Redox nanoparticle increases the chemotherapeutic efficiency of pioglitazone and suppresses its toxic side effects.

Pioglitazone is a widely used anti-diabetic drug that induces cytotoxicity in cancer cells; however, its clinical use is questioned due to its associated liver toxicity caused by increased oxidative stress. We therefore employed nitroxide-radical containing nanoparticle, termed redox nanoparticle (RNP(N)) which is an effective scavenger of reactive oxygen species (ROS) as a drug carrier. RNP(N) encapsulation increased pioglitazone solubility, thus increasing cellular uptake of encapsulated pioglitazone which reduced the dose required to induce toxicity in prostate cancer cell lines. Investigation of in vitro molecular mechanism of pioglitazone revealed that both apoptosis and cell cycle arrest were involved in tumor cell death. In addition, intravenously administered pioglitazone-loaded RNP(N) produced significant tumor volume reduction in vivo due to enhanced permeation and retention effect. Most importantly, oxidative damage caused by pioglitazone in the liver was significantly suppressed by pioglitazone-loaded RNP(N) due to the presence of nitroxide radicals. It is interesting to note that oral administration of encapsulated pioglitazone, and co-administration of RNP(N) and pioglitazone, i.e., no encapsulation of pioglitazone in RNP(N) also significantly contributed to suppression of the liver injury. Therefore, use of RNP(N) either as an adjuvant or as a carrier for drugs with severe side effects is a promising chemotherapeutic strategy.

Redox nanoparticles inhibit curcumin oxidative degradation and enhance its therapeutic effect on prostate cancer.

Curcumin is a phytochemical with diverse molecular targets and is well known for its anti-tumor potential. However, it has limited application in cancer therapy because curcumin undergoes rapid oxidative degradation at physiological conditions resulting in poor stability and bio-availability. In this study, we were able to suppress curcumin's oxidative degradation by encapsulating it in a nanoparticle that also acts as a radical scavenger. We prepared curcumin-loaded pH-sensitive redox nanoparticles (RNP(N)) by self-assembling amphiphilic block copolymers conjugated with reactive oxygen species (ROS) scavenging nitroxide radicals to ensure the delivery of minimally degraded curcumin to target regions. In vitro analysis confirmed that the entrapment of both curcumin and nitroxide radicals in the hydrophobic core of RNP(N) suppressed curcumin degradation in conditions mimicking the physiological environment. Evaluation of apoptosis-related molecules in the cells, such as ceramides, caspases, apoptosis-inducing factor, and acid ceramidase revealed that curcumin loaded RNP(N) induced strong apoptosis compared to free curcumin. Lastly, intravenous injection of curcumin loaded RNP(N) suppressed tumor growth in vivo, which is due to the increased bio-availability and significant ROS scavenging at tumor sites. These results demonstrated that RNP(N) is a promising drug carrier with unique ROS-scavenging abilities, and it is able to overcome the crucial hurdle of curcumin's limitations to enhance its therapeutic potential.

Synthesis and in vitro and in vivo evaluations of poly(ethylene glycol)-block-poly(4-vinylbenzylphosphonate) magnetic nanoparticles containing doxorubicin as a potential targeted drug delivery system.

The main challenge in antitumor chemotherapy is to enhance the curative effect and minimize the adverse effects of an anticancer drug. Administration of functionalized magnetic iron oxide nanoparticles is one of the strategies to improve sensitivity to cancer chemotherapy, and these nanoparticles are attractive materials that have been widely used in medicine for various applications, including diagnostic imaging and therapeutic applications. In this study, we describe the synthesis and characterization of drug-loaded iron oxide nanoparticles. Our aim was to obtain a biocompatible and injectable nanocarrier with anticancer activity. Iron oxide nanoparticles (IONs) were synthesized by alkali co-precipitation of iron salts followed by coating with our original surface modification agent, poly(ethylene glycol)-block-poly(4-vinylbenzylphosphonate) copolymer (PEG-PIONs). An anticancer drug doxorubicin (DOX), which clinical use is associated with cardiotoxicity, was loaded onto PEG-PIONs (PEG-PIONs/DOX), and to the best of our knowledge, this formulation showed higher drug encapsulation efficiency (drug loading capacity of the nanocarrier was 11.7%) than other formulations previously reported. PEG-PIONs/DOX had a hydrodynamic diameter of about 35nm and were stable in biological conditions over a period more than one month and showed stable and continuous in vitro drug release and antiproliferative effects on cancer cells. Fluorescent imaging indicated internalization of the PEG-PIONs/DOX in the cytoplasm of cancer cells. Biodistribution studies showed that PEG-PIONs/DOX preferentially accumulate in the tumor region via enhanced permeability and retention effect. In addition, analysis of the serum levels of enzymes indicated that PEG-PIONs/DOX reduced the cardiotoxicity associated with free DOX. These results indicate that PEG-PIONs/DOX have the potential for targeted delivery of antitumor drugs via systemic administration.

Redox nanoparticle therapeutics to cancer--increase in therapeutic effect of doxorubicin, suppressing its adverse effect.

The ultimate goal of cancer chemotherapy is to achieve a cure without causing any adverse effects. We have developed a pH-sensitive redox nanoparticle (RNP(N)), which disintegrates under acidic conditions and exposes nitroxide radicals, leading to strongly scavenging reactive oxygen species (ROS). After intravenous administration of RNP(N) to tumor bearing mice, it effectively accumulated in tumors due to the leaky neovascular and immature lymphatic system and scavenged ROS, resulting in suppression of inflammation and activation of NF-кB, after disintegration of RNP(N) in the tumors. Pre-administration of RNP(N) prior to treatments with anticancer agents, doxorubicin, to tumor-bearing mice significantly suppressed the progression of tumor size, compared to low-molecular weight 4-hydroxy-TEMPO. Interestingly, the administration of RNP(N) suppressed adverse effects of doxorubicin to normal organs due to the scavenging ROS and suppression of inflammation, which was confirmed by reduction in lactate dehydrogenase and creatine phosphokinase activities in plasma. RNP(N) is thus anticipated as a novel and ideal adjuvant for cancer chemotherapy.

PPARγ disease gene network and identification of therapeutic targets for prostate cancer.

Peroxisome proliferator-activated receptor (PPAR) belongs to the nuclear hormone receptor superfamily. Recently published reports demonstrate the importance of a direct repeat 2 (DR2) as a PPARγ-responsive element in addition to the canonical direct repeat 1 (DR1) Peroxisome proliferator response elements (PPREs). However, a comprehensive and systematic approach to constructing de novo disease-specific gene networks for PPARγ is lacking, especially one that includes PPARγ target genes containing either DR1 or DR2 site within their promoter region. Here, we computationally identified 1154 PPARγ direct target genes and constructed the PPARγ disease gene network, which revealed 138 PPARγ target genes that are associated with 65 unique diseases. The network shows that PPARγ target genes are highly associated with cancer and neurological diseases. Thirty-eight PPARγ direct target genes were found to be involved in prostate cancer and two key (hub) PPARγ direct target genes, PRKCZ and PGK1, were experimentally validated to be repressed upon PPARγ activation by its natural ligand, 15d-PGJ(2) in three prostrate cancer cell lines. We proposed that PRKCZ and PGK1 could be novel therapeutic targets for prostate cancer. These investigations would not only aid in understanding the molecular mechanisms by which PPARγ regulates disease targets but would also lead to the identification of novel PPARγ gene targets.