Abstract
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
Highlights
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 (See figure on page.) Fig. 1 Synthesis of Chlorin e6 (Ce6)-Gold nanoparticles (AuNP)-Lf capable of strong PDT by metal-enhanced reactive oxygen species (MERos) and the mechanism of Glioblastoma multiforme (GBM) treatment. a Schematic illustration of AuNP localized surface plasmon resonance (LSPR). b Mechanism of metal-enhanced fluorescence (MEF) and metal-enhanced reactive oxygen generation (MERos) by plasmon coupling between AuNP and the conjugated-photosensitizer (PS). c Oral absorption and GBM targeting through lactoferrin receptor (LfR)-mediated pathways of the GI tract, blood brain barrier (BBB) barrier, and GBM cells
Our previous study showed that approximately 19.7 GSH-AuNP were bound to one LfPEG to make Lf with a thiol-functionalized polyethylene glycol (PEG) (Lf-PEG)-AuNP conjugates, which was confirmed by using BCA assay, SDA-PAGE, and UV–Vis spectra [27]
Summary
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 current standard treatment for GBM involves multimodal therapies including surgical resection, chemotherapy, and radiotherapy. The anatomical complexity and size of the tumor influence the extent of resection This is because a balance must be achieved between maximum removal of malignant tissue and minimum surgical risk [3]. GBM is characterized by high heterogeneity between intra-tumor and inter-tumor regions at cellular and histological level This peculiarity of GBM containing tissues induces different responses to therapeutic agents, leading to failure of targeted therapy [5, 6]. The central nervous system (CNS) has a distinct microenvironment that is protected by the blood brain barrier (BBB), restricting systemically delivered drugs from accessing the brain This reduces the treatment options available for GBM. Development of more sophisticated and powerful treatments is one of the most pressing challenges
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