A novel therapeutic strategy of multimodal nanoconjugates for state-of-the-art brain tumor phototherapy

Abstract

Background The outcome of phototherapy, including photothermal therapy (PTT) and photodynamic therapy (PDT) for glioblastoma multiforme (GBM), is disappointing due to insufficient photoconversion efficiency and low targeting rate. The development of phototherapeutic agents that target GBM and generate high heat and potent ROS is important to overcome the weak anti-tumor effect. Results In this study, nanoconjugates composed of gold nanoparticles (AuNPs) and photosensitizers (PSs) were prepared by disulfide conjugation between Chlorin e6 (Ce6) and glutathione coated-AuNP. The maximum heat dissipation of the nanoconjugate was 64.5 ± 4.5 °C. Moreover, the proximate conjugation of Ce6 on the AuNP surface resulted in plasmonic crossover between Ce6 and AuNP. This improves the intrinsic ROS generating capability of Ce6 by 1.6-fold compared to that of unmodified-Ce6. This process is called generation of metal-enhanced reactive oxygen species (MERos). PEGylated-lactoferrin (Lf-PEG) was incorporated onto the AuNP surface for both oral absorption and GBM targeting of the nanoconjugate (denoted as Ce6-AuNP-Lf). In this study, we explored the mechanism by which Ce6-AuNP-Lf interacts with LfR at the intestinal and blood brain barrier (BBB) and penetrates these barriers with high efficiency. In the orthotopic GBM mice model, the oral bioavailability and GBM targeting amount of Ce6-AuNP-Lf significantly improved to 7.3 ± 1.2% and 11.8 ± 2.1 μg/kg, respectively. The order of laser irradiation, such as applying PDT first and then PTT, was significant for the treatment outcome due to the plasmonic advantages provided by AuNPs to enhance ROS generation capability. As a result, GBM-phototherapy after oral administration of Ce6-AuNP-Lf exhibited an outstanding anti-tumor effect due to GBM targeting and enhanced photoconversion efficiency. Conclusions The designed nanoconjugates greatly improved ROS generation by plasmonic crossover between AuNPs and Ce6, enabling sufficient PDT for GBM as well as PTT. In addition, efficient GBM targeting through oral administration was possible by conjugating Lf to the nanoconjugate. These results suggest that Ce6-AuNP-Lf is a potent GBM phototherapeutic nanoconjugate that can be orally administered. Graphical Abstract

Engineered Aurotherapy for the Multimodal Treatment of Glioblastoma

“…In terms of PTT, the collective oscillation of electrons on the AuNP surface causes surface plasmon resonance (SPR) in light of specific wavelength to generate a strong extinction coefficient, thereby dissipate sufficient heat [ 33 ]. In our study, the proximate conjugation of PS on AuNPs accelerated its PDT outcome [ 34 ]. The phenomenon that enhances the ability of PS to generate ROS was denoted as metal-enhanced ROS generation (MERos) and it is mediated by intersystem crossover between PS and AuNP.…”

Multifunctional nanoparticle for cancer therapy

“…Similarly, Kim et al. 177 described a nanoconjugate composed of Au nanosphere (Au nanoparticles) modified by photosensitizers by Au─S bonds for the treatment of glioblastoma multiforme with PTT and PDT. Zhang et al.…”

“…prepared a multifunctional nanoplatform (Ce6–AuNP–Lf) based on lactoferrin‐coated Au nanoparticles to deliver Chlorin e6 (Ce6) for the treatment of glioblastoma multiforme with phototherapy. 177 The PDT photosensitizer Ce6 was proximately conjugated on the surface of the PTT agent AuNP, leading to plasma crossover between Ce6 and AuNP that greatly improved the ROS production capacity of Ce6. Their results illustrated that Ce6–AuNP–Lf could effectively intervene in the progression of glioma and suppress the growth of tumors in a subcutaneous GBM mouse model by first applying PDT (671 nm), followed by PTT (532 nm).…”

“…Au nanoparticles could combine with thiol groups to form the stability Au─S bond, which provide the great potential to prepare multifunctional Au nanoparticles. Similarly, Kim et al 177 . described a nanoconjugate composed of Au nanosphere (Au nanoparticles) modified by photosensitizers by Au─S bonds for the treatment of glioblastoma multiforme with PTT and PDT.…”

Inhibition of DAMP Actions in the Tumoral Microenvironment Using Lactoferrin-Glycyrrhizin Nanoconjugate for Glioblastoma Therapy

“…Our previous studies demonstrated that the modi cation of drugs via lactoferrin (Lf) can target GBM by penetrating the blood-brain barrier (BBB) and increasing their stability and half-life of blood circulation [16,17] This was also possible because the lactoferrin receptor (LfR) is highly expressed in the blood-brain barrier (BBB) and GBM cells and on brain endothelial cells [18][19][20][21]. Moreover, Lf, a product of exocrine glands that found in many parts of the human body, prevents the partial rst-pass effects of hepatic metabolism and allow it to persist longer [22].…”