Utilization of monoclonal antibody-targeted nanomaterials in the treatment of cancer

Abstract

Due to their excellent specificity for a single epitope, monoclonal antibodies (mAbs) present a means of influencing the function of cells at the molecular level. In particular they show great promise in the treatment of cancer because they can inhibit cancer cell proliferation, tumor angiogenesis, invasiveness and malignant spread of cancerous cells. Many mAbs are in various stages of testing and 11 are currently marketed in the US or Europe for the treatment of cancers that express particular antigens such as human epidermal growth factor receptor-2, CD20, epidermal growth factor receptor and vascular endothelial growth factor. Strategies to conjugate mAbs to toxins, radioactive isotopes and chemotherapeutic drugs to improve efficacy are under intense investigation and numerous immunoconjugates have been studied in the clinical setting. However, the molecules have limitations, and so nanomaterials (NMs), which potentially offer more flexibility of design and functionality in providing platforms for binding of multiple therapeutic agents in a single structure, are being examined as an alternative. Studies utilizing mAb-targeted NMs have shown that they exhibit focused targeting, improved pharmacokinetics and improved “passive” drug delivery via leaky vasculature. Nevertheless, before they can be utilized to treat cancer, potential NM toxicity must be thoroughly investigated. Thus, rigorous testing of NM-mAb conjugates in both in vitro and in vivo systems is underway to determine how NM-mAb conjugates will interact with cells and tissues of the body. In this review, we discuss the broad range of nanomaterials that are under investigation as potential platforms for the presentation of mAbs either as single therapeutics or in combination with other drugs and their advantages and limitations in specifically targeting cancer.

Acknowledgments

This work was supported by the University of Idaho Blue Ribbon BANTech initiative and by the National Science Foundation under award number CBET-0709468.

Figures and Tables

Figure 1 Cellular uptake of mAb conjugated nanoparticle. mAb conjugated nanoparticles can be recognized by receptors on the cell membrane. Thus the nanoconjugates are internalized and trafficked along intracellular retrograde transport pathways.

Figure 2 Possible mechanisms of nanostructure extravasation. In the case of a continuous vascular endothelial barrier, nanostructures may be internalized by endothelial cells, e.g., via caveolae, transported via trans-cellular transport mechanisms and escape into the extracellular space via exocytosis. It is generally accepted that extravasation through tight gap junctions is limited to molecules or particles smaller than 10 nm.33,112 In the case of tumor vasculature, nanostructures may also escape the vasculature via transendothelial channels (TEC) and fenestrae. Molecules or particles up to 100 nm diameter may escape the vasculature via this route.1 Where the vasculature is sinusoidal/discontinuous (e.g., liver, spleen), nanostructures and large molecules may readily escape the vasculature.

Table 1 Monoclonal antibodies approved by the US food and drug administration for the treatment of cancer

Table 2 Types of nanomaterials utilized in the treatment of cancer, their advantages and limitations