pH-Sensitive Nanoparticles Codelivering Docetaxel and Dihydroartemisinin Effectively Treat Breast Cancer by Enhancing Reactive Oxidative Species-Mediated Mitochondrial Apoptosis.

Tumor growth and metastasis are the major causes of high mortality in breast cancer. We previously constructed pH-sensitive nanoparticles (D/D NPs) for the codelivery of docetaxel (DTX) and dihydroartemisinin (DHA) and demonstrated that D/D NPs showed anticancer activity in breast cancer cells in vitro. The present study further investigated the therapeutic effect of D/D NPs on orthotopic breast cancer in vivo and examined the antitumor mechanism of D/D NPs. D/D NPs significantly increased the apoptosis of 4T1 cells with a synergistic effect of DTX and DHA. D/D NPs increased reactive oxygen species, reduced mitochondrial membrane potential, increased the expression of p53, and induced cytochrome c release into the cytoplasm to activate caspase-3. In an orthotopic metastatic breast cancer mouse model derived from 4T1 cells, D/D NPs inhibited tumor growth and prevented lung metastasis due to the synergistic effect of DTX and DHA. No distinct changes were observed in the histology of major organs. These results indicate that pH-sensitive D/D NP-based combination therapy may be a promising strategy for the treatment of metastatic breast cancers via the ROS-mediated mitochondrial apoptosis pathway.

Folate acid-Cyclodextrin/Docetaxel induces apoptosis in KB cells via the intrinsic mitochondrial pathway and displays antitumor activity in vivo.

Docetaxel (DTX) is an antitumor therapeutic drug limited by solubility and selective delivery tissues. We previously prepared DTX/folate acid-Cyclodextrin (FA-CD) inclusion complexes that target folate receptors of tumor cells and showed that these complexes inhibited cancer cell proliferation by inducing apoptosis. Here we further determined the antitumor effect and apoptotic mechanism of DTX/FA-CD. DTX/FA-CD induced reactive oxygen species-mediated mitochondrial apoptosis in KB cells. DTX/FA-CD led to apoptosis accompanied with the repression of mitochondrial membrane potential and glutathione and overexpression of reactive oxygen species and catalase. DTX/FA-CD also specifically accumulated into tumor regions in KB tumor-bearing mice by active targeting. DTX/FA-CD significantly suppressed tumor growth and showed low toxicity in KB tumor xenografts. We concluded that the DTX/FA-DTX inclusion complex induced the intrinsic mitochondrial-mediated apoptosis to cause cell death. Our results showed favorable antitumor effects of DTX/FA-DTX and indicate DTX/FA-DTX could serve as a safe and effective delivery system for antitumor therapy.

Enhanced tumor delivery and antitumor response of doxorubicin-loaded albumin nanoparticles formulated based on a Schiff base.

A novel method was developed here to prepare albumin-based nanoparticles (NPs) for improving the therapeutic and safety profiles of chemotherapeutic agents. This approach involved crosslinking bovine serum albumin (BSA) using a Schiff base-containing vanillin, into NPs and loading doxorubicin (DOX) into the NPs by incubation. The resultant NPs (DOX-BSA-V-NPs) displayed a particle size of 100.5±1.3 nm with a zeta potential of -23.05±1.45 mV and also showed high drug-loading efficiency and excellent stability with respect to storage and temperature. The encapsulation of DOX into the BSA-V-NPs was confirmed by dynamic scanning calorimetry and Raman spectroscopy. DOX-BSA-V-NPs exhibited a significantly faster DOX release at pH 6.5 than pH 7.4, as well as in a solution with a higher glutathione concentration. In vitro studies showed that the cellular uptake of DOX-BSA-V-NPs was time-dependent, concentration-dependent, and faster than free DOX, while the cytotoxicity of DOX-BSA-V-NPs (IC50 value of 3.693 µg/mL) was superior to free DOX (IC50 value of 4.007 µg/mL). More importantly, DOX-BSA-V-NPs showed a longer mean survival time of 24.83 days, a higher tumor inhibition rate of 56.66%, and a decreased distribution in the heart than other DOX formulations in animal studies using a tumor xenograft model. Thus, the vanillin-based albumin NPs were shown here to be a promising carrier for tumor-targeted delivery of chemotherapeutic agents and, thus, should be further studied.

TPGS modified reduced bovine serum albumin nanoparticles as a lipophilic anticancer drug carrier for overcoming multidrug resistance.

In this study, a novel protein-polymer conjugate, d-α-tocopheryl polyethylene glycol succinate modified reduced bovine serum albumin (TPGS-Re-BSA, TRB), was synthesized for lipophilic anticancer drug delivery, and its unique ability to overcome drug resistance was explored. This conjugate was extensively characterized for its chemical structure, average molecular weight, secondary structure, degree of substitution, hydrophobicity, particle size and zeta potential. PTX-loaded nanoparticles (NPs) with diameters of 170-370 nm and drug loading efficiency of up to 13.62% were successfully prepared by the dialysis method. These drug-loaded NPs were found to exhibit a sustained release of PTX at pH 7.4, 6.5 and 5.5. Moreover, great anti-tumor activity in drug sensitive MCF-7 cells was observed in the in vitro anti-tumor studies. In particular, enhanced cytotoxicity and PTX-induced apoptosis were observed in the drug-resistant MCF-7/ADR cells compared to the Taxol and PTX-loaded BSA NPs. This could be attributed to the significant inhibition of P-gp activity and reduced ATP levels due to the presence of TRB NPs. Lastly, in vivo tumor inhibition assay verified the higher efficacy of TRB NPs. Overall, the results suggest that this TRB NPs could provide an effective carrier system for the delivery of anticancer agents.