Ultrasound is clinically used for diagnosis and interventions for musculoskeletal injuries like muscle contusion, but contrast of ultrasonography still remains a challenge in the field of the musculoskeletal system. A level of hydrogen peroxide (H2O2) is known to be elevated during mechanical tissue damage and therefore H2O2 can be exploited as a diagnostic and therapeutic marker for mechanical injuries in the musculoskeletal system. We previously developed poly(vanillin-oxalate) (PVO) as an inflammation-responsive polymeric prodrug of vanillin, which is designed to rapidly respond to H2O2 and exert antioxidant and anti-inflammatory activities. The primary aim of this study is to verify whether PVO nanoparticles could serve as contrast agents as well as therapeutic agents for musculoskeletal injuries simultaneously. In a rat model of contusion-induced muscle injury, PVO nanoparticles generated CO2 bubbles to enhance the ultrasound contrast in the injury site. A single intramuscular injection of PVO nanoparticles also suppressed contusion-induced muscle damages by inhibiting the expression of pro-inflammatory cytokines and inflammatory cell infiltration. We, therefore, anticipate that PVO nanoparticles have great translational potential as not only ultrasound imaging agents but also therapeutic agents for the musculoskeletal disorders such as contusion.
GSH depleting prodrugs and ROS generators self-assemble to generate oxidative stress nanoamplifiers that can preferentially kill cancer cells and exert immunostimulating activity.
Cancer cells are more vulnerable to reactive oxygen species (ROS)-mediated oxidative stress than normal cells due to disturbed redox balance. It can be postulated that ROS-generating drug carriers exert anticancer actions, leading to combination anticancer therapy with drug payloads. Here, we report a ROSgenerating polyprodrug of cinnamaldehyde (CA) that not only serves as a drug carrier but also synergizes with drug payloads. The polyprodrug of CA (pCA) incorporates ROS-generating CA in the backbone of an amphiphilic polymer through an acid-cleavable acetal linkage. pCA could self-assemble with tumor-targeting lipopeptide (DSPE-PEG-RGD) and encapsulate doxorubicin (DOX) to form T-pCAD micelles. At acidic pH, T-pCAD micelles release both CA and DOX to exert synergistic anticancer actions. Animal studies using mouse xenograft models revealed that T-pCAD micelles accumulate in tumors preferentially and suppress the tumor growth significantly. Based on the oxidative stress amplification and acid-responsiveness, ROS-generating pCAD micelles hold tremendous potential as drug carriers for combination anticancer therapy.
Liposomes have been extensively explored as drug carriers,
but
their clinical translation has been hampered by their low drug-loading
content and premature leakage of drug payloads. It was reasoned that
vesicle-forming prodrugs could be incorporated into the lipid bilayer
at a high molar fraction and therefore serve as a therapeutic agent
as well as a structural component in liposomal nanomedicine. Boronated
retinoic acid (BORA) was developed as a prodrug, which can self-assemble
with common lipids to form liposomes at a high molar fraction (40%)
and release all-trans retinoic acid (atRA) and hydroxybenzyl
alcohol (HBA) simultaneously, in response to hydrogen peroxide (H2O2). Here, we report fucoidan-coated BORA-incorporated
liposomes (f-BORALP) as clot-targeted antithrombotic liposomal nanomedicine
with H2O2-triggered multiple therapeutic actions.
In the mouse model of carotid arterial thrombosis, f-BORALP preferentially
accumulated in the injured blood vessel and significantly suppressed
thrombus formation, demonstrating their potential as targeted antithrombotic
nanomedicine. This study also provides valuable insight into the development
of vesicle-forming and self-immolative prodrugs to exploit the benefits
of liposomal drug delivery.
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