Use of Pep-1-guided PDA-loaded temozolomide nanoparticles a dual combination therapy against glioblastoma
Authors: Wu Hao , Liu Qi , Wei Min , Li Yuping , Ma Qiang , Wang Lianhui , Zhu Yufu , Zhang Hengzhu , Zhang Tianyi 
Published: October 2022

Abstract
Purpose:Nanoparticles of the basal polydopamine-loaded temozolomide guided by Pep-1 as a navigator were constructed for the chemotherapy and photothermal of glioblastoma.
methods:The active groups such as catechenol aminocarboxyl group and super adhesive of polydopamine were used to perform Schiff base reaction with temozolomide with amino group and Pep-1 with thiol group after functionalization to obtain Pep-1@PDA-TMZA NPs. The size and morphology were characterized by dynamic light scattering and transmission electron microscopy. The loading and assembly of the drug were analyzed by Fourier transform infrared spectroscopy and ultraviolet spectroscopy The biocompatibility of the nanoparticle carrier Pep-1@PDA was verified in U87 cells in vitro, and the cellular uptake and toxicity of Pep-1@PDA-TMZA NPs were investigated.In vivo antitumor activity study investigated the tumor inhibition of Pep-1@PDA-TMZA NPs by temozolomide chemotherapy combined with the photothermal effect of 808nm laser irradiation in tumor environment.
Results:DLS characterization revealed that the particle size was approximately 140 nm. The prepared nanoparticles had excellent dispersion stability and good biocompatibility in water and biological buffers. Pep-1@PDA-TMZA NPs had a narrow particle size distribution, homogeneous size, spherical,and smooth surface, which can be easily penetrated and can accumulate at the tumor site via the EPR effect.The Schiff base bond in the nanoparticles was a type of reversible dynamic covalent bond with extreme sensitivity to pH value. That is, its stability was positively correlated with pH value. Hence, lower pH values indicated worse stability. Therefore, under the acidic environment of the tumor, the dynamic covalent Schiff base bond of Pep-1@PDA-TMZA NPs can be broken reversibly, and TMZA is released, thereby exerting a chemotherapeutic effect in antitumor therapy.Under 808-nm laser irradiation,Pep-1@PDA-TMZA NPs can convert light energy into thermal energy after absorbing NIR to achieve the antitumor photothermal effect.Moreover, as the concentration of TMZA increased, the cytotoxicity produced by the tumor cells was significantly enhanced, showing a significant concentration dependence. When the Pep-1@PDA-TMZA NPs concentration was increased to 250 μ g / ml combined with photothermal treatment, the U87 cells and C6 cells were inhibited by 90.81% and 82.29%, respectively.In vivo studies have shown that, compared with other treatment groups, Pep-1@PDA-TMZA NPs + (Laser) had about 77.13% (P <0.05) after conventional blood tests and H & E staining analysis of major organs such as heart, liver, spleen, lung and kidney, indicating that Pep-1@PDA-TMZA NPs does not cause damage to major organs while anti-tumor
Conclusion:Pep-1- @PDA-TMZA NPs, modified with polydopamine-loaded by Pep-1, not only has considerable load rate, strong penetration, biocompatibility and targeting, but also has accurate navigation function, most importantly, Pep-1@PDA-TMZA NPs can have the dual therapeutic effects of chemotherapy and photothermal therapy and can target receptor-mediated IL-13Rα2 to promote antitumor effects. Therefore, it can be used as a potential targeted nano-delivery particle in glioblastoma treatment.