Tumor-targeted and stimulus-responsive polymeric prodrug nanoparticles to enhance the anticancer therapeutic efficacy of doxorubicin.

Polymeric prodrug nanoparticles have gained increasing attention in the field of anticancer drug delivery because of their dual functions as a drug carrier and a therapeutic agent. Doxorubicin (DOX) is a highly effective chemotherapeutic agent for various cancers but causes cardiotoxicity. In this work, we developed polymeric prodrug (pHU) nanoparticles that serve as both a drug carrier of DOX and a therapeutic agent. The composition of pHU includes antiangiogenic hydroxybenzyl alcohol (HBA) and ursodeoxycholic acid (UDCA), covalently incorporated through hydrogen peroxide (H2O2)-responsive peroxalate. To enhance cancer cell specificity, pHU nanoparticles were surface decorated with taurodeoxycholic acid (TUDCA) to facilitate p-selectin-mediated cancer targeting. TUDCA-coated and DOX-loaded pHU nanoparticles (t-pHUDs) exhibited controlled release of DOX triggered by H2O2, characteristic of the tumor microenvironment. t-pHUDs also effectively suppressed cancer cell migration and vascular endothelial growth factor (VEGF) expression in response to H2O2. In animal studies, t-pHUDs exhibited highly potent anticancer activity. Notably, t-pHUDs, with their ability to accumulate preferentially in tumors due to the p-selectin targeting, surpassed the therapeutic efficacy of equivalent DOX and pHU nanoparticles alone. What is more, t-pHUDs significantly suppressed VEGF expression in tumors and mitigated hepato- and cardiotoxicity of DOX. Given their cancer targeting ability, enhanced therapeutic efficacy and minimized off-target toxicity, t-pHUDs present an innovative and targeted approach with great translational potential as an anticancer therapeutic agent.

Acid-sensitive stable polymeric micelle-based oxidative stress nanoamplifier as immunostimulating anticancer nanomedicine.

Oxidative stress amplifying compounds could elicit selective killing of cancer cells with minimal toxicity to normal cells and also induce immunogenic cell death (ICD). However, compared to conventional anticancer drugs, oxidative stress amplifying compounds have inferior therapeutic efficacy. It can be postulated that the anticancer therapeutic efficacy and immunostimulating activity of oxidative stress amplifying hybrid prodrug (OSamp) could be fully maximized by employing ultrastable polymeric micelles as drug carriers. In this work, we developed tumour-targeted oxidative stress nanoamplifiers, composed of OSamp, amphiphilic poly(ethylene glycol) methyl ether-block-poly(cyclohexyloxy ethyl glycidyl ether)s (mPEG-PCHGE) and a lipopeptide containing Arg-Gly-Asp (RGD). Tumour targeted OSamp-loaded mPEG-PCHGE (T-POS) micelles exhibited excellent colloidal stability and significant cytotoxicity to cancer cells with the expression of DAMPs (damage-associated molecular patterns). In the syngeneic mouse tumour model, T-POS micelles induced significant apoptotic cell death to inhibit tumour growth without noticeable body weight changes. T-POS micelles also induced ICD and activated adaptive immune responses by increasing the populations of cytotoxic CD4+ and CD8+ T cells. Therefore, these results suggest that T-POS micelles hold great translational potential as immunostimulating anticancer nanomedicine.

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.

H2O2-Activatable Antioxidant Polymeric Prodrug Nanoparticles for the Prevention of Renal Ischemia/Reperfusion Injury.

Renal ischemia-reperfusion (IR) injury is an inevitable complication in various clinical settings including kidney transplantation and major vascular surgeries. Renal IR injury is a major risk factor for acute kidney injury, which still remains a major clinical challenge without effective therapy. The main cause of renal IR injury is the massive production of reactive oxygen species (ROS) including hydrogen peroxide (H2O2) that initiate inflammatory signaling pathways, leading to renal cell death. In this study, we developed fucoidan-coated polymeric prodrug (Fu-PVU73) nanoparticles as renal IR-targeting nanotherapeutics that can rapidly eliminate H2O2 and exert anti-inflammatory and antiapoptotic effects. Fu-PVU73 nanoparticles were composed of H2O2-activatable antioxidant and anti-inflammatory polymeric prodrug (PVU73) that incorporated H2O2-responsive peroxalate linkages, ursodeoxycholic acid (UDCA), and vanillyl alcohol (VA) in its backbone. Fu-PVU73 nanoparticles rapidly scavenged H2O2 and released UDCA and VA during H2O2-triggered degradation. In the study of renal IR injury mouse models, Fu-PVU73 nanoparticles preferentially accumulated in the IR injury-induced kidney and markedly protected the kidney from IR injury by suppressing the generation of ROS and the expression of proinflammatory cytokines. We anticipate that Fu-PVU73 nanoparticles have tremendous therapeutic potential for not only renal IR injury but also various ROS-associated inflammatory diseases.

H2O2-activatable hybrid prodrug nanoassemblies as a pure nanodrug for hepatic ischemia/reperfusion injury.

Self-assembling prodrugs are able to form stable nanoparticles without additional excipients and therefore have gained increasing interest in the field of drug delivery. As a natural derivative of vitamin A, all-trans retinoic acid (atRA) exerts antioxidant, anti-inflammatory, and immunostimulatory effects. However, the clinical translation of atRA has been hampered by its insufficient therapeutic efficacy. In this work, to fully maximize the therapeutic potential of atRA, we developed delicately designed self-assembling RABA (atRA-based hybrid prodrug) as a hybrid prodrug of atRA and hydroxybenzyl alcohol (HBA). RABA could form nanoassemblies and decompose to release atRA and HBA simultaneously in response to hydrogen peroxide (H2O2). In a mouse model of hepatic ischemia/reperfusion (IR) injury, RABA nanoassemblies accumulated in liver preferentially and exerted highly potent antioxidant, anti-inflammatory, and antiapoptotic effects, leading to effective protection of liver from IR injury. RABA nanoassemblies exhibited significantly higher therapeutic efficacy than the combination of equivalent atRA and HBA. Given its H2O2-responsiveness, self-assembling and self-immolating behaviors, and cooperative therapeutic actions, RABA nanoassemblies have great potential as a pure nanodrug for hepatic IR injury. This study also provides a new valuable addition in the development of prodrug self-assemblies that will emerge as next generation of drugs.