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"Fabrication of Large Loading Capacity, Stimuli-Responsive and Release-Controlled Drug Delivery Nanodevices"

Final Report Summary - CAMLC10 (Fabrication of Large Loading Capacity, Stimuli-Responsive and Release-Controlled Drug Delivery Nanodevices)

The project started in July 2011 and was successfully carried out by the Fellow according to the proposed Workplans and expected Milestones/Deliverables. The Fellow has carried out all the three workplans; WP1 was completed at the 18th month (M18) and WP2 and WP3 were completed at the 22nd and 23rd month (M22 and M23). All the planned milestones were reached and all the expected deliverables were successfully delivered. The programme involved two overall objectives (O1 and O2), and two milestones (M1 and M2), as follows:
O1 Fabrication of large loading capacity drug delivery nanodevices in a scalable way involving the synthesis of magnetic (oxide) hybrid nanoparticles (MNPs)with a mesoporous silica coating.
O2 Investigation on drug loading and its controlled release.

These steps were carried out iteratively with the ultimate objectives that an adaptive procedure be developed to learn, and thereby design how to
M1 Fabricate large interstitial hollow space drug delivery nanodevices;
M2 Maximize the drug load and control its release.

A detailed report with figures is provided but in summary the fabrication of such drug delivery nanodevices was carried out by a multi-step process:

(1) The synthesis of bare magnetite (Fe3O4) nanoparticles as a core: The synthesis of bare Fe3O4 nanoparticles was based on a modified solvothermal process, where the mixture of equivalent amount of FeCl3 and sodium acetate (NaAc) in ethylene glycol (EG) was heated to 200 °C under rigorous stirring in the presence of polyethylene glycol (PEG) and the resulting product was collected by magnetic separation, washed by ethanol and water, and dried under vacuum. The final materials possessed strong paramagnetism in either the wet or dry state.

(2) The coating of decomposable Iron oxyhydroxide (FeOOH) layer as an inner shell: The FeOOH coated Fe3O4 NPs were synthesized by the hydrolysis of Fe(NO3)3 at 120 °C in water with double layer functionalisation on Fe3O4 NPs prior to the coating. To achieve more hydrophilic surfaces oleic acid was first grafted onto the NP surface and the resulting surface rendered hydrophilic by the addition of cetyltrimethylammonium bromide (CTAB). The CTAB wrapped Fe3O4 NPs were coated by a layer FeOOH to form Fe3O4@FeOOH core-shell structured NPs.

(3) The growth of mesoporous silica layer as an outer shell: The Fe3O4@mesoporous SiO2 core-shell structured NPs were synthesised by a sol-gel process under mild basic conditions at 80 °C using a gemini surfactant C18-3-1 as the structure directing agent and tetraethyl orthosilicate (TEOS) as the silica source. The gemini surfactant C18-3-1 was synthesised by the reaction between N, N-dimethylhexadecylamine (C18H33N(CH3)2) and (3-bromopropyl)trimethylammonium bromide (Br(CH2)3N(CH3)3)Br in acetone at 60 °C for 7 days.

(4) The removal of the inner coating (FeOOH) and functionalization: In order to achieve channel sealing and drug containment the SiO2 core-shell structured NPs were functionalised with N-(3-Trimethoxysilylpropyl)diethylenetriamine (TMOS-(NH)2-NH2) in dry toluene at 130 °C, where the amine terminated NPs could be grafted by a layer of carboxyl terminated polymer via carboxyl-amine conjugation in order to stop the premature release of drug. Two approaches were used to change the surface characteristics of the nanoparticles: One involved a double layer structured ligand configuration where the Fe3O4 NPs surfaces were first capped by oleic acid (OLA) to form hydrophobic surfaces which were then rendered hydrophilic by the incorporation of other surfactants, e.g. sodium dodecyl sulfate (SDS), CTAB, poly(ethylene glycol) monooleate (PEG-OLA) and FeOOH. The second involved a covalently-grafted ligand configuration where the Fe3O4 NPs surfaces were coated by organosilane species via the formation of Si-O-Fe bonds, e.g. (3-Aminopropyl)trimethoxysilane (TMOS-NH2) and N-(3-Trimethoxysilylpropyl)diethylenetriamine (TMOS-(NH)2-NH2) and their acidized derivatives.

Studies were conducted on the ability of these functionalised nanoparticles to hold and contain a drug and to subsequently release the drug at a controlled rate; the two essential functions for effective drug delivery. The nanodevices were loaded with a drug, gentamicin sulphate, by a wet impregnation approach and shown to release the drug in a controllable way, where pH change, pore sealing and stirring speed were all shown to affect the rate of drug release. At its fastest rate, obtained by rapid stirring in aqueous suspension, complete release of the drug could be achieved in 30 mins. Zero-release was achieved by sealing the pores of the nanoparticles with PEG-BCE.

To test biological safety the cytotoxicity of the nanoparticles towards a mammalian K562 cell line was determined by incubating cells in culture with a range of nanoparticle concentrations for up to 48 hours and subsequently monitoring their metabolic activity. Naked nanoparticles demonstrated little cytotoxicity though for functionalised nanoparticles the different functional groups on the particle surfaces, the particle size and ligand configuration all significantly influenced cell cytotoxicity. Further development of the nanoparticles for clinical use will thus require particular attention to these parameters.

The project has shown that it is possible to make nanoparticles that can hold therapeutic amounts of a drug that can be released at a controlled rate. This lays the basis for a direct impact on the clinic ability to use nanotechnology based therapies in cancer prevention and treatment and will make a significant contribution to the frontier forward-moving, development and competitiveness of EU in the area. Healthcare is a main concern to remove (prevent) illness efficiently without side-effects. With the increased requirement on the low side-effect of medicines, particularly anticancer medicines, the research and development on this concern is highly competitive. Many countries have invested heavily in this area and will invest more in future. EU has planned to invest €6 billion under the FP7 in the health related research (2007-2013). The UK investment on Healthcare technology alone is accumulatively about €62 million and takes 22.7% of the whole investment by EPSRC themes on 2011 and is already the second largest area to attract funds just behind Physics.

The research lays the basis for much further work on high-capacity drug delivery nanoparticles:
• It develops a novel and alternative strategy to fabricate stimuli-responsive, release-controlled and long sustainable drug delivery nanodevices.
• It provides a scale-up tool to produce massive functional nanomaterials as the components to self-assemble into the required nanodevices.
• The use of the magnetic Fe3O4 core in this research provides a unique method to release drug by self-rotation (self-spinning) under an external magnetic field, where the contactless, controllable drug release can be triggered remotely by the external magnetic field.
• The use of the SiO2 mesoporous shell in this research provides an active base to graft many functional groups such as ligands, surfactants, peptides and other nano-components to achieve high efficient drug delivery.
• The use of the decomposable inner FeOOH layer contributes to a large loading capacity drug carrier nanodevice, where the large drug storage plus the accessible channels favour a larger amount of drug loading and a release in a sustainable way.

In addition, as a result of the project the Fellow has acquired the following competencies and skills:
• A solid background on the multidisciplinary area of materials nanoengineering, mastering the processing and characterization techniques.
• Experience in the field of drug delivery, nanotoxicity and tissue culture.
• Visibility in these areas by reviewing research grant proposals and academic papers.
• Improved his presentation skills by attending high level international conferences.
• Developed his organisation capabilities by chairing and organising international conferences.
• Developed his supervision abilities by directing PhD students.
• Promoted his personal development by attending many Personal and Professional Development events offered by the University of Cambridge in Lecturing, Supervision, Project management and Presentation.

Contact: Professor Nigel Slater, Department of Chemical Engineering and Biotechnology, University of Cambridge, Pembroke Street, Cambridge CB2 3RA, UK. e-mail: nkhs2@cam.ac.uk web: http://www.ceb.cam.ac.uk/people.php?action=view&id=4