A Water-Soluble Polymer-Lumefantrine Conjugate for the Intravenous Treatment of Severe Malaria.

Uncomplicated malaria is effectively treated with oral artemisinin-based combination therapy (ACT). Yet, there is an unmet clinical need for the intravenous treatment of the more fatal severe malaria. There is no combination intravenous therapy for uncomplicated due to the nonavailability of a water-soluble partner drug for the artemisinin, artesunate. The currently available treatment is a two-part regimen split into an intravenous artesunate followed by the conventional oral ACT . In a novel application of polymer therapeutics, the aqueous insoluble antimalarial lumefantrine is conjugated to a carrier polymer to create a new water-soluble chemical entity suitable for intravenous administration in a clinically relevant formulation . The conjugate is characterized by spectroscopic and analytical techniques, and the aqueous solubility of lumefantrine is determined to have increased by three orders of magnitude. Pharmacokinetic studies in mice indicate that there is a significant plasma release of lumefantrine and production its metabolite desbutyl-lumefantrine (area under the curve of metabolite is ≈10% that of the parent). In a Plasmodium falciparum malaria mouse model, parasitemia clearance is 50% higher than that of reference unconjugated lumefantrine. The polymer-lumefantrine shows potential for entering the clinic to meet the need for a one-course combination treatment for severe malaria.

Anti-Cancer and Immunomodulatory Activity of a Polyethylene Glycol-Betulinic Acid Conjugate on Pancreatic Cancer Cells.

Drug delivery systems involving polymer therapeutics enhance drug potency by improved solubility and specificity and may assist in circumventing chemoresistance in pancreatic cancer (PC). We compared the effectiveness of the naturally occurring drug, betulinic acid (BA), alone and in a polymer conjugate construct of polyethylene glycol (PEG), (PEG-BA), on PC cells (MIA PaCa-2), a normal cell line (Vero) and on peripheral blood mononuclear cells (PBMCs). PEG-BA, was tested for its effect on cell death, immunomodulation and chemoresistance-linked signalling pathways. The conjugate was significantly more toxic to PC cells (p < 0.001, IC50 of 1.35 ± 0.11 µM) compared to BA (IC50 of 12.70 ± 0.34 µM), with a selectivity index (SI) of 7.28 compared to 1.4 in Vero cells. Cytotoxicity was confirmed by increased apoptotic cell death. PEG-BA inhibited the production of IL-6 by 4-5.5 fold compared to BA-treated cells. Furthermore, PEG-BA treatment of MIA PaCa-2 cells resulted in the dysregulation of crucial chemoresistance genes such as WNT3A, TXNRD1, SLC2A1 and GATA3. The dysregulation of chemoresistance-associated genes and the inhibition of cytokines such as IL-6 by the model polymer construct, PEG-BA, holds promise for further exploration in PC treatment.

Synthesis, characterization of copper oxide-gold nanoalloys and their peroxidase-like activity towards colorimetric detection of hydrogen peroxide and glucose.

Bimetallic copper oxide-gold nanoalloys (CuO-Au nanoalloys) have been prepared and characterized using various techniques confirming their successful synthesis. The peroxidase-like activity of CuO-Au nanoalloys have been investigated and applied towards the colorimetric detection of glucose. CuO-Au nanoalloys as nanoenzymes exhibited peroxidase-like properties which occurred by generating the reactive oxygen species (ROS) due to the catalytic properties of CuO-Au nanoalloys.The generation of ROS was confirmed using radical and/or reactive oxygen species quenching properties of 1,3­diphenylisobenzofuran (DPBF). The rate of production of ROS was higher when CuO-Au nanoalloys were present in a solution containing DPBF and H2O2 (0.1092 min-1). The absorption peak of DPBF at 430 nm decreased confirming the generation of ROS. The CuO-Au nanoalloys were evaluated their potential use for colorimetric detection of glucose. The detection limit for glucose was obtained to be 6.75 µM. The detection of glucose took place in two steps and at different pH conditions, first glucose oxidation by glucose oxidase occurred in physiological pH (7.4) at 37 °C. The optimum conditions for the CuO-Au nanoalloys peroxidase-like activity were obtained at pH 4 and 25 °C. The chromogen, TMB (3,3',5,5'­tetramethylbenzidine) oxidation to blue coloured product TMBDI (3,5,3',5'­tetrabenzidinediimine) occurred with high intensity obtained after 6 min.

Nanomedicines for Malaria Chemotherapy: Encapsulation vs. Polymer Therapeutics.

Malaria is one of the oldest infectious diseases that afflict humans and its history extends back for millennia. It was once prevalent throughout the globe but today it is mainly endemic to tropical regions like sub-Saharan Africa and South-east Asia. Ironically, treatment for malaria has existed for centuries yet it still exerts an enormous death toll. This contradiction is attributed in part to the rapid development of resistance by the malaria parasite to chemotherapeutic drugs. In turn, resistance has been fuelled by poor patient compliance to the relatively toxic antimalarial drugs. While drug toxicity and poor pharmacological potentials have been addressed or ameliorated with various nanomedicine drug delivery systems in diseases like cancer, no clinically significant success story has been reported for malaria. There have been several reviews on the application of nanomedicine technologies, especially drug encapsulation, to malaria treatment. Here we extend the scope of the collation of the nanomedicine research literature to polymer therapeutics technology. We first discuss the history of the disease and how a flurry of scientific breakthroughs in the latter part of the nineteenth century provided scientific understanding of the disease. This is followed by a review of the disease biology and the major antimalarial chemotherapy. The achievements of nanomedicine in cancer and other infectious diseases are discussed to draw parallels with malaria. A review of the current state of the research into malaria nanomedicines, both encapsulation and polymer therapeutics polymer-drug conjugation technologies, is covered and we conclude with a consideration of the opportunities and challenges offered by both technologies.