ACS Nano: Development of nanoprobes for imaging and treatment of gliomas

As a highly invasive and highly metastatic tumor, glioma is considered to be one of
the most aggressive malignant brain tumors due to its challenges such as poor prognosis, high mortality and high recurrence rate.
Although surgical resection, radiotherapy, chemotherapy and other methods have been used clinically to treat glioma, its prognosis is still poor, and the median overall survival is only 14-17 months
.
Due to the limitation of the blood-brain barrier (BBB), most of the currently developed anti-tumor drugs are difficult to cross the BBB to reach the tumor site, and the treatment effect on glioma is not good; In addition, because these drugs lack tumor specificity, they are prone to serious toxic side effects and drug resistance
.
Improving the delivery and efficacy of antitumor drugs in gliomas and achieving on-demand and efficient treatment of gliomas in situ remains challenging
.
Recently, Liu Hong, a researcher at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, and Deju Ye, a professor at Nanjing University, have made progress
in the research of near-infrared fluorescence-magnetic resonance dual-modal imaging and chemotherapy-photodynamic combination therapy for brain glioma targeted activated organically assembled nanodiagnostic and therapeutic probes for in situ glioma 。 The results were recently published in ACS Nano
under the title Controlling Disassembly of Paramagnetic Prodrug and Photosensitizer Nanoassemblies for On-Demand Orthotopic Glioma Theranostics 。 Based on the molecular co-assembly and controlled deassembly strategies, the research team synthesized αvβ3 integrin-targeted and glutathione-responsive paramagnetic near-infrared photosensitive probes (PPa-RGD) and camptothecin prodrugs (CPT-RGD), respectively.
By optimizing the co-assembly ratio of these two molecules, a co-assembled nanodiagnostic and therapeutic probe (Co-NP-RGD) with both physiological stability and synergistic therapy was prepared (Figure 1).

。 After intravenous administration, Co-NP-RGD can effectively prolong blood circulation time compared with small molecule drugs, and with the help of a large number of cRGD targeting groups on the surface, cross the BBB, and target delivery to in situ glioma cells (U87MG and U251), on the one hand, an enhanced MRI contrast signal is generated for locating glioma in situ in the brain; On the other hand, under the action of high concentrations of glutathione in glioma cells, rapid deassembly occurs, and camptothecin original drug (CPT) and near-infrared photosensitizer (PPa) are released at the same time, thereby restoring photodynamic therapeutic function and generating an enhanced near-infrared fluorescence signal for monitoring drug release and accumulation
。 In addition, the released small molecule porphyrin photosensitizer further binds to albumin in tumor cells, which can prolong the accumulation of photosensitizer molecules in tumor cells, while the release of camptothecin can inhibit the hypoxia-inducible factor HIF-1α, thereby improving the hypoxic environment in glioma tissues and enhancing the photodynamic therapeutic effect
of deep in situ glioma 。 Under the guidance of dual-modal imaging signals, the in-situ glioma of mice was irradiated with a low-dose 690 nm laser (0.
2 W/cm2) to produce chemotherapy-photodynamic therapy synergistic therapy, which could effectively delay the growth of glioma in situ, prolong the survival of mice, and achieve efficient synergistic treatment of glioma in situ (Figure 2).

The molecular co-assembly and controlled deassembly strategies designed in this study can be further applied to the construction of other tumor-targeted and activated nanodrugs to generate the combined therapeutic effect of cancer and promote the diagnosis and treatment
of cancer.
Fig.
1 Structure and mechanism of co-assembled nanodiagnostic and therapeutic probes