Gold nanomaterials for combinatorial photochemotherapy and theranostics
Lead Research Organisation:
University College London
Department Name: School of Pharmacy
Abstract
Pancreatic cancer is the fourth most lethal cancer with disappointing prognosis profile; according to Cancer Research UK, about 19 patients in every 100 (19%) live for at least 1 year after they are diagnosed. Only about 4 out of every 100 people diagnosed (4%) live for at least 5 years, and only 3 out of every 100 (3%) live for at least 10 years. Around 8,000 patients are diagnosed with pancreatic cancer annually which is now the ninth most common cancer in the UK. At present, surgery is the preferred choice of treatment, however, in cases where operation is not possible, chemotherapy is followed by systemic drug administration. Gemcitabine is the front line drug for pancreatic cancer, with relatively moderate therapeutic performance; as a result physicians administer high gemcitabine doses to compensate for the poor drug potency which leads to unavoidable side effects including severe tiredness and breathlessness, anaemia, high risk of infection, and hair loss. In essence, current pancreatic cancer therapies have marginally improved the disease prognosis and have not addressed patient compliance issues.
In the present approach, we propose radically new therapeutic protocols that combine lasers and nanoparticles (these are small sized materials with diameters thousands of times smaller than the thickness of a human hair) to direct drugs at the diseased sites of the body in a specific manner without damaging healthy tissue. By pointing the laser beam directly to the diseased tissue, it should be possible to treat pancreatic tumours by activating the nanoparticles to release the drugs only within tumor areas and not to surrounding healthy tissue. Our proposed approach will allow us not only to guide the nanoparticles at tumor sites, but also enable us to precisely control the trajectory of the drug molecules within individual cancer cells to ensure that they reach their molecular targets. In addition, the proposed nanoparticles will be equipped with molecular imaging tags to allow for real-time monitoring of the therapeutic outcome during therapy. We envision that in the future oncologists will be able to treat cancers in a dynamic manner by continually adjusting drug dosage during treatment by gaining constant feedback information on the tumours' response to therapy by simultaneous imaging of the diseased area during treatment. The proposed concept, if successful, will constitute a conceptually new therapeutic platform which will open up new avenues in personalised therapeutics where the treatment protocols are dynamically adjusted to maximize the therapeutic outcome.
In the present approach, we propose radically new therapeutic protocols that combine lasers and nanoparticles (these are small sized materials with diameters thousands of times smaller than the thickness of a human hair) to direct drugs at the diseased sites of the body in a specific manner without damaging healthy tissue. By pointing the laser beam directly to the diseased tissue, it should be possible to treat pancreatic tumours by activating the nanoparticles to release the drugs only within tumor areas and not to surrounding healthy tissue. Our proposed approach will allow us not only to guide the nanoparticles at tumor sites, but also enable us to precisely control the trajectory of the drug molecules within individual cancer cells to ensure that they reach their molecular targets. In addition, the proposed nanoparticles will be equipped with molecular imaging tags to allow for real-time monitoring of the therapeutic outcome during therapy. We envision that in the future oncologists will be able to treat cancers in a dynamic manner by continually adjusting drug dosage during treatment by gaining constant feedback information on the tumours' response to therapy by simultaneous imaging of the diseased area during treatment. The proposed concept, if successful, will constitute a conceptually new therapeutic platform which will open up new avenues in personalised therapeutics where the treatment protocols are dynamically adjusted to maximize the therapeutic outcome.
Planned Impact
Due its multidisciplinary nature, AuXYGEN is expected to impact a number of different scientific areas spanning from nanomedicine, materials chemistry and chemical sciences in general, to biophotonics, cancer cell biology, and (pre-) clinical sciences. The new knowledge produced will be rapidly diffused to the corresponding disciplines by exploiting the PI's and the collaborators' excellent academic record in terms of publications and scientific networking.
The people who will be involved in the project will acquire diverse and transferable academic and professional skills not common in average academic institutes and working environments. In addition, there is a high probability that commercially exploitable research outputs will emerge as the proposed research area is largely unexplored (both nationally and internationally) and therefore we expect to contribute financially to the UK society through the UCL Business initiative. Finally, AuXYGEN will certainly contribute to our efforts to engage the public on the impact of modern nanotechnologies in future therapies for the benefit of the UK society and the world. In the longer term, cancer patients will benefit from the development of new therapeutic modalities based on our proposed concept.
The people who will be involved in the project will acquire diverse and transferable academic and professional skills not common in average academic institutes and working environments. In addition, there is a high probability that commercially exploitable research outputs will emerge as the proposed research area is largely unexplored (both nationally and internationally) and therefore we expect to contribute financially to the UK society through the UCL Business initiative. Finally, AuXYGEN will certainly contribute to our efforts to engage the public on the impact of modern nanotechnologies in future therapies for the benefit of the UK society and the world. In the longer term, cancer patients will benefit from the development of new therapeutic modalities based on our proposed concept.
People |
ORCID iD |
George Pasparakis (Principal Investigator / Fellow) |
Publications
Emamzadeh M
(2017)
Dual controlled delivery of squalenoyl-gemcitabine and paclitaxel using thermo-responsive polymeric micelles for pancreatic cancer
in Journal of Controlled Release
Amaral A
(2017)
Stimuli responsive self-healing polymers: gels, elastomers and membranes
in Polymer Chemistry
Joubert F
(2017)
Development of a Gemcitabine-Polymer Conjugate with Prolonged Cytotoxicity against a Pancreatic Cancer Cell Line.
in ACS macro letters
Emamzadeh M
(2018)
Dual controlled delivery of squalenoyl-gemcitabine and paclitaxel using thermo-responsive polymeric micelles for pancreatic cancer.
in Journal of materials chemistry. B
Joubert F
(2018)
Hierarchically designed hybrid nanoparticles for combinational photochemotherapy against a pancreatic cancer cell line.
in Journal of materials chemistry. B
Amaral A
(2018)
Transiently malleable multi-healable hydrogel nanocomposites based on responsive boronic acid copolymers
in Polymer Chemistry
Amaral AJR
(2019)
Cell membrane engineering with synthetic materials: Applications in cell spheroids, cellular glues and microtissue formation.
in Acta biomaterialia
Emamzadeh M
(2019)
Dual Controlled Delivery of Gemcitabine and Cisplatin Using Polymer-Modified Thermosensitive Liposomes for Pancreatic Cancer.
in ACS applied bio materials
Sanchez-Vazquez B
(2019)
Solid lipid nanoparticles self-assembled from spray dried microparticles.
in International journal of pharmaceutics
Joubert F
(2019)
Comparison of Thermoresponsive Hydrogels Synthesized by Conventional Free Radical and RAFT Polymerization.
in Materials (Basel, Switzerland)
Joubert F
(2020)
Well-defined backbone degradable polymer-drug conjugates synthesized by reversible addition-fragmentation chain-transfer polymerization
in Journal of Polymer Science
Emamzadeh M
(2021)
Polymer coated gold nanoshells for combinational photochemotherapy of pancreatic cancer with gemcitabine.
in Scientific reports
Bakhtiari S
(2023)
Nanoparticle forming polyelectrolyte complexes derived from well-defined block copolymers
in European Polymer Journal
Barnett C
(2023)
Photochemical Internalization Using Natural Anticancer Drugs, Antimetabolites, and Nanoformulations: A Systematic Study against Breast and Pancreatic Cancer Cell Lines
in Molecular Pharmaceutics
Description | 1. We have discovered that we can prolong the anticancer activity of gemcitabine (a potent anticancer drug for pancreatic cancer) by at least 4 times, if it is attached on a polymer carrier (that is long-chain molecule that can carry multiple copies of the gemcitabine molecule). 2. We have demonstrated that self-assembled nanoparticles (nano-sized objects that spontaneously form small spheres in water) of gemcitabine can be combined effectively with gold nanoparticles and exert synergistic activity against pancreatic cancer cells. This finding provides new insights in combinational photochemotherapies against lethal malignanices and constitutes a step forward towards precision medicine (medical therapeutics that target the diseased areas with extreme accuracy without damaging healthy tissue). 3. We developed new nanomedicinal formulations for pancreatic cancer which are based on gold nanoshells (GNSs). GNSs have unique optical and surface properties which enabled us to immobilize gemcitabine, a potent anticancer drug, and direct them at cancer cells; it was then possible to activate the GNSs and elicit simultaneous hyperthermic and drug-induced cytotoxicity. We demonstrated that the proposed system augments the cytotoxic activity of the parent drug owing to the synergistic effects of hyperthermia. Finally, we demonstrated that it is possible to modulate and control the cellular uptake of these nanomaterials by carefully adjusting their surface properties with the use of synthetic polymers. |
Exploitation Route | Our developed protocols to formulate gemcitabine nanoparticles are robust and simple to prepare which implies that many laboratories across the globe could consider our proposed methodology to prepare and test potent formulations for pancreatic cancer. More importantly, we have demonstrated that our approach fulfills certain criteria that are necessary for the further translation of our formulations in the clinical practice, and these are: very high drug loading capacity, very small sizes (<50-100 nm), easy formulation, multifunctionality, and controlled/tunable release profile, among others. In addition, we have developed several chemical protocols and characterization methods on widely used materials such as gold nanoparticles (spheres and nanoshells), which will be adopted by other laboratories. Finally, we have developed protocols for the synthesis of biocompatible polymers for the surface functionalization of these nanomaterials which in principle enhance their biocompatibility profile and also improve their pharmacokinetics. Therefore, it is likely that our research results will (in-)directly impact diverse fields such as chemical and pharmaceutical industries, healthcare materials. and oncology. |
Sectors | Chemicals,Healthcare,Pharmaceuticals and Medical Biotechnology |
Description | polymer-drug conjugates and gemcitabine formulations |
Organisation | University of Paris-Saclay |
Country | France |
Sector | Academic/University |
PI Contribution | We have designed block copolymers that can co-carry multiple drug molecules for pancreatic cancer. We performed the synthesis of the polymer carrier and also conducted all the in vitro testing. |
Collaborator Contribution | Professors Patrick Couvreur and Didier Desmaelle (Universite´ Paris-Sud) have provided us with gemcitabine prodrug delrivatives which we used in our formulation studies. Squalenoyl gemcitabine is a potent gemcitabine conjugate that is synthesized by our collaborators and we managed to co-formulate it with our polymeric nanocarriers. We already demonstrated very promising results which were published in Journal of Materials Chemistry B (accepted for publication in March 2018, DOI: 10.1039/c7tb02899g). |
Impact | Dual controlled delivery of squalenoyl-gemcitabine and paclitaxel using thermoresponsive polymeric micelles for pancreatic cancer. Journal of Materials Chemistry B (2018, accepted, DOI: 10.1039/c7tb02899g). Mandana Emamzadeh, Didier Desmaelle, Patrick Couvreur and George Pasparakis |
Start Year | 2016 |