The assignee for this patent application is
Reporters obtained the following quote from the background information supplied by the inventors: "Adequate supplies of oxygen are essential for the normal functioning of all multicellular organisms/metazoan species. The principle energy source for the majority of cellular processes is adenosine triphosphate (ATP). Oxidative phosphorylation is the process by which cells generate ATP from the catabolism of glucose and fatty acids, and the oxygen molecule is the metabolic substrate for this cellular respiration, acting as the terminal electron acceptor.
"Low cellular oxygen concentrations, known as hypoxia, can compromise cell function and lead to cell death and tissue damage. However, oxygen molecules are potentially toxic, since they can cause oxidative damage to macromolecules within the cell. The control of oxygen homeostasis is thus essential for maintaining cellular and therefore whole organism viability.
"The physiological oxygen tension within healthy human tissue varies according to the organ, but generally lies within the range 20-120 mmHg. Cells in different tissues experience different oxygen tensions. Cells within one tissue experience a range of oxygen tensions, depending on both distance from the nearest blood supply (the diffusion distance of oxygen through tissue is estimated to be around 150 .mu.m) and the oxygenation status of that blood supply. For instance, the pressure of O.sub.2 of the blood supply to the liver ranges from 95-105 mmHg in the hepatic artery, 50-65 mmHg in the portal vein, 35-45 mmHg in the sinusoids and 30-40 mmHg in the central vein. The different oxygen tensions that each cell experiences in a healthy liver are all perceived as normal. Indeed, the oxygen gradient along the sinusoid is the regulatory factor which creates the zonation of metabolic functioning within the sinusoid. Sensitive and adaptive mechanisms for sensing intracellular oxygen concentrations and responding to change are vital in order to maintain oxygen homeostasis. Adaptations to fluctuating oxygen levels need to be flexible and capable of responding to subtle changes.
"Hypoxia occurs when oxygen tensions are .ltoreq.7 mmHg, usually as a result of decreased partial pressure of oxygen in the blood (hypoxeamia) or a decrease in the oxygen carrying capacity of the blood (anaemia). Molecular responses to hypoxia result in the increased expression of genes involved in adaptations to hypoxia, and the promotion of a range of physiological responses and adaptations that allow cells to survive in a hypoxic environment. These target genes play critical roles in angiogenesis, metabolism, cell proliferation and cell survival. The master regulator of adaptations to hypoxia is the transcription factor hypoxia-inducible factor (HIF). FIG. 1 is schematic showing that as the oxygen levels supplying the tumour decrease consequently the presence of growth factors increase as the tumour becomes hypoxic and hence increases in size.
"Given the adverse metabolic changes that occur within tissues when they experience hypoxia, there is an opportunity to develop smart drug delivery systems that modulate release of active compounds in response to the hypoxic environment that may combat these changes. There has been an increasing interest in stimuli-responsive polymers, particularly in the fields of controlled and self-regulated drug delivery. Delivery systems based on these polymers are developed to closely resemble the normal physiological processes of the diseased state, ensuring optimum drug release according to the physiological need. Polymer architectures have been developed that exhibit a large change in their physico-chemical behaviours in response to minor signals from the environments and have been used in the fabrication of potentially useful materials for pharmaceutical and biomedical applications. The most advanced stimuli-responsive drug delivery systems have also explored a new strategy to design targeted delivery systems to treat complex diseases like cancer and related tumours.
"The interconversion of thiols and disulfides is an important biological process with regard to conformational integrity of many proteins. Polymers that contain disulfide functionality can be considered both redox and thiol responsive as they will undergo reversible conversion by both mechanisms (see Meng, F. et al, Reduction-sensitive polymers and bioconjugates for biomedical applications, Biomaterials. 30, (2009), 2180-2198). Glutathione (GSH) is a naturally occurring reducing agent, abundantly present in most cells at a concentration of 10 mM, some 5000 times higher than its extracellular levels, which provides a mechanism for triggering a response within the cellular environment. Moreover, hypoxic tumours are known to possess a reductive environment, whereby NAD(P)H dependent cytochrome P450s and other haemoproteins in hypoxic conditions mediate two-electron reduction of a wide range of substrates. This is the basis of some bioreductive drugs, such as those containing low toxicity N-oxides which can be converted to respective tertiary amines that possess antitumour activity, such as banoxantrone (AQ4.fwdarw.AQ4N conversion under hypoxia.
"Oupicky has described poly-L-lysine systems containing disulfide bonds which are reducible in the intracellular environment, providing a mechanism to facilitate DNA release and increasing transfection efficiency by 60-fold (Oupicky, D., Design and development strategies of polymer materials for drug and gene delivery applications, Advanced Drug Delivery Reviews, 60, (2008) 957).
"Microsphere compositions with disulfide cross-links have been described whereby the microspheres are composed of proteins. For instance, Mak et al report a non-chemical cross-linking method used to produce pure protein microparticles with an innovative approach, so-called protein activation spontaneous and self-assembly (PASS). This fabrication of protein microparticles is based on the idea of using the internal disulfide bridges within protein molecules as molecular linkers to assemble protein molecules into a microparticle form. The assembly process is triggered by an activating reagent-dithiothreitol (DTT), which is only involved in the intermediate step without being incorporated into the resulting protein microparticles (
"Biodegradable polymeric microcapsules based on thiol-disulfide chemistry have been described. Zelikin et al prepared poly(methacrylic acid) (PMA) cross-linked with disulfides by layer-by-layer deposition of thiolated PMA (PMASH) and poly(vinylpyrollidone) (PVP) on silica particles, followed by oxidation of the thiols to cross-link the PMA and removal of the silica and PVP by changing the pH to disrupt hydrogen bonding and form a capsular structure. (Zelikin, A. N., et al., Disulfide cross-linked polymer capsules: en route to biodeconstructible systems, Biomacromolecules, 7, (2006), 27-30).
"Others have described the development an oral thiomer-based microparticulate delivery systems for insulin by ionic gelation (Greimel A., et al., Oral peptide delivery: in vitro evaluation of thiolated alginate/poly(acrylic acid) microparticles,
"Similarly, a novel mucoadhesive microparticulate drug delivery system has been reported (Bemkop-Schnurch A., et al. Preparation and in vitro characterization of poly(acrylic acid)-cysteine microparticles, J. Controlled Release, 18, (2003), 29-38). Microparticles were prepared by the solvent evaporation emulsion technique using a poly(acrylic acid)-cysteine conjugate of an average molecular mass of 450 kDa with an amount of 308 micromol thiol groups per gram polymer.
"Yan et al. describe the use of the 3 micron diameter PMASH microcapsules described previously for loading doxorubicin and delivering the drug to colon cancer cells in vitro (Yan, Y., et al., Uptake and Intracellular fate of disulfide-bonded polymer hydrogel capsules for doxorubicin delivery to colorectal cancer cells, ACS Nano, 4, (2010), 2928-36). No demonstration of the redox-triggered release of the drug, however, is presented in the paper.
"It is disclosed in EP 1007101 A2 that polymer microspheres can be useful in the treatment of embolisation. Embolisation involves the introduction of embolic agents into the arteries feeding a tumour to starve it of its nutrients and oxygen. Drug eluting beads have been developed which in addition to the ischemia induced by the device, administer a concomitant dose of a chemotherapeutic drug, locally to the tumour in a sustained fashion, reducing systemic exposure and maximising drug levels in the tumour (see, for instance, WO 04/071495). There is evidence from pre-clinical tumour models, that embolisation alone may induce hypoxia in the tumour which in turn can initiate a number of pro-survival pathways via activation of hypoxia-inducible factor 1.alpha. (HIF-1.alpha.), leading to a more malignant phenotype with increased drug resistance and pro-angiogenic responses (Liang, B., et al., Correlation of hypoxia-inducible factor 1 alpha with angiogenesis in liver tumors after transcatheter arterial embolisation in an animal model, CVIR, 33, (2010) 806-812).
"The prior art has failed to disclose the use of hydrogel microparticles or microspheres containing disulfide groups for the controlled delivery of drugs in hypoxic environments."
In addition to obtaining background information on this patent application, NewsRx editors also obtained the inventors' summary information for this patent application: "In accordance with a first aspect of the invention, there are provided microparticles comprising a gel body, wherein the get body comprises a synthetic polymer and a drug, wherein the microparticles have an average diameter in the range 40 to 1500 .mu.m, wherein the polymer is cross-linked by groups comprising disulfide linkages and is in the form of a hydrogel.
"In accordance with a second aspect of the invention, there are provided microparticles for use in a method of treatment by embolisation, wherein the microparticles comprise a polymer and a drug, wherein the polymer is cross-linked by groups comprising disulfide linkages, and in the treatment drug is released.
"In accordance with a third aspect there are provided microparticles having an average diameter in the range 40-1200 .mu.m comprising a polymer and a drug, wherein the polymer is cross-linked by groups comprising disulfide linkages, and the polymer is a vinyl alcohol polymer.
"In accordance with a fourth aspect there are provided microparticles having an average diameter in the range 40-1200 .mu.m comprising a polymer and a cationically charged drug, wherein the polymer is cross-linked by groups comprising disulfide linkages, wherein each cross-linking group comprises 2 anionically charged groups arranged symmetrically about the disulfide unit, wherein said anionically charged groups are electrostatically associated with the drug.
"In accordance with a fifth aspect there are provided microparticles having an average diameter in the range 40-1200 .mu.m comprising a polymer and a drug, wherein the polymer is cross-linked by groups comprising disulfide linkages, for use in a method of treatment of a tumour.
"The present invention provides a novel drug delivery system useful in the chemoembolotherapy of solid tumours. The system is composed of polymer microparticles containing disulfide cross-links within the structure. The rate of drug release from the microparticles is altered when the tumour becomes hypoxic, leading to an increased release of drug as the disulfide cross-links cleave within the reductive environment of the tumour. The present invention may be used for the local targeting or tumours by either direct intratumoural administration or delivery into the tumour vasculature via an intra-arterial route."
For more information, see this patent application: Ashrafi, Koorosh; Lewis,
Keywords for this news article include: Ions, Alcohols, Cysteine, Genetics, Hydrogel, Oncology, Treatment, Chalcogens, Disulfides, Electrolytes, Sulfur Amino Acids, Cancer Gene Therapy, Inorganic Chemicals, Neutral Amino Acids, Polyethylene Glycols, Sulfhydryl Compounds, Drug Delivery Systems,
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