMT expression for restoring GBM chemosensitivity to DNA-alkylating drugs . GSK-3β is a vital negative regulator of the Wnt/β-catenin signaling pathway.…”

“…53 Pharmacologically or genetically inhibiting Wnt activity is an effective way to downregulate MGMT expression for restoring GBM chemosensitivity to DNA-alkylating drugs. 54 GSK-3β is a vital negative regulator of the Wnt/β-catenin signaling pathway. Phosphorylation of GSK-3β at Ser9 (i.e., P-GSK-3β) leads to its inactivation, thereby enhancing the reverse transcriptional activity of βcatenin.…”

Nucleic acid drug vectors for diagnosis and treatment of brain diseases

“… 680 Zhou et al co-loaded siPD-L1 and TMZ via LPNPs. 681 PAsp-g-PEI/dsb was synthesized by grafting PEI onto PAsp via disulfide bonding. PAsp-g-PEI/dsb formed complexes with siPD-L1 via electrostatic interaction.…”

Delivering the Promise of Gene Therapy with Nanomedicines in Treating Central Nervous System Diseases

“…Cationic lipids, such as 1,2‐di‐ O ‐octadecenyl‐3‐trimethylammomium‐propane (DOTMA) lipid and 1,2‐dioleoyl‐3‐trimethylammonium‐propane (DOTAP), and zwitterionic lipids, such as 1,2‐dioleoyl‐sn‐glycero‐3‐phosphoethanolamine (DOPE), have been used alone or in combination with other materials for brain gene delivery. [ 470 , 471 ] These charged LNPs usually consist of a helper lipid to stabilize the formulation, and a PEGylated lipid to reduce the opsonizations and reticuloendothelial clearance. [ 472 , 473 ] It should be noted that the ratio of various components can significantly affect the corresponding gene delivery efficiency.…”