**5. Gold nanorods-activated NIR laser plasmonic photothermal therapy**

The targeted delivery of gold-based nanohybrids to solid tumors is one of the most important and challenging problems in cancer medicine. The strongly plasmonic absorption and photothermal conversion of the gold nanoparticles have been exploited in cancer therapy through the selective localized photothermal heating of the cancer tumors.[65] To treat a tumor, the gold particles conjugated with biomolecules can be selectively targeted to cancer cells without significant binding to healthy cells. The nanoparticles in the bloodstream generally have to firstly move across the tumor blood vessels. The tumors are then exposed to an excitation source, such as NIR laser light, radiowave, or an alternating magnetic field. When the gold nanoparticles are exposed to the light radiation at their resonance wavelength, the electric field of light causes the collective oscillation of the conduction-band electrons at the particle surface. The coherent oscillation of the metal free electrons in resonance with the electro-magnetic field is called the surface plasmon resonance (SPR). The excitation of the maximum SPR absorption results in enhancement of the photophysical properties of gold particles.[66] The gold nanoparticles absorb the incident energy and convert them to heat, which raises the temperature (~42°C) of the tissue and ablates the cancerous cells by disrupting the cell membrane. The photoradiations do not often kill healthy cells because the laser power requires to heat/destroy the cancer cells much low than the healthy cells to which nanoparticles do not bind specifically. The physical heating mechanism of ablative therapies would provide an advantage against chemotherapy-resistant cancers, as well as improved tumor response when combined with chemotherapy and photoradiation.

326 Practical Applications in Biomedical Engineering

might be adversely affected.

sufficiently penetrate and damage healthy tissues.

tumors, high activating energy source must achieve at long duration of time, leading to

To the goal of the cost and performance, the development of new efficient approaches based on an advanced combination between "smart drug delivery" chemotherapy and photoradiation companied by "near-infrared (NIR) laser-adsorbing nanomaterials" to create the most effective results have been interested in medicine technology.[63] Lack of target specificity is one of the major disadvantages of many drugs. When drugs administered into human body are distributed to all organs through bloodstream, rather than to specific target organ that needs the pharmacological treatment. Biochemical and physiological barriers of certain organs also limit drug delivery to the desired organ. Chemotherapeutic drugs may destroy the cancer cells along with destroy the healthy tissue and cytotoxic effect of the drugs. To overcome these disadvantages, newer and effective methods should be developed to safely shepherd a pharmacological agent to avoid specific organs, where healthy tissue

The nanoparticles with the size smaller 100-10,000 times than the cells can be conjugated with various complementary biomolecules including DNA strands and antigens, as shown in **Figure 7**. The conjugated nanoparticles can easily pass through the cell membrane and accumulate into target sites by manipulation, which is advantageous in targeted imaging, diagnosis, and delivery.[64] The functionalization of the silica-coated nanohybrids is usually achieved by adsorption or chemical conjugation of the biomolecules to the particle surface. The silica-coated gold-based nanohybrid colloids can be surface-functionalized with mercapto-, amino-, carboxy-terminated silanes for biomolecule conjugation. Homogeneously water-dissolved biomolecules-conjugated silica-coated nanoparticles could bind to the surface of the cancer cells with greater affinity than to the noncancerous cells.

**5. Gold nanorods-activated NIR laser plasmonic photothermal therapy** 

The targeted delivery of gold-based nanohybrids to solid tumors is one of the most important and challenging problems in cancer medicine. The strongly plasmonic absorption and photothermal conversion of the gold nanoparticles have been exploited in cancer

**Figure 7.** A scheme of thiolated DNA conjugation onto the silica-coated nanoparticles.

Key features to consider when selecting a compatible particle for hyperthermia are the wavelength of maximal absorption, absorption cross-section, and shape/size of the particle. NIR laser light is ideal for in-vivo hyperthermia applications because of its low absorption by tissue chromophores (hemoglobin and water), which prevents them from damaging healthy tissue. The absorption coefficient of these tissue chromophores is as much as two orders of magnitude greater in the visible region (400-600 nm) as compared to the NIR region (650-900 nm).[66] Gold-nanoparticle-mediated photothermal therapy is predominantly designed to operate in this window of wavelengths ("NIR window") to minimize energy interaction of light-tissue, preventing damaging heating of healthy tissue. Upon tumor laser irradiation, NIR light is absorbed by the nanoparticles and heat dissipation is generated as a consequence of electron-phonon interactions. For successful cancer ablation, the tissue must be heated to a minimum temperature for a minimum duration of time to induce tumor cell death.

The plasmon absorbance of the gold particles can be easily tuned from the visible region into the NIR by simple manipulation of their aspect ratio (from sphere to rod).[66] For the gold nanospheres, this resonance occurs in the visible spectral region at about 520 nm, originating from the brilliant colour of the gold particle solution. Owing to their distinctive rod shape, the gold nanorods have two absorption peaks attributed to the free electron oscillation along the longitudinal and transverse axis, resulting in a stronger resonance band in the NIR region and a weaker band in the visible region (~520 nm for gold nanospheres). The synthesis of the colloidal gold nanorods would therefore prove effectively for photothermal therapy because they can absorb low-energy NIR light and convert it to heat in the usual way.

The gold species conjugated to antibodies can be selectively targeted to cancer cells without significant binding to healthy cells. In general, the routes to nanoparticle delivery are mainly based on an "active" mechanism and a "passive" mechanism.[67] In the active mode, the molecule ligands of antibodies, DNA, and peptides are used to recognize specific receptors on the tumor cell surface. In the passive mode, the nanoparticles without targeting ligands are accumulated and retained in the tumor interstitial space mainly. In both mechanisms, the nanoparticles in the bloodstream must first move across the tumor blood vessels. Some reports were used PEG ligand to attach the lysine-capped Au nanoparticles through lysineterminated PEG link.[68] The targeted delivery of the gold nanoparticles to solid tumors is one of the most important and challenging problems in cancer nanomedicine. It was recently observed that the colloidal gold nanoparticles were found in dispersed and aggregated forms within the cell cytoplasm and provided anatomic labeling information. The anti-EGFR antibody-conjugated nanoparticles homogeneously bind to the surface of the cancer type cells with greater affinity than to the noncancerous cells. These results were detected by using SPR scattering imaging and SPR absorption spectroscopy, in which a relatively sharper SPR absorption band with a red shifted maximum compared to that observed on noncancerous cells.[69] We recently reviewed the aqueous-based synthetic pathways of the metal nanocrystals potential in biomedical applications.[67]

Functional Inorganic Nanohybrids for Biomedical Diagnosis 329

The Au and Fe3O4 particles both in a hybrid system are known to be highly compatible with biomedicine and a consequence of extending for diagnostics and therapeutics. The Au and Fe3O4 interfaces result in drastically change the local electronic structure, leading to an enhancement of their synergistic properties. The plasmonic and magnetic properties of the nanohybrids could be optimized by adjusting the size of the two particles. In comparison with the single Au and Fe3O4 particles, the Au/Fe3O4 hybrids possessing simultaneous plasmonic and magnetic detection facilitate for cancer diagnosis and therapy. When the biomolecules-conjugated Au/Fe3O4 hybrids are dispersed in body, they could travel to the targeted cancer tumors by influence of external magnetic field. The Au and Fe3O4 particles in the hybrid system adsorb energy from irradiating laser light and from exposing external magnetic field, respectively, and convert them into heat to kill the cancer cells. By using these bifunctional materials, an abundant amount of synergistic heating within the cancer tumors is created by a simultaneous adsorption-conversion of Au and Fe3O4 species

**Figure 8** shows the use of S6 aptamer-conjugated plasmonic-magnetic Au-Fe3O4 nanohybrids for the targeted diagnosis, isolation, and photothermal destruction of human breast cancer cells.[72] Cy3-modified S6 aptamers were attached to magnetic/plasmonic nanoparticles through -SH linkage. In the multifunctional nanoparticles, gold plasmonic shells were used as both a photothermal agent and a nanoplatform; the magnetic core was used for cell isolation. The S6 aptamer-conjugated magnetic/plasmonic nanoparticles attached to the cancer cells due to the S6 aptamer-cancer cell interaction. The bioconjugated magnetic/plasmonic nanoparticles highly selectively bind to the cells, which can be used for targeted imaging and magnetic separation of a specific kind of cell from a mixture of different cancer cells. The photothermal destruction results showed a selective irreparable cellular damage to most of the cancer cells, due to the absorption of 670 nm continuous NIR

Sun et al.[10] was achieved the thermolysis of Fe(CO)5 on the surface of the Au nanoparticles in octadecene to produce Au-Fe3O4 dumbbells followed by coupling with Herceptinand Pt complex. The cisplatin complex was linked to Au surface by reacting Au-S-CH2CH2N(CH2COOH)2 with cisplatin. The coating of Herceptin antibody on Fe3O4 particles was performed by PEG3000-CONH-Herceptin. Cisplatin-Au-Fe3O4-Herceptin nanohybrids were tested to HER2-positive breast cancer cells and HER2-negative breast cancer cells. The cisplatin-Au-Fe3O4-Herceptin hybrids revealed a high efficiency in the killing of HER2 positive cancer cells. The presence of the hollow inside the nanohybrids was witnessed as an efficient carrier for targeted delivery and controlled release of cisplatin. These materials illustrated the possibility of acting as a multifunctional platform for target-specific platin delivery. Besides, other plasmon-magnetic materials of FePt/Fe2O3 yolk-shells[6] and mesoporous silica-coated Au-Fe3O4 core shells[73] were also synthesized and extensively studied for strong MRI contrast agent enhancement and carriers for anticancer drug

facilitating the heating of the cancer cells.

irradiation of the hybrid nanostructures.

delivery.
