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.