In Vivo Prostate Tumor Targeting And Imaging

Akerman et al. first reported the use of QD-peptide conjugates to target tumor vasculatures, but the QD probes were not detected in living animals (52). Nonetheless, their in vitro histological results revealed that QDs homed to tumor vessels guided by the peptides and were able to escape clearance by the reticuloendothelial system. Most recently, Gao et al. reported a new class of multifunctional QD probes for simultaneous targeting and imaging of tumors in live animals (25). This class of QD conjugates contains an amphiphilic triblock copolymer for in vivo protection, targeting ligands for tumor antigen recognition, and multiple PEG molecules for improved biocompatibility and circulation. The use of an ABC triblock copolymer has solved the problems of particle aggregation and fluorescence loss previously encountered for QDs stored in physiological buffer or injected into live animals (52-54). Detailed studies were reported on the in vivo behaviors of QDs probes, including biodistribution, nonspecific uptake, cellular toxicity, and pharmacokinetics.

Under in vivo conditions, QD probes can be delivered to tumors by both a passive targeting mechanism and an active targeting mechanism. In the passive mode, macromolecules and nanometer-sized particles are accumulated preferentially at tumor sites through an enhanced permeability and retention effect (55,56). This effect is thought to arise from two factors:

1. Angiogenic tumors, which produce vascular endothelial growth factors that hyperpermeabilize the tumor-associated neovasculatures and cause the leakage of circulating macromolecules and small particles.

2. Tumors lack an effective lymphatic drainage system, which leads to subsequent macromolecule or nanoparticle accumulation.

For active tumor targeting, Gao et al. have used antibody-conjugated QDs to target a prostate-specific cell surface antigen, prostate-specific membrane antigen (PSMA) (Fig. 6D). Previous research has identified PSMA as a cell surface marker for both prostate epithelial cells and neovascular endothelial cells (57). PSMA has been selected as an attractive target for both imaging and therapeutic intervention of prostate cancer (58). Accumulation and retention of PSMA antibody at the site of tumor growth is the basis of radioimmunoscintigraphic scanning (e.g., ProstaScint scan) and targeted therapy for human prostate cancer metastasis (59).

8. TOXICITY AND POTENTIAL CLINICAL USE

The potential toxic effects of semiconductor QDs have recently become a topic of considerable importance and discussion. Indeed, in vivo toxicity is likely a key factor in determining whether QD imaging probes would be approved by regulatory agencies for human clinical use. Recent work by Derfus et al. indicates that CdSe QDs are highly toxic to cultured cells under UV illumination for extended periods of time (60). This is not surprising, because the energy of UV-irradiation is close to that of covalent chemical bond and dissolves the semiconductor particles in a process known as photolysis, which releases toxic cadmium ions into the culture medium. In the absence of UV irradiation, QDs with a stable polymer coating have been found to be essentially nontoxic to cells and animals, for example no effect on cell division or ATP production (D. Stuart, X. Gao, and S. Nie, unpublished data). It has also been reported that the polymer-coated QDs could be toxic if significant aggregates are formed on the cell surface (61). In vivo studies by Ballou and coworkers also confirmed the nontoxic nature of stably protected QDs (42). Still, there is an urgent need to study the cellular toxicity and in vivo degradation mechanisms of QD probes. For polymer-encapsulated QDs, chemical or enzymatic degradations of the semiconductor cores are unlikely to occur. However, the polymer-protected QDs might be cleared from the body by slow filtration and excretion out of the body. This and other possible mechanisms must be carefully examined before any human applications in tumor or vascular imaging.

9. CONCLUDING REMARKS

QDs have already fulfilled some of their promises as a new class of molecular probes for cancer research. Through their versatile polymer coatings, QDs have also provided a "building block" to assemble multifunctional nanostructures and nanodevices. Multi-modality imaging probes could be created by integrating QDs with paramagnetic or superparamagnetic agents. Indeed, researchers have recently attached QDs to Fe2O3 and FePt nanoparticles (62,63) and even to paramagnetic gadolinium chelates (X. Gao and S. Nie, unpublished data). By correlating the deep imaging capabilities of MRI with ultrasensitive optical imaging, a surgeon could visually identify tiny tumors or other small lesions during an operation and remove the diseased cells and tissue completely. Medical imaging modalities such as MRI and PET can identify diseases noninvasively, however, they do not provide a visual guide during surgery. The development of magnetic or radioactive QD probes could solve this problem.

Another desired multifunctional device would be the combination of a QD imaging agent with a therapeutic agent. Not only would this allow tracking of pharmacokinetics, but diseased tissue could be treated and monitored simultaneously and in real time. Surprisingly, QDs may be innately multimodal in this fashion, because they have been shown to have potential activity as photodynamic therapy agents (64). These combinations are only a few possible achievements for the future. Practical applications of these multifunctional nanodevices will not come without careful research, but the multidisciplinary nature of nanotechnology may expedite these goals by combining the great minds of many different fields. The success seen so far with QDs points toward the success of QDs in biological systems, and predicts the success of other nanotechnologies for biomedical applications.

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