Quantum Dots for Cancer Diagnosis and Therapy: Biological and Clinical Perspectives

Hua Zhang; Douglas Yee; Chun Wang

Disclosures

Nanomedicine. 2008;3(1):83-91. 

In This Article

Challenges

The potential toxicity of the binary QDs is a cause for concern because they are made of heavy metals. The toxicity could be caused by the release of cadmium ions. Although such QDs should not be acutely toxic as long as their polymer coating is stable enough to restrain the release of cadmium, both short- and long-term safety of QDs will need to be established in toxicological studies in clinically relevant animal models. Studies in cell lines have shown that QDs do not affect cell growth under normal media conditions[55,56] and short-term administration of QDs into animals, such as pig or mice, seems not to affect the metabolism and behavior of the animals.[13,40,57] However, under all these conditions, cadmium is quarantined but not eliminated from the body, which might cause substantial regulatory concerns when QDs enter clinical trials in the future. One exception is their application in SLN mapping because most of the QDs will be removed along with the lymphatic tissue during surgery. To pave the way for clinical use, important questions, such as how rapid QDs in the tumor can be eliminated and whether QDs are excreted or remain resident in the body, and, if yes, which tissue(s) and organ(s) they reside, need to be answered. If QDs are retained in the body, careful toxicological studies in appropriate animal models must be carried out to establish the long-term safety profile of QDs.

All the in vivo animal imaging studies reported so far have been very consistent in showing that, after systemic administration, bare, nontargeted QDs and, to a certain degree, cell-targeted QDs accumulate in substantial quantities in the reticuloendothelial system (RES), which consists of phagocytic cells located in the liver, spleen, lymph nodes and bone marrow.[16,19,40,57,58] The nonspecific uptake by RES not only prevents QDs from targeting to tumor but also brings concerns of toxicity to the RES. One approach to enhance tumor targeting of QDs is to render them long-circulating in the blood through surface modifications.[16,37,46,54,55] Alteration of the surface coating, such as introducing large molecular-weight PEG molecules to decorate QDs, is a popular strategy for achieving long circulation and reducing RES uptake.[50] Prolonged circulation makes it possible for the QDs to accumulate in solid tumor tissues, despite uptake by the RES, taking advantage of the EPR effect[44] without the need for conjugation to targeting ligands. Of course, sufficient stability of the surface coating and the QDs themselves is a prerequisite for being long-circulating. An interesting alternative approach to surface coating is reported by Simberg et al..[59] Prior to injection of peptide-conjugated iron oxide nanoparticle, mice were pre-treated with decoy liposome particles to eliminate plasma opsonins that bind to nanoparticles and mediate their uptake by RES. Intravenously injected decoy liposomes prolonged the half-life of iron oxide nanoparticles, minimized RES uptake and dramatically enhanced the active targeting to xenograft breast tumor. This approach could conceivably be adapted to minimize RES uptake of QDs.

The passive-targeting approach based on the EPR effect is most effective for targeting solid, primary tumors with fairly large size (at least 2 mm) and well developed vasculature. Primary tumors at very early stage and micro-metastasis do not demand significant blood supply and are too small for the EPR effect.[44] Therefore, in these cases, tumor-specific targeting or active targeting of QDs is essential. To maximize active targeting, it is necessary to minimize nonspecific uptake of QDs by the RES, often through proper surface modification, on the basis of which specific targeting ligands are conjugated. These ligands are either small molecules, such as folate, peptides or large proteins, such as monoclonal antibodies. Demonstration of specific tumor targeting of QDs is more challenging in vivo than on tumor cells cultured in vitro for a number of reasons. Complicated anatomical structure and physiology in tissues and organ systems create barriers for QDs, such as vascular endothelium, which prevents extravasation. Protein-based ligands are susceptible to degradation, causing the loss of targeting capacity. Common conjugation chemistries usually do not enable control over how complex macromolecules, such as antibodies, are anchored to QDs, that is, sites of attachment and molecular orientation, and might lead to partial or complete loss of cell-binding activity. Finally, very few cell-targeting ligands are truly 'specific' to tumors, meaning that they only bind to cancer cells but absolutely not to other cells or binding to off-target cells at very low rate. Identifying such ideal ligand-receptor pairs is crucial for QD cancer imaging to reduce the frequency of false-positives and it requires deeper understanding of cancer biology.

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