Pyroelectric Janus nanomotors to promote cell internalization and synergistic tumor therapy.

The tumor diffusion and cell internalization are the major obstacles to improving delivery efficacy of therapeutic agents. External electric fields have shown strong effect on the cell membrane polarization and fluidity, but usually need complicated power management circuits. Herein, in situ generation of microelectric field on nanoparticles (NPs) is proposed to overcome these delivery barriers. Janus tBT@PDA-CPT NPs were developed through partially coating of polydopamine (PDA) caps on pyroelectric tetragonal BaTiO3 (tBT) NPs and then camptothecin (CPT) conjugation via disulfide linkages. For comparison, cBT@PDA-CPT NPs were prepared from non-pyroelectric cubic BaTiO3 (cBT) as control. Near-infrared (NIR) illumination on PDA caps of the Janus NPs produces asymmetric thermophoretic force to drive NP motion for tumor accumulation, deep tissue penetration and effective cell interaction. Photothermally created temperature variations on tBT NPs build pyroelectric potentials to selectively change the membrane potential of tumor cells other than normal cells and exhibit a dominated role in enhancing tumor cell internalization and cytotoxicity. The combination index analysis confirms the synergistic effect of pyroelectric dynamic therapy (PEDT), chemotherapy and photothermal therapy (PTT), leading to full inhibition of tumor growth and noticeable extension of animal survival at significant lower CPT doses. The mild PTT/PEDT, the reduced CPT dose and the selective toxicity to tumor cells have achieved favorable treatment safety after tBT@PDA-CPT/NIR treatment. Therefore, in response to the differences in membrane potentials and glutathione levels between tumor and normal cells, we have demonstrated a concise design to achieve thermophoresis-driven motion, pyroelectric potential-enhanced cell internalization and PTT/PEDT/chemotherapy-synergized antitumor treatment.

Pyroelectric Janus nanomotors for synergistic electrodynamic-photothermal-antibiotic therapies of bacterial infections.

Antibacterial electrotherapy is currently activated by external electric field or self-powered generators, but usually needs complicated power management circuits. Herein, near-infrared illumination (NIR) of pyroelectric nanoparticles (NPs) produces a built-in electric field to address the effectiveness and safety concerns in the antibacterial treatment. Janus tBT@PDA NPs were obtained by capping polydopamine (PDA) on tetragonal BaTiO3 (tBT) NPs through defining the polymerization time, followed by ciprofloxacin (CIP) loading on the PDA caps to fabricate Janus tBT@PDA-Cip NPs. NIR illumination of PDA caps creates temperature variations on tBT NPs to generate photothermal and pyroelectric effects. Finite element simulation reveals a pyroelectric potential of over 1 V and sufficient reactive oxygen species (ROS) are produced to exhibit pyroelectric dynamic therapy (PEDT). The elevated temperature on one side of the Janus NPs produces thermophoretic force to drive NP motion, which enhances interactions with bacteria and overcomes limitations in the short action distance and lifespan of ROS. The pyroelectric field accelerates CIP release through weakening the π-π stacking and electrostatic interaction with PDA and also interrupts membrane potentials of bacteria to enhance CIP invasion into bacteria. The synergistic antibacterial effect of pyroelectric tBT@PDA-Cip NPs causes the fully recovery of S. aureus-infected skin wounds and regeneration of intact epidermis, blood vessels and hair follicles, while no obvious pathological change or inflammatory lesion is detected in the major organs. Thus, the pyroelectric Janus nanomotors demonstrate synergistic PEDT/photothermal/antibiotic effects to enhance antibacterial efficacy while avoiding the necessity of excessive heat, ROS and antibiotic doses. STATEMENT OF SIGNIFICANCE: Antibacterial treatment is challenged by antibiotics-derived side effects and the evolution of resistant strains. Phototherapy is commonly associated with excessive heat and oxidative stress, and their combinations with other agents are especially encouraged to strengthen antibacterial efficacy while alleviating the associated side effects. Electric field is another activator to generate antibacterial abilities, but usually requires complicated power management and bulk electrodes, making it inconvenient in a biological setup. To address these challenges, we propose a strategy to generate microelectric field on nanoparticles themselves and achieve synergistic electrodynamic-photothermal-antibiotic therapies. The pyroelectric effect weakens interactions between nanoparticles and antibiotics to accelerate drug release, and the built-in pyroelectric field increases membrane fluidity to enhance bacterial uptake of antibiotics.