A glutathione-sensitive drug delivery system based on carboxymethyl chitosan co-deliver Rose Bengal and oxymatrine for combined cancer treatment.

At present, monotherapy of tumor has not met the clinical needs, due to high doses, poor efficacy, and the emergence of drug resistance. Combination therapy can effectively solve these problems, which is a better option for tumor suppression. Based on this, we developed a novel glutathione-sensitive drug delivery nanoparticle system (OMT/CMCS-CYS-RB NPs) for oral cancer treatment. Briefly, carboxymethyl chitosan (CMCS) was used as a carrier to simultaneously load Rose Bengal (RB) and oxymatrine (OMT). The OMT/CMCS-CYS-RB NPs prepared by ion crosslinking were spheres with a stable structure. In addition, the nanoparticles can be excited in vitro to generate a large amount of singlet oxygen, which has a good photodynamic effect. In vitro anti-tumor activity study showed that the nanoparticles after the laser enhanced therapeutic efficacy on tumor cells compared with the free drug and exhibited well security. Furthermore, OMT/CMCS-CYS-RB NPs could inhibit the PI3K/AKT signaling pathway in oxidative stress, and realize tumor apoptosis through mitochondria-related pathways. In conclusion, this combination delivery system for delivering RB and OMT is a safe and effective strategy, which may provide a new avenue for the tumor treatment.

Glutathione-sensitive IPI-549 nanoparticles synergized with photodynamic Chlorin e6 for the treatment of breast cancer.

We combined phosphoinositol-3-kinin inhibitor IPI-549 and photodynamic Chlorin e6 (Ce6) on carboxymethyl chitosan to develop a novel drug delivery nanoparticle (NP) system (Ce6/CMCS-DSP-IPI549) and evaluate its glutathione (GSH) sensitivity and targeting ability for breast cancer treatment. The NPs were spherical with a uniform size of 218.8 nm, a stable structure over 7 days. The maximum encapsulation efficiency was 64.42%, and NPs drug loading was 8.05%. The NPs released drugs within tumor cells due to their high GSH concentration, while they maintained structural integrity in normal cells, which have low GSH concentration. The cumulative release rates of IPI-549 and Ce6 at 108 h were 70.67% and 40.35% (at GSH 10 mM) and 8.11% and 2.71% (at GSH 2µM), respectively. The NPs showed a strong inhibitory effect on 4T1 cells yet did not affect human umbilical vein endothelial cells (HUVECs). After irradiation by a 660 nm infrared laser for 72 h, the survival rate of 4T1 cells was 15.51%. Cellular uptake studies indicated that the NPs could accurately release drugs into tumor cells. In addition, the NPs had a good photodynamic effect and promoted the release of reactive oxygen species to damage tumor cells. Overall, the combination therapy of IPI-549 and Ce6 is safe and effective, and may provide a new avenue for the treatment of breast cancer.

1-MT grafted carboxymethyl chitosan and its nanoparticles: Preparation, characterization and evaluation.

This work aims to synthesize two novel 1-MT (1-Methyl-DL-tryptophan) grafted CMCS (carboxymethyl chitosan) polymer prodrugs CMCS-amido-1-MT and CMCS-ester-1-MT, and to further manufacture their nanoparticles for potential biomedical applications. The polymeric prodrugs are prepared by three-step chemical synthesis. The chemical structure of drugs is confirmed by FTIR and 1H-NMR. The drug loadings of the CMCS-amido-1-MT NPs and CMCS-ester-1-MT NPs are 11.43% and 10.18%, respectively. The surface morphology of the nanoparticles is spherical or nearly spherical, while the surface is smooth and the size distribution is uniform. The average particle size is both about 200 nm, while the polydispersity index is both about 0.15. The nanoparticles have a negative charge on the surface. The particle size and its distribution change little, when the two nanoparticles are tested in the simulated blood pH environment for 7 days. However, only the CMCS-ester-1-MT nanoparticles are pH-sensitive. The cell toxicity of the CMCS-ester-1-MT nanoparticles and the original drug are both in a dose- and time-dependent manner, while the nanoparticles enter cells by endocytosis. In ECA109 cells, the CMCS-ester-1-MT nanoparticles and the original drug both induce the apoptosis. CMCS-ester-1-MT NPs can activate the ATF4/CHOP pathway in endoplasmic reticulum stress, and achieve cancer suppression through mitochondrial-related apoptosis.

Tuning mPEG-PLA/vitamin E-TPGS-based mixed micelles for combined celecoxib/honokiol therapy for breast cancer.

This study aimed to develop, evaluate, and optimize the mPEG-PLA/vitamin E-TPGS mixed micelle drug delivery system to encapsulate celecoxib (CXB) and honokiol (HNK) for intravenous treatment of breast cancer. To this end, we formulated CXB-loaded mPEG-PLA/vitamin E-TPGS (PV-CXB) and HNK-loaded mPEG-PLA/vitamin E-TPGS (PV-HNK) mixed micelles and analyzed their characteristics. The 4T1 cell line was used for cytotoxicity determination and cellular uptake experiments, and for establishing a 4T1-bearing mouse model for histopathology, immunofluorescence, terminal deoxynucleotidyl transferase-mediated nick end labeling, and Western blot analysis. The synergistic effects of PV-CXB and PV-HNK combination therapy were investigated in vitro and in vivo using the coefficient of drug interaction values. The mean size of PV-CXB and PV-HNK prepared with optimal formulation was approximately 50 nm, with a spherical shape. PV-CXB and PV-HNK combination therapy exhibited cytotoxicity in 4T1 cells in vitro. However, the toxicity of PV-CXB and PV-HNK combination therapy was not apparent in normal tissues (heart, liver, spleen, lung, and kidney) in vivo and reduced the expression of collagen fibers in tumor tissues. Moreover, the combination therapy reduced the expression of tumor growth biomarkers (Foxp3, CD4, Gr-1, CD11b, CD31, Ki67, FoxM1, and VEGF). In addition, the tumor cell apoptosis rate reached 45.71 ± 0.62%. The combined treatment with PV-CXB and PV-HNK showed synergistic effect both in vitro and in vivo. Thus, the PV-CXB and PV-HNK drug delivery system could be used as a potential combination therapy for breast cancer .