Hailiang Zhu / Zhongchang Wang AS, Nanjing University: Application of protein nanomaterials in the treatment of brain glioma

Innovation: Hailiang Zhu, Zhongchang Wang and their collaborators of Nanjing University constructed an endogenous stimulus-responsive multifunctional nanodrug-loading platform for transferrin-mediated in situ glioma, which solved the problems of drug crossing the blood-brain barrier, targeted sustained and controlled-release drugs, image tracing and tumor hypoxia, and realized the synergistic enhancement of the effect of photodynamic therapy combined with chemotherapy
.

Keywords: tumor hypoxia microenvironment, blood-brain barrier, transferrin, photodynamic therapy, pharmacokinetics
.

Figure 1.
Schematic diagram of 3D in vitro construction of ODP-TH multifunctional drug nanodelivery platform (A) and in vivo modular mechanism of action (B).

The tumor microenvironment (TME) has physicochemical characteristics that differ from normal physiological conditions, such as hypoxia, low pH, high GSH, and high vascular permeability
.
Among them, hypoxic environment is closely
related to tumor growth, metastasis and prognosis.
The uncontrolled proliferation and abnormal development of blood vessels inside the tumor determine the characteristics of high metabolism of
the tumor.
The high metabolic characteristics of tumor cells cause hypoxia microenvironment inside tumor cells, and the hypoxic microenvironment has a screening effect on tumor cells, further improving the malignancy of tumors, resulting in tumor cells being insensitive
to chemotherapy drugs or radiation therapy 。 Professor Hailiang Zhu's team from the School of Life Sciences of Nanjing University built on the development of nanodrug carrier platforms that previously focused on solving the problem of TME hypoxia (ACS Appl.
Mater.
Interfaces 2020, 12, 22, 24662–24674) Based on the homologous recognition ability of transferrin and its receptors, the first to construct an in situ glioma-targeted transferrin-mediated endogenous stimulus-responsive multifunctional nanodrug platform (Figure 1).

。 The platform solves the problems of drug crossing the blood-brain barrier, targeted sustained and controlled release drugs, image tracing and tumor hypoxia, significantly inhibits the growth of a variety of malignant tumors including central nervous system (CNS) tumors, alleviates the problem of refractory hypoxia in the microenvironment of solid tumors, and enhances the synergy of the effect of photodynamic therapy combined with chemotherapy, providing a new strategy
for the treatment of malignant tumors.

Transferrin and hemoglobin were encapsulated with chemotherapy drug Dox and photosensitizer PpIX by disulfide bond reconstitution in self-assembly, and oxygen was integrated in vitro to construct a hybrid protein nano-drug carrier platform ODP-TH
with both oxygen-carrying capacity and precise targeting function of glioma in situ 。 On the one hand, the transferrin drug carrier can specifically recognize and bind to the transferrin receptor overexpressed on the surface of tumor and brain endothelial cells, and selectively enrich it to central nervous system tumor cells through transferrin receptor-mediated crossing-brain barrier, and rapidly and continuously release
the encapsulated drug and the oxygen carried in the tumor microenvironment with low oxygen and high GSH concentration 。 On the other hand, the study of oxygen-supplied transferrin-mediated multifunctional nano-drug delivery systems for understanding the disease mechanism caused by hypoxia in the tumor microenvironment, establishing a systematic oxygen-fed drug nano-delivery platform method with good biological safety, strong targeting, rapid response and synergistic anti-tumor to solve a variety of oxygen-related gene expression disorders (MDR1, HIF-1α and P-gp) caused by hypoxia, reduce the efflux of chemotherapy drugs, and alleviate the common adverse phenomena of drug resistance in chemotherapy
。

The small particle size of the nanomaterials (30.
2±1.
2 nm) maximizes the oxygen carrying on the surface of ODP-TH, enabling the free conversion
of oxygenation conformation to deoxygenation conformation within 30 minutes in a low pO2 environment.
Strong disulfide rivets maintain morphological and functional stability
of ODP-TH in non-TME.
Once in reduced GSH-enriched TME, its excellent GSH response mechanism can ensure rapid disintegration of nanomaterials, ensuring that the synergistic therapeutic function of the entire platform can quickly function in specific cancer lesions (Figure 2).

Figure 2.
Physicochemical properties
of ODP-TH drug nanodelivery platforms.
(A) Particle size distribution of ODP-TH and transmission electron microscopy photograph.

(B) Exclusion chromatography (SEC) plot
of TH nanocoat.
(C) Ultraviolet absorption spectra (UV–vis)
of Hb, TRF, Dox, PpIX and DP-TH.
(D) Comparative statistical chart
of free sulfhydryl concentrations between different groups.
(E) Statistical chart
of oxygen release curves between different groups.
(F) Drug release curves
of ODP-TH at different times under the action of GSH (5 mm).
(G) Dependence of Dox release and GSH concentration
.
(H) The effect
of changes in pH on drug release.
(I)TH, D-TH, P-TH and ODP-TH Hydrated particle size and time-dependent diagrams
.

The team also constructed an in situ glioma animal model, and evaluated the function and pharmacological properties
of the nanoplatform across the blood-brain barrier targeting glioma by liquid chroma, tumor immunity, protein purification, cell migration detection, and multimodal imaging.
The platform enhances the synergy of the effect of multi-dimensional photodynamic therapy combined with chemotherapy based on oxygen targeted transport (Figure 3), which not only provides a new method for the complete cure of glioma in the future, but also provides new ideas
for the cross-integration and development of life science, medicine, chemistry and materials science.

Figure 3.
Efficacy
of glioma in situ.
(A) Schematic diagram
of the treatment process of glioma in situ.
(B) Real-time monitoring
of glioma development during treatment.
(C) HE staining images
of mouse brain slices in different treatment groups after the endpoint.
(D, E) Immunohistochemistry and immunofluorescence pictures
of mouse brain slices in different treatment groups.

WILEY

Paper Information:

Multifunctional Protein Hybrid Nanoplatform for Synergetic Photodynamic Chemotherapy of Malignant Carcinoma by Homologous Targeting Combined with Oxygen Transport

Song-Yu Wu, Ya-Xi Ye, Qing Zhang, Qian-Jin Kang, Zhu-Min Xu, Shen-Zhen Ren, Fan Lin, Yong-Tao Duan, Hao-Jun Xu, Zi-Yi Hu, Sui-Sui Yang, Hai-Liang Zhu, Mei-Juan Zou, Zhong-Chang Wang

Advanced Science

DOI: 10.
1002/advs.
202203742

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