Glioblastoma multiforme (GBM) is an aggressive brain cancer with a poor prognosis and few treatment options. Therefore, new and effective approaches for the treatment of GBM are urgently needed.
Based on the observation of elevated lactate in resected GBM, researchers from the Institute of Process Engineering (IPE) of the Chinese Academy of Sciences and the Second People’s Hospital of Shenzhen have developed a biomimetic formulation that uses agents targeted delivery for synergistic therapy based on lactate metabolism against GBM.
The study was published in Nature Communications on July 21.
Targeting lactate metabolism is an attractive tumor therapeutic strategy. However, there are no reports directly exploiting lactate metabolism for GBM treatments. One limitation is the existence of the blood-brain barrier, which prevents most drug molecules (including those that interfere with lactate metabolism) from reaching the brain.
Furthermore, given the complexity and infiltrative characteristics of GBM, it is highly unlikely that metabolic lactate monotherapy will effectively eliminate GBM cells. Therefore, it is vital to develop synergistic strategies to improve the therapeutic efficiency of metabolic lactate therapy.
In this study, researchers collected glioma samples from a large cohort of patients and quantified the metabolic indicators lactate LDHA and MCT4 and a representative proliferation marker Ki67.
“We observed a positive correlation between metabolic indicators of lactate and the extent of glioma proliferation,” said Professor LI Weiping of Shenzhen Second People’s Hospital. Thus, an efficient synergistic metabolism-based therapy was proposed that would directly take advantage of the elevated lactate in GBM.
The researchers fabricated self-assembling nanoparticles (NPs) composed of hemoglobin (Hb), lactate oxidase (LOX), bis[2,4,5-trichloro-6-(pentyloxycarbonyl)phenyl] oxalate (CPPO) and chlorin e6 (Ce6) using a one-pot approach. They subsequently encapsulated these self-assembled NPs with membrane materials prepared from U251 glioma cells to generate the biomimetic. [email protected] system This design concept was able to achieve targeted delivery for combination therapy.
“After the intravenous injection, the [email protected] could cross the blood-brain barrier via transcytosis from integrin- and vascular cell adhesion protein-mediated recognition, and then accumulate in GBM via homotypic recognition based on proteins associated with cell recognition function,” said Professor WEI Wei of IPE.
In tumors, LOX in NPs converted lactate to pyruvic acid and hydrogen peroxide (H2O2). Pyruvic acid inhibited the growth of cancer cells by blocking histone expression and inducing cell cycle arrest. In parallel, H2O2 acted as a local fuel to react with the delivered CPPO to release energy, which could then be used by the co-delivered photosensitizer Ce6 for the generation of cytotoxic singlet oxygen to kill the cells of the glioma
Potent therapeutic efficacy was confirmed in both cell line-derived xenograft and patient-derived xenograft (PDX) tumor models.
“Considering the formulation’s safety and potent therapeutic effects against the matched PDX model, our customized biomimetic formulation has the potential to be translated into clinical application,” said Professor MA Guanghui of IPE.
A Nature Communications peer reviewer said, “The idea behind this work is interesting.” Another reviewer emphasized that “a smart, customized, multi-targeting nanoplatform is presented to address glioblastoma multiforme. The rationale is well explained, indeed I appreciate the multi-strategy approach and biomolecular characterization.”
Source:
Headquarters of the Chinese Academy of Sciences
Journal reference:
10.1038/s41467-022-31799-y