Nanoclinics For Optical Diagnostics And Targeted Therapy

Our Institute for Lasers, Photonics, and Biophotonics has developed the concept of a nanoclinic, a complex surface functionalized silica nanoshell containing various probes for diagnostics and drugs for targeted delivery (Levy et al., 2002). Nanoclinics provide a new dimension to targeted diagnostics and therapy. These nanoclinics are produced by multistep nanochemistry in a

Targeted Diagnostic Pictures

Figure 15.11. Illustrated representation of a nanoclinic

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Figure 15.11. Illustrated representation of a nanoclinic reverse micelle nanoreactor, a method discussed in detail in Section 15.2. An illustrated representation of a nanoclinic is shown in Figure 15.11.

These nanoparticles are subsequently surface-functionalized to target specific cells for biological sites. These nanoclinics are ~30-nm silica shells that can encapsulate various optical, magnetic, or electrical probes as well as platforms containing externally activatable drugs or therapeutic agents (see Figure 15.11). The size of these nanoclinics is small enough to enter the cell in order for them to function from within the cell. Through the development of nanoclinics (functionalized nanometer-sized particles that can serve as carriers), new therapeutic approaches to disease can be accomplished from within the cell. At our Institute, integration of the ferrofluid, nanotechnology, and peptide hormone targeting has resulted in the fabrication of multifunctional nanoclinics. One example of a nanoclinic is a multilayered nanosized structure consisting of an iron oxide core, a two-photon optical probe, and a silica shell with a LH-RH targeting hormone analogue, covalently coupled to the surface of the shell. This protocol can produce nanoclinics with a tunable size from 5 to 40nm in diameter. They are small enough to be able to diffuse into the tissue and enter the cells (by endocytotic processes) and are large enough to respond to the applied magnetic field at 37°C. High-resolution transmission electron microscopy shows that the structure of the nanopar-ticle is composed of a crystalline core corresponding to Fe2O3 and one amorphous silica layer (bubble). The same crystalline/amorphous structure was obtained by electron diffraction of the particle and also confirmed by x-ray diffraction.

The two-photon dye is able to absorb one photon (with a wavelength of 400 nm) or two photons (with a wavelength of 800nm) by direct two-photon absorption. The selective interaction and internalization of these nanoclinics with cells was visualized using two-photon laser scanning microscopy, allowing for real-time observation of the uptake of nanoclinics (Bergey et al., 2003). Two different types of particles were used in this study: LH-RH-positive (surface-coupled) and LH-RH-negative (spacer arm only). A suspension of nanoclinics was added to adherent (KB) oral epithelial carcinoma cells (LH-RH receptor positive), and uptake was observed using laser scanning microscopy. The time-dependent uptake of the LH-RH-positive nanoclinics by LH-RH receptor bearing cells was identified. A similar accumulation was not observed in LH-RH-negative nanoclinics studies or LH-RH-positive nan-oclinics incubated with receptor-negative cells (UCI-107). Thus, targeting of LH-RH receptor-specific cancer cells and the specific effects of the nanoclin-ics were demonstrated.

The multifunctional nanoclinics containing the magnetic Fe2O3 nanoparti-cles also produced a new discovery for targeted therapy, a new effect that to our knowledge has not previously been reported, that being the selective lysing of cancer cells in a dc magnetic field using magnetic nanoclinics. Magnetic probes or particles have been investigated as a potential alternative treatment for cancer. Studies have demonstrated that the hyperthermic effect generated by magnetic particles coupled to a high-frequency ac magnetic field (requiring tremendous power) could be used as an alternate or adjuvant to current therapeutic approaches for cancer treatment. This hyperthermic effect (heat produced by the relaxation of magnetic energy of the magnetic material) was shown to effectively destroy tumor tissue surrounding the probes or particles. This approach resulted in reduction of the tumor size by hyperther-mic effect when the particles were directly injected into the tissue and were exposed to an alternating magnetic field. However, no targeted therapy using a dc magnetic field has been reported previously, to our knowledge. Our work demonstrated the use of a dc magnetic field at a strength typically achievable by magnetic resonance imaging (MRI) systems for selectively destroying cancer cells. AFM studies together with a detailed study of magnetization behavior suggest mechanical disruption of the cellular structure by alignment of the nanoclinic.

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