A new biomimetic formulation developed to combat glioblastoma multiforme

A new biomimetic formulation developed to combat glioblastoma multiforme

Glioblastoma multiforme (GBM) is an aggressive brain cancer with a poor prognosis and limited treatment options. Therefore, novel and effective approaches to 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 Shenzhen Second People’s Hospital developed a biomimetic formulation using targeted transporters for synergistic therapy against GBM based on lactate metabolism.

The study was published in The nature of communication on July 21.

Targeting lactate metabolism is an attractive treatment strategy for tumors. However, there are no reports directly using lactate metabolism for the treatment of GBM. 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.

Moreover, considering the complexity and infiltrative characteristics of GBM, it is highly unlikely that monotherapy of lactate metabolism would effectively eliminate GBM cells. Therefore, it is vital to develop synergistic strategies to increase the therapeutic efficacy of lactate metabolic therapy.

In this study, researchers collected glioma samples from a large cohort of patients and quantified the lactate metabolic indicators LDHA and MCT4 and the representative proliferation marker Ki67.

“We observed a positive correlation between indicators of lactate metabolism and the extent of glioma proliferation,” said prof. LI Weiping from Shenzhen Second People’s Hospital. Thus, an effective synergistic metabolism-based therapy was proposed to directly take advantage of the elevated lactate in GBM.

Researchers have produced 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 create a biomimetic [email protected] System. This design concept was able to achieve targeted delivery for combination therapy.

“After intravenous injection, [email protected] could cross the blood-brain barrier through integrin-derived transcytosis and vascular cell-adhesion-protein-mediated recognition and then accumulate in GBM through homotypic recognition based on proteins associated with cell recognition function,” said Prof. WEI Wei from IPE.

In tumors, LOX in the NP converted lactate into pyruvic acid and hydrogen peroxide (H2O2). Pyruvic acid inhibited cancer cell growth by blocking histone expression and inducing cell cycle arrest. At the same time, 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 to generate cytotoxic singlet oxygen to kill glioma cells.

Strong therapeutic efficacy was confirmed in both cell line-derived xenograft and patient-derived xenograft (PDX) tumor models.

“Given the formulation’s safety and potent therapeutic effects against the corresponding PDX model, our personalized biomimetic formulation has the potential to translate into clinical application,” said Prof. MA Guanghui of IPE.

Reviewer from The nature of communication he said: “The idea of ​​this work is interesting.” Another reviewer emphasized that “a multi-targeted, personalized, smart nanoplatform to address glioblastoma multiforme is presented. The rationale is well explained, I really appreciate the multi-strategy approach and the biomolecular characterization.”

Source:

Headquarters of the Chinese Academy of Sciences

Link to journal:

10.1038/s41467-022-31799-y

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