A ROS-Responsive Simvastatin Nano-Prodrug and its Fibronectin-Targeted Co-Delivery System for Atherosclerosis Treatment.

Nanoprodrugs with responsive release properties integrate the advantages of stimuli-responsive prodrugs and nanotechnology. They would provide ultimate opportunity in fighting atherosclerosis. In this study, we synthesized a redox-responsive nanoprodrug of simvastatin (TPTS) by conjugating α-tocopherol polyethylene glycol derivative to the pharmacophore of simvastatin with a thioketal linker. TPTS formed nanoparticles and released parent simvastatin in the presence of hydrogen peroxide. Moreover, by taking advantage of the self-assembly behavior of TPTS, we developed a fibronectin-targeted delivery system (TPTS/C/T) to codelivery simvastatin prodrug and ticagrelor. In vitro and in vivo experiments indicated that TPTS and TPTS/C/T had good stability, which could reduce off-target leakage of drugs. They greatly inhibited the M1-type polarization of macrophages; reduced intracellular reactive oxygen species level and inflammatory cytokine; and TNF-α, MCP-1, and IL-1ß were secreted by macrophage cells, thus providing enhanced anti-inflammatory and antioxidant effects compared with free simvastatin. TPTS/C/T realized targeted drug release to plaques and synergistic therapeutic effects of simvastatin and ticagrelor on atherosclerosis treatment in an ApoE-/- mouse model, resulting in excellent atherosclerosis therapeutic efficacy and a promising biosafety profile. Therefore, this study provides a new method for manufacturing statin nanodrugs and a new design idea for related responsive drug release nanosystems for atherosclerosis.

A versatile modular preparation strategy for targeted drug delivery systems against multidrug-resistant cancer cells.

Nanotechnology is widely used in targeted drug delivery, but different drug delivery systems need to 're-determine' different synthesis schemes, which greatly limits the further expansion of targeted nanomedicine applications. In this study, we propose a facile and versatile modular stacking strategy to fabricate targeted drug delivery systems to enable tailored designs for patient-specific therapeutic responses. The systems were constructed by a pH-sensitive prodrug module and a mitochondrial targeting module via self-assembly. Using this modular strategy, we successfully prepared two targeting nano-drug delivery systems, TPP-DOX and PK-DOX, where the mitochondrial targeting molecules were triphenylphosphonium (TPP) and 1-(2-Chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide (PK11195), respectively. Confocal laser microscopy and flow cytometry tests revealed that TPP-DOX and PK-DOX exhibited high mitochondria targeting capability and greatly improved the drug retention in drug-resistant cells. The antitumor activity tests showed that the IC50 values of TPP-DOX and PK-DOX in MCF-7/ADR cells were 2.5- and 8.2-fold lower than that of free DOX, respectively. These results indicated that PK was more effective than TPP. The studies on their therapeutic effects on human breast cancer resistant cells verified the feasibility of the modular approach, indicated that the two modular targeted drug delivery systems: (1) retain the drug toxicity and cell-killing effect of the prodrug module, (2) have precise targeting capabilities due to mitochondrial targeting module, (3) enhance drug uptake, reduce drug efflux and reverse the multidrug resistance effect to a certain extent. The results show that modular stacking is a practical, effective and versatile method for preparing targeting drugs with broad application prospects. This study provides an easy approach on preparing customizable targeted drug delivery systems to improve precision therapies.

A multifunctional nano-delivery system enhances the chemo-co-phototherapy of tumor multidrug resistance via mitochondrial-targeting and inhibiting P-glycoprotein-mediated efflux.

Despite the excellent progress of chemotherapy and phototherapy in tumor treatment, their effectiveness on multidrug-resistant (MDR) tumors is still unsatisfactory. One of the main obstacles is drug efflux caused by P-glycoprotein in MDR cells. Herein, we developed a nano-delivery system that combines a P-glycoprotein inhibitor with chemotherapy and phototherapy to overcome MDR. Briefly, the system is prepared by the self-assembly of a ROS-triggered doxorubicin prodrug (PTD) and mitochondrial-targeted D-α-tocopherol polyethyleneglycol succinate (TPP-TPGS), in which a photoactive drug, IR780, is encapsulated (PTD/TT/IR780). PTD/TT/IR780 can target the release of TPP-TPGS, doxorubicin and IR780 at the mitochondrial site of MDR cells through ROS trigger. D-α-Tocopherol polyethyleneglycol succinate (TPGS) is a P-glycoprotein inhibitor, which will reduce the efflux of doxorubicin and IR780 from MDR cells. Under irradiation of an 808 nm near-infrared laser, IR780 generates heat and ROS, causing mitochondrial damage and prompting MDR cell apoptosis. At the same time, ROS can reduce the ATP content, which inhibits the P-glycoprotein function. In addition, an increase in the ROS generates positive feedback, allowing more nanoparticles to be cleaved and further promoting payload release in MDR cells, thereby enhancing the synergistic efficacy of chemotherapy and phototherapy. The in vitro cellular assay showed that PTD/TT/IR780 significantly inhibited MDR cell proliferation at a very low drug concentration (IC50 = 0.27 µg mL-1 doxorubicin-equivalent concentration). In vivo animal experiments based on BALB/c nude mice bearing MCF-7/ADR tumors confirmed a superior antitumor efficacy and an excellent biosafety profile. These findings demonstrate that this multifunctional nanoplatform provides a new approach for the treatment of MDR tumors.