Summary: Researchers found a positive correlation between glioblastoma cell proliferation and indicators of lactate metabolism. Based on this observation, researchers developed a biomimetic formulation with targeted delivery agents for lactate metabolism-based synergistic therapy against glioblastoma brain cancer.
Source: Chinese Academy of Sciences
Glioblastoma multiforme (GBM) is an aggressive brain tumor with a poor prognosis and few treatment options. New and effective approaches to GBM treatment are therefore urgently needed.
Based on the observation of elevated lactate in resected GBM, researchers at the Institute of Chemical Engineering (IPE) of the Chinese Academy of Sciences and Shenzhen Second People’s Hospital have developed a biomimetic formulation containing drugs for targeted delivery for lactate metabolism-based synergistic therapy against GBM used.
The study was published in nature communication on July 21st.
Targeting lactate metabolism is an attractive tumor therapy strategy. However, there are no reports using lactate metabolism directly for GBM treatments.
One limitation is the existence of the blood-brain barrier, which prevents most drug molecules (including those that disrupt lactate metabolism) from reaching the brain.
Furthermore, given the complexity and infiltrating properties of GBM, it is highly unlikely that metabolic lactate monotherapy would be effective in eliminating GBM cells. Therefore, it is important to develop synergistic strategies to improve the therapeutic efficiency of lactate metabolism therapy.
In this study, researchers collected glioma samples from a large patient cohort and quantified the lactate metabolism indicators LDHA and MCT4 and a representative proliferation marker Ki67.
“We observed a positive correlation between lactate metabolism indicators and the extent of glioma proliferation,” said Prof. LI Weiping of Shenzhen Second People’s Hospital. Therefore, an efficient metabolic-based synergistic therapy was proposed that would directly utilize the increased lactate in GBM.
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 then encapsulated these self-assembled NPs with membrane materials made from U251 glioma cells to generate the biomimetic [email protected] System. This design concept could achieve targeted delivery for combination therapy.
“After intravenous injection, the [email protected] could pass the blood-brain barrier via transcytosis derived from integrin and vascular cell adhesion protein-mediated recognition, and then accumulated in GBM through homotypic recognition based on cell recognition function-associated proteins,” said Prof. WEI Wei of IPE.
In tumors, LOX converted lactate to pyruvic acid and hydrogen peroxide in the NPs (H2O2). Pyruvic acid inhibited cancer cell growth by blocking histone expression and inducing cell cycle arrest. In parallel, the H2O2 acted as a local fuel to react with the delivered CPPO and release energy that could then be used by the co-delivered photosensitizer Ce6 for the generation of cytotoxic singlet oxygen to kill glioma cells.
Strong therapeutic efficacy has been confirmed in both cell line-derived xenografts and patient-derived xenografts (PDX) tumor models.
“Considering the safety of the formulation and the strong therapeutic effect against the adapted PDX model, our personalized biomimetic formulation has the potential to be transferred to clinical application,” said Prof. MA Guanghui from the IPE.
an appraiser nature communication said: “The idea of this work is interesting.” Another reviewer emphasized that “a multi-targeted, personalized, smart nanoplatform to target glioblastoma multiforme is presented. The rationale is well explained, I indeed appreciate the multi-strategy approach and the biomolecular characterization.”
About this brain cancer research news
Author: LI Xiangyu
Source: Chinese Academy of Sciences
Contact: LI Xiangyu – Chinese Academy of Sciences
Picture: The picture is credited to LU Guihong
Original research: Open access.
“Genetically engineered biomimetic nanoparticles achieve targeted delivery and efficient metabolic-based synergistic therapy against glioblastoma“ by LU Guihong et al. nature communication
Genetically engineered biomimetic nanoparticles achieve targeted delivery and efficient metabolic-based synergistic therapy against glioblastoma
Glioblastoma multiforme (GBM) is an aggressive brain tumor with a poor prognosis and few treatment options.
Here, based on the observation of increased lactate (LA) in resected GBM, we develop biomimetic therapeutic nanoparticles (NPs) that deliver drugs for synergistic therapy on LA metabolism.
Because our self-assembling NPs are encapsulated in membranes derived from glioma cells, they easily cross the blood-brain barrier and target GBM through homotypic recognition.
After reaching the tumors, lactate oxidase in the NPs converts LA into pyruvic acid (PA) and hydrogen peroxide (H2O2). The PA inhibits cancer cell growth by blocking histone expression and inducing cell cycle arrest.
In parallel, the H2O2 responds with the delivered to[2,4,5-trichloro-6-(pentyloxycarbonyl)phenyl] Oxalate to release energy used by the included photosensitizer, chlorin E6, to generate cytotoxic singlet oxygen to kill glioma cells.
Such synergism ensures potent therapeutic effects against both glioma cell line-derived and patient-derived xenograft models.