New Nanoscale Drug Delivery Systems and their Application to HIV/AIDS treatment

Lead Research Organisation: University of Liverpool
Department Name: Chemistry

Abstract

HIV/AIDS is described by the World Health Organisation as a global pandemic. Estimates show that over 25 million people have died since 1981 and over 33 million people including adults and children are currently living with the disease. In 2005, AIDS claimed an estimated 3.3 million lives globally, including more than 570,000 children. The prevalence of HIV/AIDS continues to increase and it is expected that over 90 million will ultimately be infected in Africa alone. The UK had the highest growth in HIV/AIDS infection in western Europe in the period between 2001 - 2007 with a 64% increase.

HIV treatment suffers from many issues including the need for patient compliance with a very strict regime of medication. HIV mutation leads to resistance to existing therapies but the ability of therapies to target HIV in the body is critical to the success of medication. HIV resides in various sites throughout the body but there are both cellular and tissue sites which are particularly difficult for drugs to reach. These so called 'sanctuary sites' have the potential to be targeted by particles of drug, rather than dissolved drug molecules.

Cancer research has shown the benefits of particulate nanomedicine drug delivery approaches. The use of nanoscale polymer carriers which act as vehicles to transport and deliver poorly soluble drugs to the desired site of action, has been beneficial for tumour targeting as the particle nature of the nanomedicine drives the accumulation in tumour tissues. Cellular and tissue sanctuary sites in HIV infection have been widely speculated to also be ideal candidates for particle-based approaches but there has been limited work in this area.

Branched polymers may operate as particle-like drug delivery vehicles and many have been shown to have therapeutic advantages. The best materials are however very expensive to synthesise and would not be viable for treatments in populations such as the sub-Saharan regions (over 20 milllion HIV infections) where cost is a critical component of treatment choice. The University of Liverpool has developed a new class of materials, Polydendrons, that offer many of the benefits of the most sophisticated branched polymers, but can be produced relatively cheaply. In early work, prototype materials have been produced with particle sizes of >40nm and encapsulation capabilities. These materials are unique and still at a very early stage of development.

This proposal will simultaneously explore the synthesis of Polydendrons and their ability to intervene in HIV treatments. They will be studied as drug carriers of specific size, shape and surface functionality and their ability to target HIV in sanctuary sites will be established. A collaboration between the departments of Chemistry and Molecular and Clinical Pharmacology over 4.5 years is proposed with input from global pharmaceutical companies and HIV clinicians. This approach of material synthesis with integrated pharmacology will considerably accelerate the development of potential new therapies leading to a leading position for the UK that will be applicable to other health issues such as cancer, tuberculosis and hepatitis C.

Planned Impact

The key focus of the proposal is the introduction of a new material class and the demonstration of its utility in nanomedicine approaches - initially in improving HIV therapies. Additionally the programme will establish the British Society for Nanomedicine at a highly timely stage in the global investigation of nanotechnology in future therapy development.

The beneficiaries of the research therefore fall into a number of groups including scientists, clinicians, general public, patients and industry.

The introduction of a new class of materials has been shown many times to ignite new research concepts in fields that often span disciplines that are far removed from the original published concepts. The materials within this proposal are derived from branched polymers and this particular class of materials has shown many times that breakthroughs and new ideas may lead to new companies, commercial impact in existing industries (medicine/engineering/ nanotechnology/data storage/coatings to name a few) and enhance ongoing research programmes.

Within the field of nanomaterials and nanomedicine, a series of ongoing societal and governmental debates are discussing the safety and application of nanoscale technologies. Uniquely, this programme aims to introduce new nanomaterials, simultaneously evaluate the pharmacology and toxicology of the materials and establish the British Society for Nanomedicine to facilitate contact between researchers, academics/industry and regulators and engagement with the public. Collectively, this will have impact across pharmacology research, drug delivery, polymer materials and nanomaterials researchers. Importantly this proposal seeks to engage with regulatory authorities and generate real data that may impact future policy. We also aim to interact internationally to coordinate nanomedicine activities focussed on drug delivery.

The programme aims to generate therapy options that will be commercially protected and attractive for industrial exploitation. With the correct conversion of therapy options into medicines, the potential impact will spread to clinicians and HIV patients (in the first instance) to improve the care and outcomes within a disease that currently has killed over 25 million people and has 33 million living with HIV. The scale of the potential high impact on HIV patients arises from the need for high levels of patient compliance with therapies that require multiple pills to be taken several times each day over a lifetime. A positive impact on either the required dose of existing drugs, the number of tablets or the number of different drugs used would improve the quality of life for a large number of patients.

The materials proposed are covered by a patent filing that is owned by the University of Liverpool. It is expected that many more patents will flow that potentially will generate a significant commercial opportunity for the UK, initially through a spin-out company and later through production of medicine for international health benefits.

The project seeks to generate convincing chemical and pharmacological data over a 4.5 year period to allow commercial uptake towards the end of the programme. It is important to note that NO NEW DRUGS are being developed and therefore the new delivery vehicles may be seen as excipients for future drugs in mutliple disease areas. It is hoped that within 10 years of the start date, and supported by the critical early data and follow on research, Polydendrons may see themselves in early clinical trials.

Overall, the research proposed has the potential for multiple areas of impact. The researchers employed for the project will be highly trained during the research through exposure to multiple disciplines and therefore be extremely employable on conclusion of this initial research.

Publications

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Alhilfi Tamara (2012) Synthesis of branched polymers by direct one-pot ambient-temperature "living" anionic polymerisation in ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY

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Alhilfi Tamara (2012) Synthesis of branched polymers by direct one-pot ambient-temperature "living" anionic polymerisation in ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY

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Cauldbeck H (2016) Controlling drug release from non-aqueous environments: Moderating delivery from ocular silicone oil drug reservoirs to combat proliferative vitreoretinopathy. in Journal of controlled release : official journal of the Controlled Release Society

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Cauldbeck H (2018) Modulated release from implantable ocular silicone oil tamponade drug reservoirs. in Journal of polymer science. Part A, Polymer chemistry

 
Description A new material platform has been developed that has the potential as a new nanomedicine carrier of drugs
Exploitation Route The materials has been licenced to a third party company non-exclusively and also form part of the portfolio for a UoL spinout company
Sectors Agriculture, Food and Drink,Chemicals,Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description The results have generated considerable industrial impact and discussions with several companies across disparate market sectors. Further funding has been received to study the use of the materials in cancer therapies
First Year Of Impact 2016
Sector Agriculture, Food and Drink,Chemicals,Healthcare,Pharmaceuticals and Medical Biotechnology
Impact Types Societal

 
Description Membership of Innovate UK Emerging Technologies and Industries Steering Committee
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
 
Description CRUK Multidisciplinary award
Amount £1,054,422 (GBP)
Funding ID 21094 
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2016 
End 09/2020
 
Description Innovate UK Open Funding Call
Amount £179,180 (GBP)
Organisation Innovate UK 
Sector Public
Country United Kingdom
Start 04/2017 
End 04/2018
 
Description MRC Funding for Imaging
Amount £914,582 (GBP)
Funding ID MR/K015931/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start  
 
Description National Institutes of Health (US)
Amount £2,100,000 (GBP)
Funding ID R01AI134091 
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start 07/2018 
End 06/2023
 
Description New Branched Polymers Excipients and Emulsions for Enhanced Drug Delivery
Amount £1,660,068 (GBP)
Funding ID EP/R024804/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 07/2018 
End 06/2022
 
Description Brazil 
Organisation Federal University of Santa Maria
Country Brazil 
Sector Academic/University 
PI Contribution Hosted a visiting scientist from Departamento de Ciências Farmacêuticas, Universidade Federal de Santa Catarina P.O. Box 476, Florianópolis, SC, 88040-900, Brazil to undertake the evaluation of novel nanomaterials intended for drug delivery strategies. The Liverpool team provided hands on training and direct research relating to in vitro immunological characterisation, in vitro drug disposition assays and physiologically-based pharmacokinetic modelling. The collaboration has resulted in two publications.
Collaborator Contribution Adny Silva spent a period of 8 months at Liverpool learning various assays for pre-clinical assessment of nanomaterials that were generated by her and her colleagues in Departamento de Ciências Farmacêuticas, Universidade Federal de Santa Catarina P.O. Box 476, Florianópolis, SC, 88040-900, Brazil. The Brazilian collaborators therefore generated the materials and helped characterise them in Liverpool. They also co-wrote the two publications.
Impact Silva AH, Locatelli C, Filippin-Monteiro FB, Martin P, Liptrott NJ, Zanetti-Ramos BG, Benetti LC, Nazari EM, Albuquerque CA, Pasa AA, Owen A, Creczynski-Pasa TB. Toxicity and inflammatory response in Swiss albino mice after intraperitoneal and oral administration of polyurethane nanoparticles. Toxicol Lett. 2016 Mar 30;246:17-27. doi: 10.1016/j.toxlet.2016.01.018. Epub 2016 Jan 25.
Start Year 2014
 
Description EU Nanocharacterisation Laboratory 
Organisation University of Glasgow
Department English Language
Country United Kingdom 
Sector Academic/University 
PI Contribution The University of Liverpool team provide critical expertise developed through EPSRC grant funded activity, to the Horizon 2020 funded European Nanocharcterisation Laboratory
Collaborator Contribution Additional input from multiple EU partners to characterise candidate nanomedicines
Impact No outputs as yet
Start Year 2015
 
Description Industrial collaboration on polymers from multi vinyl monomers (degradable consumer products) 
Organisation Croda Europe Ltd
Country United Kingdom 
Sector Private 
PI Contribution Materials synthesised for evaluation
Collaborator Contribution Project review and in-house materials evaluation
Impact Materials evaluated for a range of applications
Start Year 2018
 
Description Study of process and materials innovation for potential benefits 
Organisation INEOS Chlor Vinyls
Country United Kingdom 
Sector Private 
PI Contribution Materials studied, and produced for internal evaluation
Collaborator Contribution Pilot scale polymer synthesis using novel additives, evaluation of products and reporting
Impact Materials have been seen to be of interest
Start Year 2018
 
Title BRANCHED POLYESTER CARRYING DENDRONS 
Description Branched polyesters carrying dendrons are a useful class of nanomaterials which exhibit good handling properties and stability, can degrade to a high extent, and are effective encapsulation materials. They can be used to make nanoprecipitated particles which may for example be used in therapy. Furthermore, these materials can be synthesised by economical and tailorable processes. The materials can be prepared by the ring-opening polymerisation (ROP) of monofunctional lactone monomers and difunctional lactone monomers, using dendron initiators. 
IP Reference WO2017118842 
Protection Patent application published
Year Protection Granted 2017
Licensed No
Impact None as yet
 
Title BRANCHED POLYMERS 
Description The present invention relates to a branched amphiphilic polymer, suitable for stabilizing an emulsion, comprising a plurality of polymer chains comprising hydrophobic chain ends; a plurality of polymer chains comprising functional chain ends capable of associating to a biological substrate; and a plurality of branching units. The present invention also relates to pharmaceutical compositions containing said branched amphiphilic polymers, their methods of use, and methods for their preparation. 
IP Reference WO2018029462 
Protection Patent application published
Year Protection Granted 2018
Licensed No
Impact None as yet but ongoing discussions
 
Title Branched polyester carrying dendrons 
Description The invention relates to a product which is a branched polyester carrying dendrons. The invention also relates to a method of prepg. a branched polyester carrying dendrons, comprising ring-opening polymn. (ROP) of a monofunctional lactone monomer and a difunctional lactone monomer, using a dendron initiator. A product obtainable by the inventive method is also claimed. Use of a product in encapsulation is also directed. A pharmaceutical compn. comprising a product of the invention is also directed. 
IP Reference WO2017118842 
Protection Patent application published
Year Protection Granted 2017
Licensed No
Impact First example of polyester polydendron material class
 
Title COMPOSITIONS OF EFAVIRENZ 
Description The present inventions relates to a solid composition and an aqueous dispersion comprising nanoparticles of the anti-retroviral drug efavirenz. The solid composition and aqueous dispersion additionally comprise a mixture of a hydrophilic polymer and a surfactant. The surfactant is selected from vitamin-E-polyethylene glycol-succinate (Vit- E-PEG-succinate), a polyoxyethylene sorbitan fatty acid ester, N-alkyldimethylbenzylammonium chloride, sodium deoxycholate, dioctyl sodium sulfosuccinate, polyethyleneglycol-12-hydroxystearate, polyvinyl alcohol (PVA), and a block copolymer of polyoxyethylene and polyoxypropylene, or a combination thereof. The hydrophilic polymer is suitably selected from polyvinyl alcohol (PVA), a polyvinyl alcohol-polyethylene glycol graft copolymer, a block copolymer of polyoxyethylene and polyoxypropylene, polyethylene glycol, hydroxypropyl methyl cellulose (HPMC), and polyvinylpyrrolidone, or a combination thereof. The present invention also relates to processes for preparing both the solid composition and the aqueous dispersion, as well as to their use in therapy for the treatment and/or prevention of retroviral infections such as human immunodeficiency virus (HIV). 
IP Reference WO2013034925 
Protection Patent application published
Year Protection Granted 2013
Licensed No
Impact The patent is supporting a human clinical trial and has initiated interest from global charities and the NIH (US)
 
Title Mucoadhesive emulsions using branched polymer emulsifiers 
Description The present invention relates to a branched amphiphilic polymer, suitable for stabilizing an emulsion, comprising a plurality of polymer chains comprising hydrophobic chain ends; a plurality of polymer chains comprising functional chain ends capable of assocg. to a biol. substrate; and a plurality of branching units. The present invention also relates to pharmaceutical compns. contg. said branched amphiphilic polymers, their methods of use, and methods for their prepn. 
IP Reference WO2018029462 
Protection Patent application published
Year Protection Granted 2018
Licensed Commercial In Confidence
Impact Generation of Innovate UK funding and commercial evaluation
 
Title Oil-in-water nanoemulsion, method for producing nanoemulsion and pharmaceutical composition 
Description An oil-in-water emulsion comprises an emulsifier which is a non-gelled branched polymer (e.g., a branched vinyl polymer), wherein the ends of at least some of the chains of the polymer terminate in an alkyl chain of = 5 carbon atoms, and wherein the oil-in-water emulsion takes the form of particles having a z-av. diam. of = 1000 nm. This is useful in facilitating the carrying of hydrophobic materials within aq. systems to enhance oral drug delivery. 
IP Reference WO2016124925 
Protection Patent application published
Year Protection Granted 2016
Licensed No
Impact Innovate UK funding for mucoadhesive emulsions and further patents
 
Title PARTICLES CONTAINING BRANCHED POLYMERS 
Description Particles comprising a branched polymer and either a block copolymer or a linear dendritic hybrid represent a category of useful materials. They may be used in for example drug delivery applications. They may be prepared by a method comprising the steps of: dissolving the branched polymer and block copolymer or linear dendritic hybrid, and optionally other component(s),in a solvent to form a solution; adding said solution to a different liquid; and removing said solvent to form a dispersion of co-precipitated particles. 
IP Reference WO2016009227 
Protection Patent application published
Year Protection Granted 2016
Licensed Yes
Impact None as yet
 
Title POLYDENDRONS 
Description A method of preparing a non-gelled branched vinyl polymer scaffold carrying dendrons, comprising the living or controlled polymerization of a monofunctional vinyl monomer and a difunctional vinyl monomer, using a dendron initiator and at least one further initiator. 
IP Reference WO2014199174 
Protection Patent application published
Year Protection Granted 2014
Licensed Yes
Impact None as yet
 
Title POLYDENDRONS 
Description A method of preparing a pH-responsive non-gelled branched vinyl polymer scaffold carrying dendrons, comprismg the living or controlled polymerization of a mono functional vinyl monomer and a difunctional vinyl monomer, using a dendron initiator. 
IP Reference WO2014199175 
Protection Patent application published
Year Protection Granted 2014
Licensed Yes
Impact None as yet
 
Title Particles containing branched polymers useful for drug delivery applications 
Description The invention relates to the particles comprising both a branched polymer and a block copolymer. The invention also relates to the particles comprising both a branched polymer and a linear dendritic hybrid. The invention also claims a compn. contg. inventive particles dispersed in water or an aq. phase. The invention also provides a method of treatment, comprising administering a therapeutically effective amt. of particles or compn. 
IP Reference WO2016009227 
Protection Patent application published
Year Protection Granted 2016
Licensed No
Impact Branched polymers shown to have advantages as drug delivery vehicles
 
Description Academic outreach 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Postgraduate students
Results and Impact Research Seminar (invited) to inform audience of Nanomedicine and impact of new therapeutic research
Year(s) Of Engagement Activity 2018
 
Description Colorectal Therapies Healthcare Technologies Co-operative Workshop Nanoparticle-Enhanced Radiotherapy, UCL, London 27th October 2017 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Dissemination and discussion of optimal approaches that may be taken for therapy options for colorectal cancer
Year(s) Of Engagement Activity 2017
 
Description Early Career Researcher Meeting - BSNM 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact The British Society for Nanomedicine was initiated from EPSRC funded research. This was the annual Early Career Researcher Meeting, held at the Crick Institute in London
Year(s) Of Engagement Activity 2018
URL https://www.britishsocietynanomedicine.org/
 
Description Meeting with Industry (AZ) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Industry/Business
Results and Impact Significant interest in nanomedicine activities. Event allowed detailed engagement in discussion to evaluate future collaboration activities
Year(s) Of Engagement Activity 2015
 
Description Meeting with industry (Revolymer) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Industry/Business
Results and Impact Engagement with research activities and future licence/collaborative research opportunities
Year(s) Of Engagement Activity 2015
 
Description Pint of Science 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact The international Pint of Science public engagement science festival aiming to communicate contemporary scientific developments to the general public in an interesting, engaging and approachable way by bringing scientists to the pub and other accessible places.
Year(s) Of Engagement Activity 2017
URL https://news.liverpool.ac.uk/2017/04/03/drink-think-pint-science-festival-coming-liverpool/
 
Description Princes Teaching Institute CPD 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact CPD for teachers. Presentation designed to update teachers with up to date information to allow teaching knowledge in Nanomedicine
Year(s) Of Engagement Activity 2014
 
Description Schools Outreach activity 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Vardean College/RSC Sixth former science meeting. Engagement with 6th formers to explain current progress in Nanomedicine
Year(s) Of Engagement Activity 2016
 
Description University of Liverpool Open House 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Public engagement activity to engage public with UoL research and Nanomedicine
Year(s) Of Engagement Activity 2018
 
Description Website for the British Society for Nanomedicine 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact As part of the creation and launch of the British Society for Nanomedicine as website has been created allowing access to information for children, schools, the public and scientists (academic and industrial)

The Society now has >300 members globally and has held multiple meetings
Year(s) Of Engagement Activity 2012
 
Description Website update for British Society for Nanomedicine 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact The British Society for Nanomedicine website was updated and release. This is focussed on outreach and public engagement
Year(s) Of Engagement Activity 2018
URL https://www.britishsocietynanomedicine.org/