Technologies for the Treatment of Brain Diseases
Lead Research Organisation:
University College London
Department Name: Pharmaceutics
Abstract
The Grand Challenge is the treatment of brain diseases. Brain diseases span pain, sleep disorders, schizophrenia, mood disorders and neurodegenerative conditions. At any time 450 million persons worldwide are living with mental, neurological or behavioural illnesses and 24 million people worldwide suffer from dementias. The treatment of brain diseases is hampered by the blood brain barrier (BBB), a barrier between the blood and the brain which does not permit the passage of most drug molecules, due to the tightness of the intercellular capillary junctions, low uptake activity of capillary cells and the activity of efflux transporters. Previous attempts to target drugs to the brain and cross the BBB have involved the use of targeting ligands, e.g. mouse monoclonal antibodies for carrier mediated uptake or the inhibition of the above mentioned efflux transporters. However all of the particulate-based strategies (including the use of mouse monoclonal antibodies) that have been investigated over the last two decades have yet to yield any clinical products and the inhibition of the high capacity efflux transporters, which incidentally are not merely confined to the BBB, is not a viable clinical option. Our multidisciplinary consortium drawn from academia and industry (GSK) propose a new nanoscience based strategy founded on two recent significant findings: a) chitosan amphiphile based nanoparticles significantly increase the central activity of hydrophobic and peptides drugs via the intravenous and crucially oral routes, b) apolipoprotein E targeted nanoparticles bypass the brain capillary efflux transporters and cross the BBB, increasing drug delivery to the brain. The project aims to use these data to create an optimised nanotechnology brain delivery platform for peptides and low molecular weight drugs with low brain permeability. These drug classes represent the bulk of the compounds which are trapped in the drug development bottleneck due to: a) their poor brain exposure and b) the absence of suitable brain targeting strategies. Candidate drugs to be used are potential treatments for schizophrenia, pain and sleep disorders. These compounds and their potential indications are particularly relevant to the call (targeting psychiatric diseases) and a specific output of the project is a candidate medicine for the treatment of psychiatric or neurological disorders. The project will involve a significant level of particle engineering, where particle matrix chemistry, surface chemistry (including the discovery and evaluation of other BBB targeting peptides) and particle size will be systematically varied and the impact of these variations tested using in vitro and animal models. The resulting pharmacokinetic, pharmacodynamic and mechanistic data will inform the optimisation of the platform which is the ultimate goal of the project. Fundamentally the mechanism of brain permeation of the drug cargoes will be studied and elucidated en route to the optimised nanosystem and this will also fulfil a requirement of regulators and health providers, who desire an underlying mechanistic basis for new health technologies. Stage 2 of the project (GSK fully supported) will focus on the development of a clinical medicine based on the nanotechnology platform.Public engagement activities will occur via our nanomedicines.org website and also via public communication of science events. The key beneficiaries of the project will be patients, carers and the pharmaceutical industry as the platform will pave the way for novel therapeutic targets to be exploited. The engagement of scientists, with a past history of collaboration and a strong track record in nanoscience innovation, therapeutic target discovery, lead identification, drug targeting, translating scientific concepts to clinical products and basic brain physiology makes the consortium ideally suited to deliver the nanoscience based drug targeting goals of the Grand Challenge.
Publications
Lalatsa A
(2012)
Delivery of peptides to the blood and brain after oral uptake of quaternary ammonium palmitoyl glycol chitosan nanoparticles.
in Molecular pharmaceutics
Santander-Ortega M
(2012)
Hydration forces as a tool for the optimization of core-shell nanoparticle vectors for cancer gene therapy
in Soft Matter
Garrett NL
(2012)
Exploring uptake mechanisms of oral nanomedicines using multimodal nonlinear optical microscopy.
in Journal of biophotonics
Moger J
(2012)
Imaging cortical vasculature with stimulated Raman scattering and two-photon photothermal lensing microscopy
in Journal of Raman Spectroscopy
Siew A
(2012)
Enhanced oral absorption of hydrophobic and hydrophilic drugs using quaternary ammonium palmitoyl glycol chitosan nanoparticles.
in Molecular pharmaceutics
Lalatsa A
(2012)
Amphiphilic poly(L-amino acids) - new materials for drug delivery.
in Journal of controlled release : official journal of the Controlled Release Society
Lalatsa A
(2012)
A prodrug nanoparticle approach for the oral delivery of a hydrophilic peptide, leucine(5)-enkephalin, to the brain.
in Molecular pharmaceutics
Garrett N
(2012)
Label-free imaging of polymeric nanomedicines using coherent anti-stokes Raman scattering microscopy
in Journal of Raman Spectroscopy
Mazza M
(2013)
Nanofiber-based delivery of therapeutic peptides to the brain.
in ACS nano
Torrado JJ
(2013)
The oral delivery of amphotericin B.
in Therapeutic delivery
Cassano R
(2013)
Dextran-pegylated microparticles for enhanced cellular uptake of hydrophobic drugs.
in European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V
Uchegbu IF
(2013)
Nanomedicines and nanodiagnostics come of age.
in Journal of pharmaceutical sciences
Fisusi F
(2013)
Abstract 4519: Lomustine nanoparticles are effective brain cancer treatments.
in Cancer Research
Uchegbu I
(2014)
Chitosan amphiphiles provide new drug delivery opportunities
in Polymer International
Chooi KW
(2014)
Physical characterisation and long-term stability studies on quaternary ammonium palmitoyl glycol chitosan (GCPQ)--a new drug delivery polymer.
in Journal of pharmaceutical sciences
Lalatsa A
(2014)
Strategies to deliver peptide drugs to the brain.
in Molecular pharmaceutics
Santander-Ortega M. J.
(2014)
Optimisation of Synthetic Vector Systems for Cancer Gene Therapy - The Role of the Excess of Cationic Dendrimer Under Physiological Conditions
in CURRENT TOPICS IN MEDICINAL CHEMISTRY
Fisusi F
(2015)
Abstract 5530: Chitosan amphiphile nanoparticles reduced the myelosuppressive effects of lomustine
in Cancer Research
Lalatsa A
(2015)
Chitosan amphiphile coating of peptide nanofibres reduces liver uptake and delivers the peptide to the brain on intravenous administration.
in Journal of controlled release : official journal of the Controlled Release Society
Marimuthu P
(2015)
Abstract 5527: Oral administration of a nano-enabled form of Met-Enkephalin peptide controls pancreatic cancer growth
in Cancer Research
Zakharova L
(2015)
The polyacrylic acid/modified chitosan capsules with tunable release of small hydrophobic probe and drug
in Colloids and Surfaces A: Physicochemical and Engineering Aspects
López-Dávila V
(2016)
Efficacy of DOPE/DC-cholesterol liposomes and GCPQ micelles as AZD6244 nanocarriers in a 3D colorectal cancer in vitro model.
in Nanomedicine (London, England)
Santander-Ortega M
(2016)
Polymers and Nanomaterials for Gene Therapy
Simão Carlos MI
(2017)
Limiting the level of tertiary amines on polyamines leads to biocompatible nucleic acid vectors.
in International journal of pharmaceutics
Bonaccorso A
(2017)
Nose to brain delivery in rats: Effect of surface charge of rhodamine B labeled nanocarriers on brain subregion localization.
in Colloids and surfaces. B, Biointerfaces
Gewin Virginia
(2018)
It takes more than a vow
in NATURE
Godfrey L
(2018)
Nanoparticulate peptide delivery exclusively to the brain produces tolerance free analgesia.
in Journal of controlled release : official journal of the Controlled Release Society
Fisusi FA
(2018)
Nanomedicines in the treatment of brain tumors.
in Nanomedicine (London, England)
Patel S
(2020)
A Self-Assembling Lipidic Peptide and Selective Partial V2 Receptor Agonist Inhibits Urine Production.
in Scientific reports
Soundararajan R
(2020)
Hyaluronidase Coated Molecular Envelope Technology Nanoparticles Enhance Drug Absorption via the Subcutaneous Route.
in Molecular pharmaceutics
Al-Kulabi A
(2021)
Nanoparticulate Mycophenolic Acid Eye Drops - Analytical Validation of a High Performance Liquid Chromatography Assay and Stability Studies.
in Pharmaceutical nanotechnology
He S
(2021)
Down-regulation of GP130 signaling sensitizes bladder cancer to cisplatin by impairing Ku70 DNA repair signaling and promoting apoptosis.
in Cellular signalling
Badr MY
(2021)
A polymeric aqueous tacrolimus formulation for topical ocular delivery.
in International journal of pharmaceutics
Description | The project resulted in the development of oral to brain peptide delivery pharmaceutical nanotechnology and the discovery that peptide nanofibres could be used to deliver peptides to the brain. The project also uncovered mechanistic insights into these two technologies. |
Exploitation Route | Nanomerics aims to become a multimillion pound company with its own pharmaceutical products based on its Molecular Envelope Technology and also aims to form partnerships with drug discovery companies in order to enable difficult molecules to transition into the clinic. Founded Nanomerics Ltd (Company Number = 073730430) in September 2010. Attracted a TSB grant (101163) into Nanomerics for the development of METDoloron, an oral neuropeptide medicine for the treatment of chronic neuropathic pain. Has signed deals with partner pharmaceutical companies for paid for feasibility work and an option to licence. |
Sectors | Healthcare |
URL | http://www.nanomerics.com |
Description | The findings support the use of innovative polymer for drug development by Nanomerics Ltd. |
First Year Of Impact | 2013 |
Sector | Healthcare |
Impact Types | Economic |
Description | Technology Strategy Board |
Amount | £1,550,000 (GBP) |
Funding ID | 16939-124181 |
Organisation | Innovate UK |
Sector | Public |
Country | United Kingdom |
Start | 07/2012 |
End | 07/2014 |
Title | DELIVERY OF DRUGS |
Description | The present invention relates to a composition comprising a hydrophilic drug and an amphiphilic carbohydrate compound for use in therapy wherein the composition is intranasally administered to the human or animal body. The composition can be used to treat a variety of disorders, including schizophrenia, obesity, pain and sleep disorders, psychiatric diseases, neurodegenerative conditions, brain cancers and infective diseases. |
IP Reference | WO2015063510 |
Protection | Patent application published |
Year Protection Granted | 2015 |
Licensed | No |
Impact | This discovery will enable the delivery of peptides to the brain. |
Title | DELIVERY OF HYDROPHILIC PEPTIDES |
Description | A composition comprises nanofibres for the delivery of a peptide across the blood brain barrier in a method of therapy of the human or animal body, wherein the nanofibres comprise a peptide conjugated to a lipophilic group. Further, a compound comprises a Dalargin or a derivative having one or more substituted, deleted or inserted aminoacyl units, and, conjugated to an aminoacyl group preferably via a side chain, a lipophilic group, optionally via a linker. |
IP Reference | WO2012004610 |
Protection | Patent granted |
Year Protection Granted | 2012 |
Licensed | Yes |
Impact | This intellectual property has been licensed to Nanomerics Ltd. |
Title | POLYMERIC MICELLAR CLUSTERS AND THEIR USES IN FORMULATING DRUGS |
Description | Polymeric micellar clusters formed from amphiphilic carbohydrate polymers and their uses in formulating drugs is disclosed, and in particular the finding that amphiphilic carbohydrate polymers are capable of self assembling to form micellar clusters in which the carbohydrate amphiphiles aggregate into hierarchically organised micellar clusters of individual aggregates. The micellar clusters may be transformed into stable nanoparticles with drugs, especially hydrophobic drugs that have poor aqueous solubility, and may improve the transfer of hydrophobic drugs across biological barriers. |
IP Reference | US2010159014 |
Protection | Patent granted |
Year Protection Granted | 2010 |
Licensed | Yes |
Impact | This technology underpins the UCL spin out company Nanomerics Ltd. |
Company Name | Nanomerics |
Description | Nanomerics develops a nanoparticle drug delivery system designed to facilitate the delivery of hydrophobic pharmaceutical products via ocular, oral and nose-to-brain routes. |
Year Established | 2010 |
Impact | The company is now attracting revenues and will turn over £0.5 M in 2013. |
Website | http://www.nanomerics.com |