Oxidative Stress Amplifying Polyprodrug Micelles as Drug Carriers for Combination Anticancer Therapy.

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 ROS-generating 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.

Clot-Targeted Antithrombotic Liposomal Nanomedicine Containing High Content of H2O2-Activatable Hybrid Prodrugs.

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.

Nanoassemblies of Self-Immolative Boronate-Bridged Retinoic Acid Dimeric Prodrug as a Clot-Targeted Self-Deliverable Antithrombotic Nanomedicine.

All trans-retinoic acid (atRA) has potent anti-inflammatory and antiplatelet activity, but its clinical translation as an antithrombotic drug has been hampered by its low therapeutic efficacy. Here, we describe a facile and elegant strategy that converts atRA into systemically injectable antithrombotic nanoparticles. The strategy involves the dimerization of two atRA molecules using a self-immolative boronate linker that is cleaved specifically by hydrogen peroxide (H2O2) to release anti-inflammatory hydroxybenzyl alcohol (HBA), followed by dimerization-induced self-assembly to generate colloidally stable nanoparticles. The boronated atRA dimeric prodrug (BRDP) could form injectable nanoparticles in the presence of fucoidan that serves as an emulsifier and a targeting ligand to P-selectin overexpressed on the damaged endothelium. In response to H2O2, fucoidan-decorated BRDP (f-BRDP) nanoassemblies dissociate to release both atRA and HBA, while scavenging H2O2. In a mouse model of ferric chloride (FeCl3)-induced carotid arterial thrombosis, f-BRDP nanoassemblies target the thrombosed vessel and significantly inhibit thrombus formation. The results demonstrate that dimerization of atRA molecules via a boronate linker enables the formation of stable nanoassemblies with several benefits: high drug loading, drug self-delivery, on-demand multiple antithrombotic actions, and simple fabrication of nanoparticles. Overall, this strategy provides a promising expedient and practical route for the development of translational self-deliverable antithrombotic nanomedicine.

Tumor-targeted redox-regulating and antiangiogenic phototherapeutics nanoassemblies for self-boosting phototherapy.

Cancer cells are equipped with abundant antioxidants such as glutathione (GSH) that eliminate reactive oxygen species (ROS) to deteriorate the therapeutic efficacy of photodynamic therapy (PDT). Another challenge in PDT is circumventing PDT-induced hypoxic condition that provokes upregulation of pro-angiogenic factor such as vascular endothelial growth factor (VEGF). It is therefore reasonable to expect that therapeutic outcomes of PDT could be maximized by concurrent delivery of photosensitizers with GSH depleting agents and VEGF suppressors. To achieve cooperative therapeutic actions of PDT with in situ GSH depletion and VEGF suppression, we developed tumor targeted redox-regulating and antiangiogenic phototherapeutic nanoassemblies (tRAPs) composed of self-assembling disulfide-bridged borylbenzyl carbonate (ssBR), photosensitizer (IR780) and tumor targeting gelatin. As a framework of tRAPs, ssBR was rationally designed to form nanoconstructs that serve as photosensitizer carriers with intrinsic GSH depleting- and VEGF suppressing ability. tRAPs effectively depleted intracellular GSH to render cancer cells more vulnerable to ROS and also provoked immunogenic cell death (ICD) of cancer cells upon near infrared (NIR) laser irradiation. In mouse xenograft models, tRAPs preferentially accumulated in tumors and dramatically eradicated tumors with laser irradiation. The design rationale of tRAPs provides a simple and versatile strategy to develop self-boosting phototherapeutic agents with great potential in targeted cancer therapy.

Targeted echogenic and anti-inflammatory polymeric prodrug nanoparticles for the management of renal ischemia/reperfusion injury.

Ischemia/reperfusion (IR) injury is an inevitable pathological event occurring when blood is resupplied to the tissues after a period of ischemia. One of major causes of IR injury is the overproduction of reactive oxygen species (ROS) including hydrogen peroxide (H2O2), which mediates the expression of various inflammatory cytokines to exacerbate tissue damages. The overproduced H2O2 could therefore serve as a diagnostic and therapeutic biomarker of IR injury. In this study, poly(boronated methacrylate) (pBMA) nanoparticles were developed as nanotheranostic agents for renal IR injury, which not only generate CO2 bubbles to enhance the ultrasound contrast but also provide potent preventive effects in a H2O2-triggered manner. The surface of pBMA nanoparticles was decorated with taurodeoxycholic acid (TUDCA) that binds P-selectin overexpressed in inflamed tissues. In the mouse model of renal IR injury, TUDCA-coated pBMA (T-pBMA) nanoparticles preferentially accumulated in the injured kidney and markedly enhanced the ultrasound contrast. T-pBMA nanoparticles also effectively prevented renal IR injury by scavenging H2O2 and suppressing the expression of inflammatory cytokines. Treatment progress of IR injury could be also monitored by echogenic T-pBMA nanoparticles. Given their targeting ability, excellent H2O2-responsiveness, anti-inflammatory activity and H2O2-triggered echogenicity, T-pBMA nanoparticles have excellent translational potential for the management of various H2O2-related diseases including IR injury.