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

Journal of Nanobiotechnology

Hyung Shik Kim¹  Dong Yun Lee²  Tae-Eun Park³  Minwook Seo³ 

[1] Department of Bioengineering, College of Engineering, and BK FOUR Biopharmaceutical Innovation Leader for Education and Research Group, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, 04763, Seoul, Republic of Korea;Department of Bioengineering, College of Engineering, and BK FOUR Biopharmaceutical Innovation Leader for Education and Research Group, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, 04763, Seoul, Republic of Korea;Institute of Nano Science and Technology (INST), Hanyang University, 04763, Seoul, Republic of Korea;Elixir Pharmatech Inc., 07463, Seoul, Republic of Korea;Department of Biomedical Engineering, College of Information-Bio Convergence Engineering, Ulsan National Institute of Science and Technology (UNIST), 44919, Ulsan, Republic of Korea;

关键词: Generation of metal-enhanced reactive oxygen species (MERos);    Photodynamic photothermal combination therapy (PDT + PTT);    Glioblastoma multiforme (GBM);    Gold nanoparticles (AuNPs);    Oral absorbable GBM targeting;   

DOI  :  10.1186/s12951-021-01220-9

来源: Springer

【 摘 要 】

BackgroundThe 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.ResultsIn 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.ConclusionsThe 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

【 授权许可】

CC BY