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Organic Nanoparticles Based on D-A-D Small Molecule: Self-Assembly, Photophysical Properties, and Synergistic Photodynamic/Photothermal Effects.

ABSTRACT: Cancer is one of the major diseases threatening human health. Traditional cancer treatments have notable side-effects as they can damage the immune system. Recently, phototherapy, as a potential strategy for clinical cancer therapy, has received wide attention due to its minimal invasiveness and high efficiency. Herein, a small organic molecule (PTA) with a D-A-D structure was prepared via a Sonogashira coupling reaction between the electron-withdrawing dibromo-perylenediimide and electron-donating 4-ethynyl-N,N-diphenylaniline. The amphiphilic organic molecule was then transformed into nanoparticles (PTA-NPs) through the self-assembling method. Upon laser irradiation at 635 nm, PTA-NPs displayed a high photothermal conversion efficiency (PCE = 43%) together with efficient reactive oxygen species (ROS) generation. The fluorescence images also indicated the production of ROS in cancer cells with PTA-NPs. In addition, the biocompatibility and photocytotoxicity of PTA-NPs were evaluated by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and live/dead cell co-staining test. Therefore, the as-prepared organic nanomaterials were demonstrated as promising nanomaterials for cancer phototherapy in the clinic.

SUBMITTER: Yue L

PROVIDER: S-EPMC8781609 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background and Purpose:The development of multiple drug resistance (MDR) to chemotherapy and single modal therapy remains unsatisfied for the eradication of tumor, which are major obstacles in cancer therapy. This novel system with excellent characteristics for inhibition of P-glycoprotein (P-gp), and for near-infrared fluorescence (NIRF) imaging-guided chemo-photothermal therapy (PTT), has been identified as a promising way to MDR and achieve synergistic cancer therapy. Methods:In this study, we successfully synthesized a multifunctional theranostic system, which was developed through FDA-approved self-assembling drugs, which contain anticancer drug doxorubicin (Dox), imaging and high photothermal conversion drug indocyanine green (ICG) and P-gp regulator TPGS (the system named T/Dox-ICG). We studied the characterization of T/Dox-ICG NPs, including the TEM, SEM, DLS, UV-vis-NIR, zeta potential, CLSM, in vitro FL imaging, in vitro photothermal effect, in vitro Dox and ICG release. We used CLSM to verify the location of intracellular distribution of Dox in SCG 7901/VCR cells, Western blot was performed to demonstrate the TPGS-mediated inhibition of P-gp. And, the cytotoxicity of materials against SCG 7901/VCR cells was studied by the MTT assay. Results:The TEM showed the T/Dox-ICG NPs had good monodispersity with diameters of 19.03 nm, Dox and ICG could be released constantly from T/Dox-ICG NPs in vitro. In vitro cell experiments demonstrated higher Dox accumulation and retention in the nucleus. Western blot showed TPGS could obviously inhibit the expression of P-gp. In vitro cytotoxicity assay showed more significant cytotoxicity on MDR cells (SCG 7901/VCR) with only 8.75% of cells surviving. Conclusion:MDR cancer therapy indicates that it may be important to develop a safer system that can simultaneously inhibit the drug transporters and monitor the delivery of chemotherapeutic agents, and combination therapy have raised widespread concern on tumor treatment.

Project description:The limited clinical efficacy of monotherapies in the clinic has urged the development of novel combination platforms. Taking advantage of light-triggered photodynamic treatment combined together with the controlled release of nanomedicine, it has been possible to treat cancer without eliciting any adverse effects. However, the challenges imposed by limited drug loading capacity and complex synthesis process of organic nanoparticles (NPs) have seriously impeded advances in chemo-photodynamic combination therapy. In this experiment, we utilize our previously synthesized porphyrin-grafted lipid (PGL) NPs to load highly effective chemotherapeutic drug, doxorubicin (DOX) for synergistic chemo-photodynamic therapy. Methods: A relatively simple and inexpensive rapid injection method was used to prepare porphyrin-grafted lipid (PGL) NPs. The self-assembled PGL NPs were used further to encapsulate DOX via a pH-gradient loading protocol. The self-assembled liposome-like PGL NPs having a hydrophilic core were optimized to load DOX at an encapsulation efficiency (EE) of ~99%. The resultant PGL-DOX NPs were intact, highly stable and importantly these NPs successfully escaped from the endo-lysosomal compartment after laser irradiation to release DOX in the cytosol. The therapeutic efficacy of the aforementioned formulation was validated both in vitro and in vivo. Results: PGL-DOX NPs demonstrated excellent cellular uptake, chemo-photodynamic response, and fluorescence imaging ability in different cell lines. Under laser irradiation, cells treated with a low molar concentration of PGL-DOX NPs reduced cell viability significantly. Moreover, in vivo experiments conducted in a xenograft mouse model further demonstrated the excellent tumor accumulation capability of PGL-DOX NPs driven by the enhanced permeability and retention (EPR) effect. Through fluorescence imaging, the biodistribution of PGL-DOX NPs in tumor and major organs was also easily monitored in real time in vivo. The inherent ability of porphyrin to generate ROS under laser irradiation combined with the cytotoxic effect of the anticancer drug DOX significantly suppressed tumor growth in vivo. Conclusion: In summary, the PGL-DOX NPs combined chemo-photodynamic nanoplatform may serve as a potential candidate for cancer theranostics.

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Organic Nanoparticles Based on D-A-D Small Molecule: Self-Assembly, Photophysical Properties, and Synergistic Photodynamic/Photothermal Effects.

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