aq4n and Breast-Neoplasms

Hypoxia, or a lack of oxygen, occurs in 50-60% of solid human tumours. Clinical studies have shown that the presence and extent of hypoxia in a tumour cannot be predicted by size or histopathological stage but it is predictive of a poor outcome following radiotherapy, chemotherapy and surgery. However, as a physiological feature of tumours, it can be exploited and researchers have developed many hypoxia-selective chemotherapies or bioreductive drugs that are in varying stages of clinical development. These agents are prodrugs that have two key requirements for their biological activation: they require the reductive environment of a hypoxic tumour cell and the appropriate complement of cellular reductase enzymes. To overcome tumour heterogeneity in reductase enzyme levels and enhance bioreductive drug metabolism a gene therapy strategy can be employed. We have reviewed this field and also present our own pre-clinical research using gene therapy to enhance bioreductive drug treatment for the treatment of cancer. We have specifically focused on studies enhancing lead clinical bioreductive drugs. We consider the metabolic requirements for their activation and we highlight the key in vivo studies supporting the future clinical development of hypoxia-targeted gene-directed enzyme prodrug therapy.

Topics: Alkylating Agents; Animals; Anthraquinones; Breast Neoplasms; Cytochrome P-450 Enzyme System; Cytochromes; Cytochromes b5; Female; Genetic Therapy; Humans; Hypoxia; Hypoxia-Inducible Factor 1; Mice; Mitomycin; Neoplasms; Nitric Oxide Synthase; Prodrugs; Xanthine Oxidase

The hypoxic microenvironment promotes tumor resistance to most treatments, especially highly oxygen-dependent sonodynamic therapy (SDT).. In view of the aggravation of hypoxia by oxygen consumption during SDT, a biomimetic drug delivery system was tailored to integrate SDT with hypoxia-specific chemotherapy. In this system, mesoporous titanium dioxide nanoparticles (mTNPs) were developed to deliver the hypoxia-activated prodrug AQ4N with high loading efficiency. Subsequently, a red blood cell (RBC) membrane was coated onto the surface of mTNP@AQ4N. RBC-mTNPs@AQ4N inherited the immune escape ability from RBC membranes, thus efficiently reducing the immunological clearance and improving the work concentration. Upon activation by ultrasound (US), mTNPs as sonosensitizers generate reactive oxide species (ROS), which not only induce apoptosis and necrosis but also disrupt RBC membranes to achieve the US-mediated on-demand release of AQ4N. The released AQ4N was activated by hypoxia to convert into toxic products, which effectively supplemented the inefficiency of SDT in hypoxic tissues. Importantly, SDT-aggravated hypoxia further potentiated this hypoxia-specific chemotherapy of AQ4N.. Based on the sequential strategy, RBC-mTNPs@AQ4N exhibited an excellent synergistic therapeutic effect, thus potentially advancing the development of SDT in cancer treatments.

Topics: Animals; Anthraquinones; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Drug Delivery Systems; Erythrocyte Membrane; Female; Humans; MCF-7 Cells; Mice, Inbred BALB C; Nanoparticles; Porosity; Reactive Oxygen Species; Titanium; Tumor Hypoxia; Ultrasonic Therapy; Xenograft Model Antitumor Assays