Cell Surface Properties

In general, one thinks of targeting cancer cells by use of a highly specific surface material that absolutely identifies only that cancer cell within the entire body. Some studies, however, have demonstrated that cancer cells growing in different sites of the body can have altered surface properties that could facilitate non-specific nanoparticle binding and uptake; colloidal iron hydroxide (CIH) nanoparticle association and uptake appears to be enhanced for transformed cells,69 and CIH nanoparticles show differences in cell surface interactions following transformation of chick embryo fibroblasts.70 Such observations suggest that generic cell-surface charge differences might provide a targeting strategy for nanoparticles that could be, even if not highly discriminating, used to enrich nanoparticle delivery to cancer cells through non-specific associations. In combination with other targeting strategies, surface charge differences might provide a useful adjunct. For example, some cancer cells express unique sets of surface enzymes that might be useful to activate a prodrug once a nanoparticle has been localized to the surface of a cancer cell. In this regard, a number of proteases have been shown to be significantly up-regulated by oncogenic conversion.71 A proof of concept for this type of specific application has been described using a polymer-based fluorogenic substrate PB-M7VIS that serves as a selective proteobeacon.36

A number of overexpressed growth factor receptors have been used to selectively target cancer cell surfaces, and the description of many of these targets has been reviewed.72 With regard to targeting nanoparticles, it is important to remember that once engaged by the targeting ligand, some of these surface components are internalized whereas others will remain at the cell surface. Matching the type of nanoparticle material and its potential cargo with the likely fate of the targeted structure can be critical to optimizing the desired outcome. It is also possible that once bound, ligand-nanoparticle complexes could lead to receptor internalization that might not occur by the presence of the targeting ligand alone. The basis for this difference might come from the potential for nanoparticles to contain a coordinated ligand matrix to sequester of cell-surface receptors in a manner that facilitates internalization.

Antibody-based targeting of nanoparticles to solid tumors has been a highly promising strategy that is augmented by the enhanced vascular permeability (EPR effect) of solid tumors. For example, an antibody-directed (anti-p185HER2) liposome loaded with an anti-neoplastic can be an effective cancer therapeutic approach.73 Blood cell-based cancers (e.g., leukemias and lymphomas) can also be targeted by nanoparticles as a way to reduce unwanted systemic side effects. Nanoparticles could be targeted to T-cell leukemia cells using an antibody to a surface cluster of differentiation (CD) antigen, CD3, on the surface of lymphocytes.74 B-cell lymphomas can be targeted by anti-idiotypic antibodies specific for the unique monoclonal antibody expressed by each individual cancer.75 In both of these cases, the potential for these B- and T-cell-derived cancer cells to actively take up particles on their surfaces as part of their normal function in antigen surveillance and presentation might facilitate and even augment the desired outcome using a targeted nanoparticle.

Efficient, targeted delivery of gene therapy elements and/or antigens to antigen presentation cells (APC) has long been a goal for the induction of anti-cancer cell immune responses. Nano-particles provide an exciting possibility to achieve this goal. Coating nanoparticles with mannan facilitates their uptake by APCs such as macrophages and dendritic cells that acts to target these materials to local-draining lymph nodes following their administration.76 Such an approach is likely to provide additional synergy in APC activation because polymer nanoparticles are efficiently phagocytosed by dendritic cells.77 Many APCs express LDL-type receptors, and molecules that interact with this class of receptors could be a means of targeting as well.78 Interestingly, LDL receptors can be an attractive targeting strategy for cancers because many tumors of different origins express elevated levels of this receptor.79 Therefore, LDL-based nanoparticles could be useful in targeting cancer.31

It might also be possible to intentionally alter the surfaces of cancer cells to improve nano-particle targeting. Cells could be transfected with a protein that expresses the appropriate acceptor peptide recognized by a surface-applied bacterial biotin ligase.80 Although there would be multiple issues to overcome prior to clinical application, this approach outlines one strategy where cancer cells might be altered to express a unique surface structure such as biotin that could be very selectively targeted. Reversed-response targeting might also be performed using discriminating cell-surface properties. Hepatocytes can be targeted using nanocapsules decorated with the surface antigen of hepatitis B virus (SAgHBV).81 Because liver cells may lose their capacity to bind SAgHBV following oncogenic conversion, this targeting strategy could be used to deliver cyto-protective materials to normal hepatocytes and enhance the efficacy of chemotherapeutics aimed at liver cancers. Similarly, hepatocytes exclusively express high affinity cell-surface receptors for asialoglycoproteins, and this ligand-receptor system has been used to target albumin nanoparticles to non-cancer cells of the liver.8 Nanoparticles coated with galactose might also be used to target the liver.82

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