大小鼠雾化给药仪/大小鼠雾化器

ECM microenvironment. The compound 2,4-dinitrophenol
(DNP) is a mitochondrial uncoupling agent once used as a
weight loss drug; it stimulates metabolism and generates heat
by inhibiting mitochondrial adenosine triphosphate (ATP)
production.16 Due to its capacity for uncoupling oxidative and
phosphorylation pathways, energy generated by electron
transfer in the respiratory chain is converted to dissipated
heat instead of generating ATP. Because DNP raises the
temperature of exposed cells biologically,17 it has been
proposed as a suitable candidate for cellular biological
hyperthermia.
Although DNP, with a half-life of only 3 h, is easily
eliminated, it can still induce thermoregulatory dyshomeo-
stasis.18,19 Nevertheless, DNP has recently been shown to be a
safe and effective chemical agent that can reverse diabetes,
steatohepatitis, and fibrosis in animal models of obesity when
administered via controlled-release delivery preparations,
rather than as a hyperthermia-inducing agent.20,21 However,
a fibrotic site-specific delivery and release nanosystem has not
been described that enables deep penetration and high
exposure to DNP within the ECM able to achieve biological
hyperthermia. Based on the enhanced permeability and
retention (EPR) effect in fibrotic foci,22 a hybrid nanoparticle
containing fibroblast-derived exosomes and liposomes (ELs),
possessing both the biomimetic properties (homologous
targeting) of exosomes and the drug-loading capabilities of
liposomes, is described in the present study. ELs have the
advantages of reduced accumulation in nonfibrotic tissues,
prolonged circulatory times, and increased accumulation and
penetration of pulmonary fibrotic tissue.23,24 Moreover, matrix
metalloproteinase (MMP)-9, a substance mainly secreted and
released by activated fibroblasts (myofibroblasts) and macro-
phages, is involved in the pathological progression of fibrosis
within the ECM.25,26 GPQGIAGQR(GPO)4GG (GPQ) is a
triple-helical peptide with an MMP-9-cleaved bond, and its
modified liposomes possess MMP-9-responsive lipid bilayer
disrupting and cargo-releasing properties.27 Therefore, GPQ-
modified EL (GPQ-EL) may result in fibrosis-specific delivery
able to release DNP into the ECM, thus reducing adverse
effects.
In this study, DNP-loaded GPQ-EL nanoparticles (GPQ-
EL-DNP) were constructed for biological hyperthermia to
induce specific remodeling of the ECM microenvironment and
to enhance the efficacy of pro-apoptosis for fibrosis therapy
(Figure 1A). Using a murine model of fibrosis, administration
of GPQ-EL-DNP loaded with simvastatin (SIM), a pro-
apoptotic drug, preferentially targeted the fibrotic focus and
disrupted the lipid bilayer with an MMP-9 trigger, thus
inducing high exposure to DNP locally. Subsequently, the
collagen was denatured by DNP via biological hyperthermia,
leading to a remodeled ECM microenvironment with
significantly reduced stiffness and suppressed fibroblast
activation. As a result, drug delivery in the remodeled ECM
and the apoptotic sensitivity of fibroblasts were both enhanced,
and SIM achieved a comprehensive, enhanced antifibrotic