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PEGylated Liposomes Remotely Loaded with the Combination of Doxorubicin, Quinine, and Indocyanine Green Enable Successful Treatment of Multidrug-Resistant Tumors.

ABSTRACT: Multidrug resistance (MDR) of cancer cells remains a major obstacle to favorable outcomes of treatment with many drugs, including doxorubicin. Most of the clinical trials failed to demonstrate the benefit of the drug efflux transporter P-glycoprotein (P-gp) inhibitors to circumvent P-gp-mediated drug resistance in vivo. The present study explored the therapeutic potential of combined treatment with liposomal doxorubicin, P-gp inhibitor quinine, and the photodynamic therapy (PDT) using indocyanine green (ICG) in the adenocarcinoma drug-resistant tumor model. Liposomes were actively co-remotely loaded with doxorubicin and quinine, and ICG was passively adsorbed. The liposomes were characterized by differential scanning calorimetry (DSC) and cryogenic transmission microscopy (Cryo-TEM). We found that quinine impaired the crystalline structure of doxorubicin. In vitro, treatment with single agents themselves was insufficient to inhibit the growth of HT-29 MDR1 cells. However, pegylated liposomal doxorubicin and quinine (PLDQ) significantly diminished HT-29 MDR1 cell survival. Furthermore, survival inhibition intensified by the addition of ICG to the PLDQ (ICG + PLDQ). In vivo, ICG + PLDQ significantly decreased tumor growth when combined with tumor irradiation with NIR light (** p < 0.01). ICG + PLDQ + irradiation was superior to single treatments or combinational treatments without irradiation. These findings suggest that ICG + PLDQ can overcome P-gp-mediated MDR in cancer cells.

SUBMITTER: Grabarnick Portnoy E

PROVIDER: S-EPMC8708987 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background:Glioma represents the most common malignant brain tumor. Outcomes of surgical resection are often unsatisfactory due to low sensitivity or resolution of imaging methods. Moreover, the use of traditional chemotherapeutics, such as doxorubicin (DOX), is limited due to their low blood-brain barrier (BBB) permeability. Recently, the development of nanotechnology could overcome these obstacles. Materials and methods:Hydrophobic superparamagnetic iron oxide nanoparticles (SPIO NPs) were prepared with the use of thermal decomposition method. They were coated with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG 2000) and DOX using a thin-film hydration method followed by loading of indocyanine green (ICG) into the phospholipid layers. Details regarding the characteristics of NPs were determined. The in vitro biocompatibility and antitumor efficacy were established with the use of MTT assay. In vivo fluorescence and magnetic resonance (MR) imaging were used to evaluate BBB penetration and accumulation of NPs at the tumor site. Antitumor efficacy was evaluated using measures of tumor size, median survival times, body weights, and H&E staining. Results:The multifunctional NPs generated had an average diameter of 22.9 nm, a zeta potential of -38.19 mV, and were capable of providing a sustained release of DOX. In vitro experiments demonstrated that the SPIO@DSPE-PEG/DOX/ICG NPs effectively enhanced cellular uptake of DOX as compared with that of free DOX. In vivo fluorescence and MR imaging revealed that the NPs not only effectively crossed the BBB but selectively accumulated at the tumor site. Meanwhile, among all groups studied, C6 glioma-bearing rats treated with the NPs exhibited the maximal degree of therapeutic efficacy, including smallest tumor volume, lowest body weight loss, and longest survival times, with no obvious side effects. Conclusion:These results suggest that the SPIO@DSPE-PEG/DOX/ICG NPs can not only function as a nanoprobe for MR and fluorescence bimodal imaging, but also as a vehicle to deliver chemotherapeutic drugs to the tumor site, to achieve the theranostic treatment of glioma.

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PEGylated Liposomes Remotely Loaded with the Combination of Doxorubicin, Quinine, and Indocyanine Green Enable Successful Treatment of Multidrug-Resistant Tumors.

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