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an electromagnetic wave (see section 2.3.1), where this absorbed photon energy is transferred to phonons in the lattice and dissipated as heat. A relatively new phenomenon, the potential of photothermal therapies has only been realised over the last 15 years. As such it has not yet been subjected to the same level of theoretical treatment as magnet hyperthermia. The electromagnetic wave is provided by a near-infra-red laser (typically an 808 nm laser powered at 0.3–5 W cm⁻²), which crucially is more transparent to body tissue and can penetrate deeper into the tissue than optical light. While the science in this area is still at the research stage, several inorganic nanomaterials are proving to be ideal materials for photothermal therapies. The front runner is gold nanoparticles (see recent reviews [8, 34]), as well as carbon nanotubes (CNTs) and MNPs such as SPION and larger magnetite MNPs. Once again, bacterial magnetosomes have proved to be excellent candidates with increases of temperature of up to 50 °C (under 1 W cm⁻² laser power) [31]. Meanwhile, synthetically produced magnetite MNPs coated in macrophage biological coating have proved to be excellent photothermal agents. The macrophage coating renders them invisible to the immune system, offering them longer circulation time and also targeting them to the cancer cells. Furthermore, the magnetic properties of the particles mean they can be magnetically targeted to the tumour in vivo, with photothermal therapy resulting in tumours five times smaller by weight compared to treatment with non-macrophage coated MNPs [10].

      2.4.1.4 Theragnostics

      Theragnostics is quite simply the combination of both an imaging/diagnostic modality with a treatment of the disease (figure 2.8(Di)). It stands to reason that once a nanoparticle has been designed to locate a disease and visualised it, it would seem sensible and economical to provide a drug-payload or therapeutic treatment on the same particle, which has already reached its target. There is some debate as to whether or not theragnostics falls between two stools, in the sense that designing a combined ‘all singing, all dancing’ nanoparticle may end up doing both jobs to an okay standard, whereas actually designing a particle for one specific purpose may achieve better results. However, as we have seen throughout this section on nanomedicine, many nanomaterials, as well as coating and drugs, are multifunctional, so many theragnostic treatments are thus widely reported in the literature. For example, MNPs can use magnetic force to target the MNP to the site of a tumour, can be visualised with MRI and MPI, and can be heated with either a magnetic field or photothermia. Gold can be visualised with SPR and heated with photothermia, while both can be decorated with drugs and targeting agents such as biomarkers and antibodies and coated with biocompatible/targeting/smart activating polymers/membranes. Thus, a therapy can quite often couple as a imaging tool/diagnostic without any extra complexity and thus biological or synthetic penalty, and this is where the real advantages lies. The number of theragnostics currently being researched is too vast to describe here, so we will examine one example with multiple features. Figure 2.8(Dii) shows Fe@Si–DOX–CD–PEG [19]. Here a SPION forms a magnetic centre which can be magnetically targeted to the tumour. It can also be used as an MRI contrast enhancer offering targeting and imaging capability. The SPION is then coated in nanoporous silica, in which DOX can be loaded into the pores acting as a drug trap. This particle is then coated with PEG to provide biocompatible and cancer responsive cyclodextrin, which blocks the pores until the nanoparticle reaches the cancer site. At the site the cyclodextrin is cleaved off releasing the DOX from the silica pores [19].

      2.4.1.5 Nanosensors in healthcare and medicine

      Nanomaterials are ideal sensors because of their very large surface area. Furthermore, because of their small size, they are comparable in scale to many biological targets/disease markers making them particularly useful in biological sensing. Finally, the specific nanoscale properties covered in section 2.2 (particularly optical SPR) are very dependent on subtle chances at the surface of the particles, yielding very sensitive sensors.

      Within medical sensoring, the central dogma for the last 50 years has been the use of antibodies raised against a specific biological target to detect that target. Initially in the 1960s this was done with radio labelling of the antibodies and detecting radioactivity. While this is a very sensitive technique, it is not very accessible and has many safety drawbacks. The 1970s saw the development of more accessible immunosorbent techniques such as the enzyme-linked immunosorbent assay (ELISA), where detection is achieved through an antibody attached to an enzyme, which when coupled to its substrate produces a detectible response (usually a definitive colour change). There are many forms of this assay but all use an antibody raised against the target to ‘capture’ the target, and an antibody linked to an enzyme detection system. Different types of ELISA include direct ELISA, where the primary antibody is already functionalised with an enzyme for detection, and sandwich ELISA, which has more steps and uses a primary antibody immobilised on the surface to catch the target and further antibodies to specifically bind to the target. Non-specific antibodies to bind to these which contain the enzyme detection system are then added. One of the best-known examples of ELISA sensing is in healthcare, and is the pregnancy test. This is a sandwich ELISA colorimetric sensor for the pregnancy hormone human chorionic gonadotropin (hCG). The test uses capillary flow to move the analyte (urine) along the test strip and over the immobilised antibodies. Most nanosensors will use antibodies in the form of an immunosorbent assay to target biomarkers and specific proteins, as they are well established, very sensitive, accessible and accurate. However, in recent years there has been a move to use nanoparticles as the detection system instead of enzyme assays, due to potential interactions of the enzyme with the sample and the higher intensity and thus sensitivity of the SPR signal. In this system antibodies can be attached to gold nanoparticles using the strong sulphur–gold bond, by simply adding a cysteine amino acid residue to the antibody. Furthermore, with SPR, there are many more sophisticated improvements that can be made on this simple assay, as this property (outlined in section 2.3.1) is ideally sensitive for nanosensing and can be tuned extensively. Furthermore, much more information, such as spacial information, can be obtained from SPR sensors, which cannot be achieved from simple colorimetric assays.

      Increasingly, the SPR light emitted by gold and silver nanoparticles is serving as very sensitive colorimetric detection methods for very small quantities of target. One such target is microRNA (MiRNA). Some of these short strands of RNA are markers for the early signs of some cancers, so would be very useful to detect. However, they are present in very low concentrations. Recent work has used a DNA sandwich assay to detect the specific MiRNA [35]. Here, folded capture DNA containing the complementary sequence to the target MiRNA is immobilised on a gold surface (through a sulphur bond) and unfolds to bind the MiRNA specifically. This subtle change to the surface can be detected by a shift in the SPR signal [35]. Then a gold nanoparticle can be added with more single stranded DNA attached, designed to bind further up the capture DNA only if the MiRNA has bound, and placing the gold nanoparticle in close proximity to the gold surface, greatly enhancing the SPR refractive index signal and changing the resonance angle. This is enhanced further by adding more DNA to create a DNA supersandwich (figure 2.10(A)). This allows detection of MiRNA at concentrations as low as 8 × 10⁻¹⁵ Molar [35].

      Figure 2.10. Two examples of ultra-sensitive nanosensors using SPR from gold nanoparticles. (A) A DNA supersandwich assay for the detection of very low concentrations of MiRNA. The numbering on the experimental schematic (top) corresponds to the numbering on the data (below right). A schematic showing how the data is collected from the gold surface is shown below left (adapted from images from [35], copyright 2016, with permission from Elsevier). (B) A molecular ruler measuring the extended distance of hybridising flexible ssDNA to more rigid dsDNA. (i) Example spectral

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