Keywords
Hollow Mesoporous Prussian Blue, antibiotic resistance, antibacterial nanoplatform, photothermal therapy
Introduction
Over the past decades, the ever-growing emergence of bacterial infections causes devastating consequences to public health worldwide1. Clinically, the most widely employed and effective therapeutic method of bacterial infections is antibiotics treatment2-3. However, the overuse of antibiotics has given rise to the appearance of multidrug-resistant (MDR) bacteria which weakens the effectiveness of most antibiotics4. Moreover, high-dose antibiotics treatment has great potential to induce severe adverse effects and systemic toxicity such as angioedema, thrombophlebitis, anaphylactic shock and so on5-6. Thus, there is an urgent requirement for development of new effective antibacterial strategies which make rational use of conventional antibiotics and minimize antibiotic dose.
Recently, nanoparticle (NP)-based local “on-demand” antibacterial drugs delivery systems have received burgeoning attention since they can prolong drugs retention at the infected area with low undesired drugs diffusion, improved therapeutic efficacy and reduced toxicity7-9. For instance, Gu and co-workers reported levofloxacin hydrochloride-loaded, silver core-embedded mesoporous silica for synergistically combating drug-resistant bacterial infections10; Wu and co-workers developed ciprofloxacin-loaded photothermal PDA/GC hydrogel for combined chemo-photothermal therapy of bacterial infections11; Han and co-workers successfully fabricated rifampicin-loaded endogenous stimulus–responsive liposome nanoreactors for a combined therapy of bacterial infections12. Although NP-based drugs delivery systems can effectively enhance antibacterial efficacy and lower biological toxicity of antibacterial drugs, therapeutic effect of single modality of chemotherapy based on drugs delivery systems is still unsatisfactory due to poor diffusivity of drugs in targeted sites13, which will seriously hamper their practical applications in clinic. Chemotherapy-based synergistic therapy is a particularly encouraging strategy to strengthen the bactericidal effect for combating bacterial infections14 .
Photothermal therapy (PTT) triggered by near-infrared (NIR) laser has been applied as one of the most effective antibacterial strategies15-16. PTT can cause bacterial death through hyperthermia-induced denaturation of bacterial enzymes and irreversible bacterial destruction17. Comparing with antimicrobials, this strategy presented many advantages for antibacterial application as follow: (1) NIR laser has high spatial resolution and a deep penetration ability to tissues with minimal invasiveness18; (2) PTT can efficiently kill bacteria in a short time (only a few minutes)19-20; (3) PTT has broad-spectrum antibacterial ability and can efficiently eliminate MDR bacterial strains with less probability to induce drug resistance21; (4) NIR laser can focus on a targeted area to accelerate blood circulation with little influence on the whole body22-23. Unfortunately, the locally high temperature required to completely eradicate the bacteria may cause severe thermal injury to the surrounding healthy tissues24. Combination of chemotherapy and PTT is an especially promising approach for overcoming the limitations of PTT alone.
To date, numerous nanomaterials have been developed as photothermal agents, including palladium NPs25, carbon nanomaterials26, black phosphorus27, Au nanorods28 and so on. Among these nanomaterials, Prussian blue (PB) approved by USA Food and Drug Administration (FDA) as a clinical drug gains great popularity for PTT due to the eminent advantages of strong NIR radiation absorption ability, high photothermal efficiency, excellent chemical stability, splendid biocompatibility and low-cost29-30. More encouragingly, we have successfully prepared hollow mesoporous PB (HMPB) that has larger drug loading capacity owing to interior hollow cavity and more rough mesoporous surface compared with PB. Simultaneously, HMPB possess almost the same photothermal ability as PB. These unique features of HMPB make it an ideal photothermal agent as well as drug carrier, which can effectively combine chemotherapy and PTT31.
Herein, we fabricated a robust surface-adaptive, on-demand antibacterial nanoplatform by covering hyaluronic acid (HA) on ofloxacin loaded HMPB to exert the strong synergistic antibacterial effect involving antibiotic and PTT killing. As showed in Scheme 1, for the first time, we utilized the hyaluronic acid (HA)-modified HMPB as a nanocarrier to load the ofloxacin, a traditional antibiotic with broad spectrum of antibacterial property against both gram-positive and gram-negative bacteria, even MDR bacteria. HA with excellent biocompatibility was employed as the capping agent to prevent unwanted ofloxacin release in this system. Meanwhile, HA on the surface of HMPB acted in the role of “on-demand” releasing agent which can be degraded by hyaluronidase (HAase) secreted in numerous bacteria. The encapsulated ofloxacin could be released and further efficiently combat pathogenic bacteria at the infected area when the coating layer HA of the resulted OHH NPs was degraded by overexpressed HAase generated by bacteria. The intelligent behavior of “on-demand” release of this nanoplatform could considerably enhanced bioavailability of ofloxacin and reduced toxicity of ofloxacin. Additionally, under NIR light irradiation, the nanocarrier showed photothermal effect, which could generate locally increased temperature to inactivate bacteria. In summary, the OHH NPs exhibited surface-adaptive characteristic and on-demand synergistically antibacterial capability originated from the released ofloxacin and produced hyperthermia under NIR light irradiation, which could significantly improve the antibacterial efficacy and lowered the dosage of ofloxacin. Furthermore, this powerful antibacterial nanoplatform was successfully employed for the treatment of K.pneumoniae -infected wound.