Surgery: light – thermal – and electrical application – Light – thermal – and electrical application – Light application
Reexamination Certificate
2001-02-08
2003-03-11
Gibson, Roy (Department: 3739)
Surgery: light, thermal, and electrical application
Light, thermal, and electrical application
Light application
C607S100000, C424S497000
Reexamination Certificate
active
06530944
ABSTRACT:
BACKGROUND OF THE INVENTION
In many applications, it is desirable to target cells and tissue for localized heating or imaging. The therapeutic effects range from the destruction of cancerous cells and tumors, to the therapeutic or cosmetic removal of benign tumors and other tissue. Techniques which effect precise localized heating and illumination would allow one to enjoy therapeutic and diagnostic benefits, while minimizing the collateral damage to nearby cells and tissue. It is desirable that such techniques be amenable to both in vitro and in vivo therapeutic and diagnostic applications of induced hyperthermia and imaging, respectively, of cells and tissue.
A potentially useful in vivo application of such a technique would be in cancer reatment. For example, metastatic prostate cancer is a leading cause of mortality in American men. Estimates indicate that greater than one in every eleven men in the U.S. will develop prostate cancer. Accurate determination of the extent of local disease is often difficult. Methods for accurately detecting and imaging localized prostate disease are greatly needed. In addition, localized prostate cancer is generally treated with either radical prostatectomy or radiation therapy. Both of these procedures are plagued by significant morbidity. Minimally invasive treatment strategies with low associated morbidity should be feasible and would dramatically improve prostate cancer therapy.
A number of techniques have been investigated to direct therapeutic and diagnostic agents to tumors. These have included targeting of tumor cell surface molecules, targeting regions of activated endothelium, utilizing the dense and leaky vasculature associated with tumors, and taking advantage of the enhanced metabolic and proteolytic activities associated with tumors. Antibody labeling has been used extensively to achieve cell-selective targeting of therapeutic and diagnostic agents. A number of approaches have been taken for antibody-targeting of therapeutic agents. These have included direct conjugation of antibodies to drugs such as interferon-alpha (Ozzello, et al., 1998), tumor necrosis factor (Moro, et al., 1997), and saporin (Sforzini, et al., 1998). Antibody conjugation has also been used for tumor-targeting of radioisotopes for radioimmunotherapy and radioimmunodetection (Zhu, et al., 1998). Currently, there is a commercial product for detection of prostate cancer (ProstaScint) that is an antibody against prostate-specific membrane antigen conjugated to a scintigraphic target (Gregorakis, et al., 1998). Immunoliposomes or affinity liposomes are liposome drug carriers with antibodies conjugated to their surfaces. These drug carriers can be loaded with cytotoxic agents, such as doxorubicin, for destruction of cancerous cells. Antibody targeting is also under investigation for cell-selective gene therapy.
Virus particles have been developed that display single chain antibodies on their surface, allowing specific targeting of a wide variety of cell types (Yang, et al., 1998; Jiang, et al., 1998; Chu & Dornburg, 1997; Somia, et al., 1995). To target regions of activated endothelium, immunoliposomes have been made with antibodies to E-selectin on their surfaces. It may be possible to achieve similar targeting efficiencies with small tumor-specific peptides (Pasqualini, et al., 1997). Recently, tumors have been imaged using protease-activated near-infrared fluorescent probes (Weissleder, (1999). These agents could be administered systemically, were accumulated in the tumors due to the abundant and leaky vasculature, and were activated by the elevated proteolytic enzymes.
The nanoparticles that are the subject of this invention are amenable to these types of targeting methodologies. The nanoparticle surfaces can easily be modified with antibodies, peptides, or other cell-specific moieties. A specific embodiment of these nanoparticles act as absorbers of radiation. These nanoparticles have tunable excitation wavelengths and undergo nonradiative decay back to the ground state by emission of heat. This heat can be used to effect local hyperthermia. Alternatively, these nanoparticles, in addition to acting as absorbers, may scatter light and thereby act as contrast agents as a means to image the local environment in which they reside. Other nanoparticles that are also the subject of this invention are strong visible and infrared fluorophores. Their strong emission is used in imaging applications. It is known that solid metal nanoparticles (i.e. solid, single metal spheres of uniform composition and nanometer dimensions) possess interesting optical properties. In particular, metal nanoparticles display a pronounced optical resonance. Metal nanoparticles are similar to metal colloids in this regard, exhibiting a strong optical absorption due to the collective electronic response of the metal to light. Metal colloids have a variety of useful optical properties including a strong optical absorption and an extremely large and fast third-order nonlinear optical (NLO) polarizability. These optical properties are attributed to the phasic response of electrons in the metallic particles to electromagnetic fields. This collective electron excitation is known as plasmon resonance. At resonance, dilute metal colloid solutions have the largest electronic NLO susceptibility of known substances. However, the utility of these solutions is limited because their plasmon resonance is confined to relatively narrow wavelength ranges and cannot readily be shifted. For example, silver particles 10 nm in diameter absorb light maximally at approximately 355 nm, while similar sized gold particles absorb maximally at about 520 nm. These absorbance maximums are insensitive to changes in particle size and various dielectric coatings on the particles. However, the nanoparticles of this invention are more amenable to a directed shift in their plasmon resonance and hence absorption or scattering wavelengths tan these solid metal nanoparticles.
There have been earlier efforts for therapeutic uses of compositions that emit heat upon excitation, however, these are distinguishable from the present invention. In U.S. Pat. No. 4,983,159, Rand describes the induction of hyperthermia to a neoplasm using particles which exhibit a heating hysteresis when subjected to an alternating magnetic field. However, the particles used in the '159 patent are more properly described as microparticles and are much larger than the analogous nanoparticles used herein. U.S. Pat. Nos. 4,106,488 and 4,303,636 to Gordon describe particles of nanometer scale dimensions. However, the excitation source is different from that which is used herein and outside the scope of the present invention. As such, it is believed that the underlying physical excitation mechanisms of these earlier works differs from that of the present invention.
A serious practical limitation to realizing many applications of solid metal nanoparticles is the inability to position the plasmon resonance at technologically important wavelengths. For example, solid gold nanoparticles of 10 nm in diameter have a plasmon resonance centered at 520 nm. This plasmon resonance cannot be controllably shifted by more than approximately 30 nanometers by varying the particle diameter or the specific embedding medium.
One method of overcoming this problem is to coat small nonconducting particles with these metals. For example, the reduction of Au on Au
2
S (reduction of chloroauric acid with sodium sulfide) particles has been shown to red shift the gold colloid absorption maximum from 520 nm to between approximately 600 nm and 900 nm, depending on the amount of gold deposited on the Au
2
S core and the size of the core. Zhou, et al. (1994). The ratio of the core radius to shell thickness can be controlled by changing the reactant concentrations or by stopping the reaction. In this case, the diameter of the particle core is directly proportional to the red shift in the wavelength of light that induces gold plasmon resonance. However, gold-sulfide particle diameters are
Halas Nancy J.
Hirsch Leon R.
West Jennifer L.
Gibson Roy
Rice University
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