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.
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