Jiawen Chen

A Self-Assembled Albumin-Based Nanoprobe for In Vivo Ratiometric Photoacoustic pH Imaging

A photoacoustic nanoprobe is self-assembled from human serum albumin and two types of dye molecules, one is inert to pH and the other is pH sensitive. This probe and the quantitative ratiometric photoacoustic pH imaging method are shown to have high safety, be easy-to-operate, and have depth-independent accuracy for real-time in vivo pH imaging of entire tumors. These features make them promising for future cancer prognosis and therapeutic planning.

H2O2-responsive liposomal nanoprobe for photoacoustic inflammation imaging and tumor theranostics via in vivo chromogenic assay

Significance Hydrogen peroxide is closely associated with many important physiological and pathological events. Herein, we develop a liposomal nanoprobe for in vivo H2O2-responsive chromogenic assay, which is highly specific and sensitive to H2O2. Using such a nanoprobe, photoacoustic imaging of H2O2-related inflammation processes in mice induced by either LPS or bacteria is realized. Meanwhile, such a nanoprobe, by reacting with endogenous H2O2 produced by tumor cells, allows sensitive photoacoustic imaging of early-stage small tumors and orthotopic brain glioma and even enables accurate differentiation of metastatic sentinel lymph nodes from nonmetastatic ones. Furthermore, owing to its H2O2-responsive near-infrared absorbance, selective photothermal ablation of tumors is also achieved, illustrating the promise of using this nanoproble for tumor theranostics with great specificity. Abnormal H2O2 levels are closely related to many diseases, including inflammation and cancers. Herein, we simultaneously load HRP and its substrate, 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), into liposomal nanoparticles, obtaining a Lipo@HRP&ABTS optical nanoprobe for in vivo H2O2-responsive chromogenic assay with great specificity and sensitivity. In the presence of H2O2, colorless ABTS would be converted by HRP into the oxidized form with strong near-infrared (NIR) absorbance, enabling photoacoustic detection of H2O2 down to submicromolar concentrations. Using Lipo@HRP&ABTS as an H2O2-responsive nanoprobe, we could accurately detect the inflammation processes induced by LPS or bacterial infection in which H2O2 is generated. Meanwhile, upon systemic administration of this nanoprobe we realize in vivo photoacoustic imaging of small s.c. tumors (∼2 mm in size) as well as orthotopic brain gliomas, by detecting H2O2 produced by tumor cells. Interestingly, local injection of Lipo@HRP&ABTS further enables differentiation of metastatic lymph nodes from those nonmetastatic ones, based on their difference in H2O2 contents. Moreover, using the H2O2-dependent strong NIR absorbance of Lipo@HRP&ABTS, tumor-specific photothermal therapy is also achieved. This work thus develops a sensitive H2O2-responsive optical nanoprobe useful not only for in vivo detection of inflammation but also for tumor-specific theranostic applications.

Drug-induced co-assembly of albumin/catalase as smart nano-theranostics for deep intra-tumoral penetration, hypoxia relieve, and synergistic combination therapy

ABSTRACT The abnormal tumor microenvironment (TME) featured with hypoxia, acidosis, dense extracellular matrix and increased tumor interstitial fluid pressure is closely related with the resistance of tumors to various therapies. Herein, a unique type of biocompatible nanoscale delivery system is fabricated by utilizing a chemotherapeutic drug, paclitaxel (PTX), to induce co‐assembly of catalase and human serum albumin (HSA), the latter of which is pre‐modified with chlorine e6 (Ce6), forming smart multifunctional HSA‐Ce6‐Cat–PTX nanoparticles via a rather simple one‐step method. Upon intravenous injection, HSA‐Ce6‐Cat–PTX nanoparticles show high tumor accumulation and efficient intra‐tumoral diffusion, likely owning to their changeable sizes that can maintain large initial sizes (˜ 100 nm) during blood circulation and transform into small protein‐drug complexes (< 20 nm) within the tumor. Meanwhile, catalase within those nanoparticles could trigger decomposition of endogenic TME H2O2 to generate oxygen in‐situ so as to relieve tumor hypoxia. This effect together with PTX‐induced intra‐tumoral perfusion enhancement is able to dramatically modulate TME to favor the anti‐tumor effect in the combined photodynamic/chemotherapy with HSA‐Ce6‐Cat–PTX. Thus, our work presents a simple drug‐induced self‐assembly strategy to fabricate enzyme‐loaded therapeutic albumin nanoparticles for synergistic cancer combination therapy. Graphical abstract Figure. No Caption available.

Albumin-Templated Manganese Dioxide Nanoparticles for Enhanced Radioisotope Therapy

Although nanoparticle-based drug delivery systems have been widely explored for tumor-targeted delivery of radioisotope therapy (RIT), the hypoxia zones of tumors on one hand can hardly be reached by nanoparticles with relatively large sizes due to their limited intratumoral diffusion ability, on the other hand often exhibit hypoxia-associated resistance to radiation-induced cell damage. To improve RIT treatment of solid tumors, herein, radionuclide 131 I labeled human serum albumin (HSA)-bound manganese dioxide nanoparticles (131 I-HSA-MnO2 ) are developed as a novel RIT nanomedicine platform that is responsive to the tumor microenvironment (TME). Such 131 I-HSA-MnO2 nanoparticles with suitable sizes during blood circulation show rather efficient tumor passive uptake owing to the enhanced permeability and retention effect, as well as little retention in other normal organs to minimize radiotoxicity. The acidic TME can trigger gradual degradation of MnO2 and thus decomposition of 131 I-HSA-MnO2 nanoparticles into individual 131 I-HSA with sub-10 nm sizes and greatly improves intratumoral diffusion. Furthermore, oxygen produced by MnO2 -triggered decomposition of tumor endogenous H2 O2 would be helpful to relieve hypoxia-associated RIT resistant for those tumors. As the results, the 131 I-HSA-MnO2 nanoparticles appear to be a highly effective RIT agent showing great efficacy in tumor treatment upon systemic administration.

NIR-II light activated photodynamic therapy with protein-capped gold nanoclusters

The use of near-infrared (NIR) light for photodynamic therapy (PDT) is a promising strategy to circumvent the limitations of current PDT, in which visible light with limited tissue penetration depth is usually used. In the present study, alkyl thiolated gold nanoclusters (AuNCs) were co-modified with human serum albumin (HSA) and catalase (CAT), and then employed as a multifunctional, optical, theranostic nano-agent. In the AuNC@HSA/CAT system, the AuNCs were able to produce singlet oxygen under excitation by a 1,064-nm laser, which locates in the second NIR window (NIR-II), and featured much lower tissue absorption and scattering, enabling NIR-II-triggered PDT. The HSA coating greatly improved the physiological stability of the nanoparticles, which showed efficient tumor retention after intravenous injection, as revealed by detecting the AuNC fluorescence. Moreover, the presence of CAT in the nanoparticles triggered decomposition of tumor endogenous H2O2 to generate oxygen, thereby enhancing the efficacy of PDT by relieving tumor hypoxia. Compared with conventional PDT using visible light, NIR-II-triggered PDT exhibits remarkably increased tissue penetration. Thus, we developed a new type of photosensitizing nano-agent that simultaneously enables in vivo fluorescence imaging, tumor hypoxia relief, and NIR-II light-induced in vivo PDT in the treatment of cancer.

Core–shell TaOx@MnO2 nanoparticles as a nano-radiosensitizer for effective cancer radiotherapy

Improving tumor oxygenation and concentrating X-ray radiation energy inside the tumor have received considerable attention in cancer radiotherapy. Herein, core-shell tantalum oxide@manganese dioxide (TaOx@MnO2) nanostructures are prepared as an efficient radiosensitizer for enhancing radiotherapy (RT). In these nanostructures, the TaOx core serves as a RT sensitizer that efficiently concentrates X-ray radiation energy inside the tumor, while the MnO2 shell may trigger the decomposition of endogenous H2O2 in the tumor microenvironment (TME) to generate oxygen and overcome hypoxia-associated radiation resistance. In vitro and in vivo experiments demonstrated that the synthesized TaOx@MnO2-PEG nanostructures could accomplish an excellent synergistic radiotherapy sensitization effect. Furthermore, TaOx@MnO2-PEG nanoparticles could also serve as promising agents for MR/CT dual-modal imaging. In brief, our study highlights a new type of multifunctional radiosensitizer agent to enhance radiotherapy treatment by means of simultaneously concentrating radiation energy inside tumors and overcoming tumor hypoxia, promising for applications in tumor radiotherapy.

Tumor‐pH‐Responsive Dissociable Albumin–Tamoxifen Nanocomplexes Enabling Efficient Tumor Penetration and Hypoxia Relief for Enhanced Cancer Photodynamic Therapy

Despite the promises of applying nano-photosensitizers (nano-PSs) for photodynamic therapy (PDT) against cancer, severe tumor hypoxia and limited tumor penetration of nano-PSs would lead to nonoptimized therapeutic outcomes of PDT. Therefore, herein a biocompatible nano-PS is prepared by using tamoxifen (TAM), an anti-estrogen compound, to induce self-assembly of chlorin e6 (Ce6) modified human serum albumin (HSA). The formed HSA-Ce6/TAM nanocomplexes, which are stable under neutral pH with a diameter of ≈130 nm, would be dissociated into individual HSA-Ce6 and TAM molecules under the acidic tumor microenvironment, owing to the pH responsive transition of TAM from hydrophobic to hydrophilic. Upon systemic administration, such HSA-Ce6/TAM nanoparticles exhibit prolonged blood circulation and high accumulation in the tumor, where it would undergo rapid pH responsive dissociation to enable obviously enhanced intratumoral penetration of HSA-Ce6. Furthermore, utilizing the ability of TAM in reducing the oxygen consumption of cancer cells, it is found that HSA-Ce6/TAM after systemic administration could efficiently attenuate the tumor hypoxia status. Those effects acting together lead to remarkably enhanced PDT treatment. This work presents a rather simple approach to fabricate smart nano-PSs with multiple functions integrated into a single system via self-assembly of all-biocompatible components, promising for the next generation cancer PDT.

NIR Organic Dyes based on Phenazine-cyanine for Photoacoustic Imaging-guided Photothermal Therapy

As non-invasive diagnosis and therapy methods, photoacoustic (PA) imaging and photothermal therapy (PTT) have attracted extensive attention. Herein, two new acceptor-donor-acceptor near-infrared organic phenazine-cyanine dyes PH-1 and PH-2 were reported for photoacoustic imaging-guided photodynamic therapy. In the strong donor phenazine molecule, the electron-withdrawing indole salt unit was introduced for absorption to the near-infrared region. To improve water solubility, the two organic dyes were assembled with human serum albumin (HSA) to form nanoparticles of appropriate sizes, i.e., PH-1@HSA and PH-2@HSA, which showed excellent stability in both weakly acidic and weakly basic environments. Moreover, the results showed that PH-1@HSA and PH-2@HSA nanoparticles can effectively transform luminous energy to thermal energy in vitro and in vivo, and they can be utilized for PA imaging. Importantly, PH-1@HSA can accumulate in mice subcutaneous tumors by enhanced permeability and retention (EPR) and damage cancer tissues effectively.