Nanomaterials in Medicine:

Transcription

1 Nanomaterials in Medicine: Multifunctional theranostics carriers M. Angelakeris, associate professor Department of Physics, Aristotle University 54124, Thessaloniki-Greece M. A n g e l a k e r i s : N a n o m a t e r i a l s i n M e d i c i n e : M u l t i f u n c t i o n a l t h e r a n o s t i c s c a r r i e r s 1 / 3 3

2 Greece is a country in Southern Europe, located at the crossroads of Europe, Asia, and Africa. Its mainland is located at the southernmost tip of the Balkan Peninsula. Greece has a vast number of islands (6000), being in the Aegean Sea and in the Ionian Sea. Thessaloniki is the second-largest city in Greece and the capital of the administrative region of Central Macedonia. The Aristotle University of Thessaloniki is the largest university in Greece. The main campus is located in the centre of the city of Thessaloniki. It comprises 10 faculties which consist of 40 schools with ~2000 faculty members and ~ sudents (10% MSc, PhD). Aristotle BC was a Greek philosopher and scientist born in the city of Stagira, close to Thessaloniki. His writings cover many subjects including physics, biology, zoology, metaphysics, logic, ethics, aesthetics, poetry, theater, music, rhetoric, linguistics, politics and government and constitute the first comprehensive system of Western philosophy. At the request of king Philip of Macedon, he tutored his son Alexander the Great beginning in 343 BC. The faculty of Science was founded in 1925, along with the Aristotle University of Thessaloniki, the Faculty of Physics and Mathematics first opened its doors in autumn today it consists of Schools of physics, chemistry, mathematics, biology, geology and Informatics. M. A n g e l a k e r i s : N a n o m a t e r i a l s i n M e d i c i n e : M u l t i f u n c t i o n a l t h e r a n o s t i c s c a r r i e r s 2 / 3 3

3 Nanomaterials in Medicine: Multifunctional theranostics carriers Nanotheranostics Modern Medicine M. Angelakeris, associate professor Department of Physics, Aristotle University 54124, Thessaloniki-Greece Nanomaterials Bio-practice M. A n g e l a k e r i s : N a n o m a t e r i a l s i n M e d i c i n e : M u l t i f u n c t i o n a l t h e r a n o s t i c s c a r r i e r s 3 / 3 3

4 Nanomaterials Nanotechnology Nanotechnology, is the engineering and manufacturing of matter at an atomic or molecular level. It is the shrinking of modern technology to a microscopic scale that is measured in nanometers. The idea of nanotechnology has been around, surprisingly, since 1959 when the theoretical physicist Richard Feynman conceived of the idea and foresaw its use in the future. Nanotechnology is used to create cosmetics, sunscreen, cleaning products, and many other consumer products. M. A n g e l a k e r i s : N a n o m a t e r i a l s i n M e d i c i n e : M u l t i f u n c t i o n a l t h e r a n o s t i c s c a r r i e r s 4 / 3 3

5 Nanomaterials Nanotechnology applications The 2000s have seen the beginnings of the applications of nanotechnology in commercial products. Examples include titanium dioxide and zinc oxide nanoparticles in sunscreen, cosmetics and some food products; silver nanoparticles in food packaging, clothing, disinfectants and household appliances such as Silver Nano; carbon nanotubes for stain-resistant textiles; and cerium oxide as a fuel catalyst. Nanotechnology is also being applied to or developed for a variety of industrial and purification processes. Purification and environmental cleanup applications include the desalination of water, water filtration, wastewater treatment, groundwater treatment. M. A n g e l a k e r i s : N a n o m a t e r i a l s i n M e d i c i n e : M u l t i f u n c t i o n a l t h e r a n o s t i c s c a r r i e r s 5 / 3 3

6 Nanomaterials Nanotechnology applications Nanotechnology is being used to help treat disease and prevent health issues. The umbrella term for this kind of nanotechnology is Nanomedicine. Researchers are developing customized nanoparticles at sizes analogous to the molecules that can deliver drugs directly to diseased cells in your body. When it's perfected, this method should greatly reduce the damage treatment such as chemotherapy does to a patient's healthy cells. M. A n g e l a k e r i s : N a n o m a t e r i a l s i n M e d i c i n e : M u l t i f u n c t i o n a l t h e r a n o s t i c s c a r r i e r s 6 / 3 3

7 Nanomaterials From 1 to 3 nanodimensions 1D: Multilayer Films 2D: Ordered Arrays 3D: Nanoparticles 15 nm Our group s main scientific interests are magnetic nanostructure preparation and structure correlation with collective magnetic behavior. Relevant publications on multilayers, arrays, nanoparticles: M. A n g e l a k e r i s : N a n o m a t e r i a l s i n M e d i c i n e : M u l t i f u n c t i o n a l t h e r a n o s t i c s c a r r i e r s 7 / 3 3

8 Nanomaterials Nanoparticle History The last 20 years following the novel properties, enhanced features of multilayers scientists aimed their efforts to analogous system with 3 nanodimensions. Initially metallic nanoparticles randomly oriented in solution or on substrates. Gradually, bimetallic particles with varying stochiometry, morphological features and tunable macroscopic features. Nanoparticles: Spheres with diameter < 50 nm < atoms M. A n g e l a k e r i s : N a n o m a t e r i a l s i n M e d i c i n e : M u l t i f u n c t i o n a l t h e r a n o s t i c s c a r r i e r s 8 / 3 3 Reproducibility Arrangement Uniformness Stability Morphology

9 Nanomaterials Synthesis Approach Top-down Methods Bottom-up Methods Nd 2 Fe 14 B nanoparticles Size depends on milling time Fe 3 O 4 nanoparticles Size depends on Fe(CO) 5 /oleic acid Intermetallics (2011). Phys. Rev. B (2006). M. A n g e l a k e r i s : N a n o m a t e r i a l s i n M e d i c i n e : M u l t i f u n c t i o n a l t h e r a n o s t i c s c a r r i e r s 9 / 3 3

10 Nanomaterials Nanomaterials for Nanomedicine 1 G : Physics To design, control and measure property response at the nanoparticle unity. The oals project 2 G : Chemistry To achieve and reproduce nanoscale multicomponent fabrication. 3 G : Biology To introduce multifunctionality without sparing enhanced performance. 4 G : Medicine To increase biocompatibilty and sustain enhanced mulifunctionality in-vivo. M. A n g e l a k e r i s : N a n o m a t e r i a l s i n M e d i c i n e : M u l t i f u n c t i o n a l t h e r a n o s t i c s c a r r i e r s 1 0 / 3 3

11 Bio-practice Nanomaterials in biomedicine Why Nanoparticles? Flexible, Selective & Effective 1. External: effectively and externally stimulated can be delivered at cellular levels 2. Nano: only few tens of nanometer in size and therefore, allows easy passage into several tumors whose pore sizes are in nm range. 3. Alternative: with the possibility to obtain stable colloids using nanoparticles, they can be administered through a number of drug delivery routes. 4. Selective: can be targeted through specific binding agents making the treatment much more selective and effective. M. A n g e l a k e r i s : N a n o m a t e r i a l s i n M e d i c i n e : M u l t i f u n c t i o n a l t h e r a n o s t i c s c a r r i e r s 1 1 / 3 3

12 Bio-practice Particles used in vivo in biomedicine interface with living tissues and biological fluids are by definition classified as biomaterials and divided as: From materials to biomaterials The body reacts to biotolerant materials by encapsulating them; typical examples are PMMA, silicon and glass and include the silica-coated nanoparticles. Bioinert materials have minimal interactions with surrounding tissue; stainless steel, titanium and aluminum oxide are good examples. Bioactive materials, when placed in vivo, interact with the bone or soft tissue; however, none of the magnetic nanoparticles are presently known to be bioactive. A biocompatible material produces a specific and well-defined host response, which is necessarily non-toxic. Biodegradable materials are commonly associated with environmentally friendly products that are capable of decomposing back into natural elements. M. A n g e l a k e r i s : N a n o m a t e r i a l s i n M e d i c i n e : M u l t i f u n c t i o n a l t h e r a n o s t i c s c a r r i e r s 1 2 / 3 3

13 Bio-practice Nanomaterials in biomedicine Getting back to the basics of nanomaterials for better nanomedicine Assess the interactions of the now-vast library of nanomaterials with biological systems based on hydrodynamic diameters and the nature of the surface molecules. The responses of nanomaterials to biological systems either the direct responses of the cell to the nanomaterial surface, or indirect responses such as the presence of the nanomaterial initiating known cellular functions Accurate measurement of something as fundamental as the hydrodynamic diameter becomes a tricky operation because of effects of protein corona formation, adding layers of complexity. True effectiveness and potential side-effects of a particular non-medical system based on particle uptake by cells and clearance from the biological system will govern its approval and adoption in the clinic. M. A n g e l a k e r i s : N a n o m a t e r i a l s i n M e d i c i n e : M u l t i f u n c t i o n a l t h e r a n o s t i c s c a r r i e r s 1 3 / 3 3

14 Bio-practice Nanomaterials in biomedicine Nanoparticles due to their multivalency and multifunctionality, pose challenge for understanding their pharmacokinetics because different components will have different features that affect their toxicity, distribution, clearance and catabolism. Dose Concentration Dosology Dimensions Size Surface Area Aspect Ratio Durability Chemictry Crystal Structure Surface Cover Functionalization M. A n g e l a k e r i s : N a n o m a t e r i a l s i n M e d i c i n e : M u l t i f u n c t i o n a l t h e r a n o s t i c s c a r r i e r s 1 4 / 3 3

15 Bio-practice Nanomaterials in biomedicine Synthesis rules Synthesis in water Synthesis in organic medium Water Solubilization Solvent free synthesis M. A n g e l a k e r i s : N a n o m a t e r i a l s i n M e d i c i n e : M u l t i f u n c t i o n a l t h e r a n o s t i c s c a r r i e r s 1 5 / 3 3

16 Bio-practice Nanomaterials in biomedicine Size rules > 100 nm <10 nm nm Best tumor accumulation ~ 20 nm Best IO crystal size for AMFdriven hyperthermia nm Minimum Stealth coated IO particle for hyperthermia best for magnetic capture Best tumor penetration M. A n g e l a k e r i s : N a n o m a t e r i a l s i n M e d i c i n e : M u l t i f u n c t i o n a l t h e r a n o s t i c s c a r r i e r s 1 6 / 3 3

17 Bio-practice Nanomaterials in biomedicine Biocompatibility rules The toxicity of nanoparticles depends on materials and morphological parameters including composition, degradation, oxidation, size, shape, surface area and structure. When compared to micron-sized particles, nano-sized particles can be generally more toxic because they have larger surface area (hence, more reactive), for a given mass, to interact with cell membranes and deliver toxicity. They are also retained for longer periods in the body (more circulation or larger clearance time) and, in principle, can be delivered deeper into the tissue due to their size. The surface coating and their morphology play an important role in determining nanoparticle toxicity. M. A n g e l a k e r i s : N a n o m a t e r i a l s i n M e d i c i n e : M u l t i f u n c t i o n a l t h e r a n o s t i c s c a r r i e r s 1 7 / 3 3

18 Modern Medicine Fields of interest Cell Fate Control Drug Delivery Magnetic Hyperthermia MRI Bioseparation Cell Capture BioSensing Cellular Proteomics Cell Tracing M. A n g e l a k e r i s : N a n o m a t e r i a l s i n M e d i c i n e : M u l t i f u n c t i o n a l t h e r a n o s t i c s c a r r i e r s 1 8 / 3 3

19 Modern Medicine Medical Nanoprobes A medical nanoprobe: Specific Targeting: specific ligands or antibodies can be attached on the surface to develop a active-specific targeted system. Multimodal Imaging: in order to obtain multimodal imaging magneticfluorescent composites, organic fluorophores can be conjugated on the nanoparticle surface through spacer molecules or they can be include in a protective shell. Therapy carrier: therapeutic agents can be associated to the nanoparticles surface via electrostatic interactions or via covalent bonds, stimuli-responsive release can be operated by a change in the ph or by enzymatic action. Nanoparticle Biocompatibility: The surface is coated with amphiphilic or antibiofouling polymers to enhance biocompatibility of the nanoparticles and to increase the blood circulation time. M. A n g e l a k e r i s : N a n o m a t e r i a l s i n M e d i c i n e : M u l t i f u n c t i o n a l t h e r a n o s t i c s c a r r i e r s 1 9 / 3 3

20 Modern Medicine Nanoparticle functionalization (a) Prior to use, the surface of the nanoparticles must be modified to provide both biocompatibility and functionality (specific binding and targeting moieties). Nanoparticle M. A n g e l a k e r i s : N a n o m a t e r i a l s i n M e d i c i n e : M u l t i f u n c t i o n a l t h e r a n o s t i c s c a r r i e r s 2 0 / 3 3

21 Modern Medicine Medical Nanoprobes (b) They can then be guided to the targeting location either using tailored magnetic field gradients or by injecting into the appropriate vasculature. Nanoparticle M. A n g e l a k e r i s : N a n o m a t e r i a l s i n M e d i c i n e : M u l t i f u n c t i o n a l t h e r a n o s t i c s c a r r i e r s 2 1 / 3 3

22 Modern Medicine Medical Nanoprobes (c) After localization at the target, the properties of the particles and/or the attached probes provide novel functionality. This could be as contrast agents for established imaging methods such as MRI or the development of new imaging modalities such as Magnetic Particle Imaging. Nanoparticle M. A n g e l a k e r i s : N a n o m a t e r i a l s i n M e d i c i n e : M u l t i f u n c t i o n a l t h e r a n o s t i c s c a r r i e r s 2 2 / 3 3

23 Modern Medicine Medical Nanoprobes (d) The dynamic relaxation of the nanoparticles, when subject to an alternating magnetic field can be used for therapeutics (hyperthermia), imaging (magnetic particle imaging) or diagnostics (biosensing). Nanoparticle M. A n g e l a k e r i s : N a n o m a t e r i a l s i n M e d i c i n e : M u l t i f u n c t i o n a l t h e r a n o s t i c s c a r r i e r s 2 3 / 3 3

24 Modern Medicine Medical Nanoprobes (e) The functionalized molecule on the surface could be a drug that can be released in response to external stimuli such as ph, temperature or an alternating magnetic field. Nanoparticle M. A n g e l a k e r i s : N a n o m a t e r i a l s i n M e d i c i n e : M u l t i f u n c t i o n a l t h e r a n o s t i c s c a r r i e r s 2 4 / 3 3

25 Modern Medicine Medical Nanoprobes (f) Moving the particles with magnetic field gradients allows for magnetic targeting, delivery and in vitro separations and diagnostics; the latter can be effective in ultra-immunoassays where only small quantities of blood (such as in infants) can be drawn to concentrate the signal. Nanoparticle M. A n g e l a k e r i s : N a n o m a t e r i a l s i n M e d i c i n e : M u l t i f u n c t i o n a l t h e r a n o s t i c s c a r r i e r s 2 5 / 3 3

26 Modern Medicine Issues to consider endocytosis It is important that nanoparticle formulations have the ability to overcome the main biological barriers that prevent them from reaching their targets. However, intravenous injection of nanomaterials introduces new concerns such as dosage, distribution and circulation times making their use and development similar to pharmaceuticals. Possible changes in behavior upon injection and interactions with cells such as specific binding and endocytosis. These interactions can also result in nanoparticle agglomeration or regions of high concentration with inter-particle interactions leading to altered properties. Rapid clearance of nanoparticles from circulation can substantially reduce their biomedical functionality. Active clearance of nanoparticles is mainly due to their recognition by macrophages of the mononuclear phagocyte system. Nanoparticles have a large surface to volume ratio and tend to absorb plasma-proteins (opsonization), which are easily recognized by macrophages making them vulnerable to rapid clearance before reaching their target. The overall size of the nanoparticles (hydrodynamic size), surface charge and functionalization play a large role in their distribution and circulation time; however, these parameters may change upon interaction with blood constituents. M. A n g e l a k e r i s : N a n o m a t e r i a l s i n M e d i c i n e : M u l t i f u n c t i o n a l t h e r a n o s t i c s c a r r i e r s 2 6 / 3 3 exocytosis

27 Nanotheranostics Theranostics arises from the combination of the terms "Therapeutics" and "Diagnostics" and is used to describe a proposed process of diagnostic therapy for individual patients - to test them for possible reactions when taking a new medication and to tailor a treatment for them based on personalized test results. The prefix Nano means that nanomaterials deliver the treatments. A major challenge in Theranostics for the 21 st century is to be able to detect disease biomarkers non-invasively at an early stage of disease progression and choose and administer personalized medical treatment factoring individual genetic and phenotypic characteristics. M. A n g e l a k e r i s : N a n o m a t e r i a l s i n M e d i c i n e : M u l t i f u n c t i o n a l t h e r a n o s t i c s c a r r i e r s 2 7 / 3 3

28 Nanotheranostics Issues to consider Adjusting the conditions Optimizing the carrier Material Choice Size Shape Magnetic profile Concentration Colloidal Stability the conditions Frequency Field intensity Colloidal Particles Clinical Application Choosing the proper agent Short & Long term side effects From lab to clinical trials Optimizing the treatment biocompatibilty toxicity In-vivo efficiency the side-effects Short-term Long-term extraction M. A n g e l a k e r i s : N a n o m a t e r i a l s i n M e d i c i n e : M u l t i f u n c t i o n a l t h e r a n o s t i c s c a r r i e r s 2 8 / 3 3

29 Nanotheranostics Modern Medicine Activation of cell signals Magnetic nanoparticles may also be used to generate mechanical stimulations on cells which can induce changes in cell activity such as differentiation, growth and death. a. Clusterisation b. Translational Force c. Heat generation Under an external magnetic field, magnetic nanoparticles can move around on cell membrane surfaces and exert translational forces. Simultaneously, by attaching proper ligands on MNPs binding of MNPs to special cell-surface receptors may be achieved and heat-triggered mechanical stimulations can activate cellular signaling pathways. Advantages a. Spatial b. Temporal c. Remote Control of Cellular Activities Magnetic stimulation in human endothelial cells Cellular morphology tubular shape = prestage of angiogenesis M. A n g e l a k e r i s : N a n o m a t e r i a l s i n M e d i c i n e : M u l t i f u n c t i ot. nr. a l Pisanic t h e r a nii, obiomaterials s t i c s c a r r i e28 r s / 3 3 (2007)

30 Nanotheranostics Controlled Drug-release Cargo can be released in response to external stimuli: light or a magnetic field internal stimuli: natural biochemistry inside cells using redox, enzymes, or a ph change in the cellular compartments Magnetically triggered drug release system MNPs which generate heat upon exposure to an oscillating magnetic field, causing the CB rings to slip off the stalks, thus releasing a cargo of either rhodamine B or doxorubicin. MDA-MB-231 breast cancer cells When MNPs are loaded with doxorubicin and exposed to an oscillating magnetic field, 37% of the cells are killed, with apoptotic bodies indicated by arrows M. A n g e l a k e r i s : N a n o m a t e r i a l s i n M e d i c i n e : M u l t i f u n c t i o n a l t h e r a n o s t i c s c a r r i e r s 3 0 / 3 3

31 Nanotheranostics Nanorobots Scientists and researchers are discovering new ways that nanotechnology can be used in the near future. It will be used for drug delivery, treatment and detection of cancer and other diseases, imaging, and much more. One of the more interesting uses of nanotechnology in medicine is the "nanorobot." The nanorobot is a microscopic robot that can be used for cancer treatment, drug delivery, or even heart bypass surgery. As it enters the bloodstream through a tiny incision and travels through the many veins and arteries it has the capability of finding specific cancer cells and treating them. This could effectively eliminate the side effects of radiation and chemotherapy as they would not be needed. Nanorobots could also cut down on surgery time, recovery time, and the various-side effects related to procedures such as heart bypass surgery. M. A n g e l a k e r i s : N a n o m a t e r i a l s i n M e d i c i n e : M u l t i f u n c t i o n a l t h e r a n o s t i c s c a r r i e r s 3 1 / 3 3

32 Nanotheranostics Challenges in nanoparticle design Biodistribution and passive targeting: surface morphology, particle size and surface charge determine pharmatokinetics, toxicity and biodistribution Direct targeting: the efficiency of site-specific delivery depends on profile of cargo-loaded MNPs, field strength, depth of target tissue, rate of blood flow and vascular supply Application driven functionalization Hyperthermia: control heat distribution, multiple trajectories, aggregates Magnetic Resonance Imaging: enhanced cellular internalization, slower clearance from tumor site, sizedependent tissue distribution Cell imaging and tracking: cell membrane receptor recognition, long-term in-vivo monitoring, uptake initiation and/or enhancement Future Directions Future Goals In vitro bio-microelectromechanical system (bio-mems): engineered motor proteins, transport and assemble non-biological cargo Cell-adhesive patches: MNPs loaded at cellular surface, control cytotoxicity, retention of cell basic cellular functions Multifunctional role: (diagnosis, monitoring and treatment) M. A n g e l a k e r i s : N a n o m a t e r i a l s i n M e d i c i n e : M u l t i f u n c t i o n a l t h e r a n o s t i c s c a r r i e r s 3 2 / 3 3

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