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Professor Li Weiping of the Department of Neurosurgery of the First Affiliated Hospital of Shenzhen University and others developed biomimetic nanomaterials
based on the changes in lactate metabolism levels in surgically resected GBM tissue samples.
The nanomaterial is derived from the human glioma U251 cell line by co-extrusion of porous membranes to produce M-coated HLPCs
.
Membrane-encapsulated glioma cells easily cross the blood-brain barrier and are easily identified
.
M@HLPC in tumors, the loaded lactate oxidase converts lactic acid to pyruvate and hydrogen
peroxide.
PA blocks histone expression and induces cell cycle arrest to inhibit cancer cell growth; H2O2 reacts with bisoxalate to release energy, and the co-delivered photosensitizer chlorophyll E6 is used to produce cytotoxic singlet oxygen that kills glioma cells
.
The researchers used transmission electron microscopy, fluorescence analysis and other methods to carry out in vitro penetration experiments, in situ GBM model tests and CDX model tests in mice, which confirmed the good stability of M@HLPC, efficient permeability to BBB and effect on GBM-targeted therapy, and no obvious biological toxicity.
It provides new directions and possibilities
for improving the treatment effect of brain tumors.
The results were published online in Nature Communications in July 2022
.
- Excerpted from the article chapter
【Ref: Lu G, et al.
Nat Commun.
2022 Jul 21; 13(1):4214.
doi: 10.
103 8/s41467 -022-31799-y.
】
Research background
Glioblastoma (GBM) is highly aggressive, has a poor prognosis, and has limited
treatment.
Professor Li Weiping of the Department of Neurosurgery of the First Affiliated Hospital of Shenzhen University and others developed biomimetic nanomaterials
based on the changes in lactate (LA) metabolism levels in surgically resected GBM tissue samples.
This nanomaterial is derived from the human glioma U251 cell line by co-extrusion of porous membranes to produce M-coated HLPC (labeled M@HLPC).
Membrane-encapsulated glioma cells easily cross the blood-brain barrier (BBB) and are easily identified
.
M@HLPC in tumors, the loaded lactate oxidase (LOX) converts lactic acid to pyruvate (PA) and hydrogen peroxide (H2O2).
PA blocks histone expression and induces cell cycle arrest to inhibit cancer cell growth; H2O2 reacts with bis[2,4,5-trichloro-6-(pentyloxycarbonyl)phenyl] oxalate (CPPO) to release energy, and the co-delivered photosensitizer chlorophyll e6 (Ce6) is used to produce cytotoxic singlet oxygen to kill glioma
。
The researchers used transmission electron microscopy, fluorescence analysis and other methods to carry out in vitro penetration experiments, mouse in situ GBM model tests and CDX model tests, which confirmed the good stability of the M@HLPC, the efficient permeability of BBB and the effect on GBM-targeted therapy, and there was no obvious biological toxicity.
It provides new directions and possibilities
for improving the treatment effect of brain tumors.
The results were published online in Nature Communications in July 2022
.
Study results
The results of the study are as follows:1.
M@HLPC constructed clinical and animal model studies found a positive correlation between the level of LA metabolic markers and the degree of glioma proliferation, so the authors used elevated LA in GBM to develop "LA metabolic therapy" for GBM; At the same time, the LA metabolite H2O2 is used as a substance for chemical reaction with CPPO to produceO2-induced apoptosis.
Realization of so-called chemically excited photodynamic therapy (PDT).
The authors constructed a biomimetic nanomaterial M@HLPC with a collaborative therapeutic system, coated with U251 cell membrane (M), and self-assembled nanomaterials
composed of Hb, LOX, CPPO and Ce6.
Each component that makes up a M@HLPC is evaluated experimentally to retain all its functions
.
2.
The penetration of BBB from M@HLPC nanomaterials and the ability to target gliomas The authors confirmed through in vitro penetration tests that M@HLPC can cross the BBB and target glioma cells, and further confirmed by glioma mouse models that HLPCs wrapped with membrane material from glioma cells can M@HLPC improve the ability to penetrate BBBs and target gliomas
。
3.
M@HLPC synergistic anti-tumor in vitro cell experiments showed that there were two approaches of anti-tumor activity: (1) exogenous PA can terminate tumor cell proliferation through the "NAMPT-NAD+-histone" axis; (2) M@HLPC chemically stimulates PDT to produce cytotoxic O2, inducing apoptosis
of tumor cells.
The synergistic effect of metabolic therapy and chemostimulated PDT together leads to a decrease
in tumor cell viability.
4.
Therapeutic effect of M@HLPC on CDX model By constructing a U251-luc xenograft mouse model, a powerful anti-tumor effect can be observed after M@HLPCM treatment, and the median survival of mice can be significantly prolonged
.
Blood and organ sections of mice M@HLPC detected no lesions or other abnormalities, indicating the safety of
M@HLPC.
5.
The construction of hM@HLPC and the efficacy verification of the PDX model are used to further study the clinical applicability of biomimetic nanomedicines, and to construct a human glioma cell membrane-encapsulated nanomedicine system (hM@HLPC).
After successful construction, it was injected into the GBM PDX mouse model, and the fluorescence method showed that the hM@HLPC had a high intensity effect, and the MRI showed that the tumor of the mouse model hM@HLPC significantly shrunk and the median survival time was significantly prolonged
.
Conclusion of the study
In summary, the research team developed a biomimetic targeted drug delivery and synergistic therapy system M@HLPC; M@HLPC has good stability, efficient BBB permeability and tumor targeting, and demonstrates strong tumor suppression in mouse xenograft tumor models by the combined effect of metabolic therapy and chemically excited PDT agents; Further use of hM@HLPC has achieved significant efficacy in personalized treatment of patient-derived tumor models, indicating that the hM@HLPC system has great translational potential
in the development of clinically relevant GBM therapies.
