Novel Nanoparticle-Based Approaches To Target B-Cell Malignancies.

Introduction: Current approaches to the management of B-cell malignancies include the use of systemic treatments with cytotoxic chemotherapeutics that are not targeted to the tumor cell itself. By improving the ability to deliver lethal agents to the malignant cell clone, such as by targeting the unique tumor idiotype, it is possible that the therapeutic index of our current armamentarium could be improved, thereby optimizing patient outcomes. Nanoparticles represent one attractive approach in this area, since their high surface to volume ratio provides a strong driving force for diffusion into the tumor microenvironment.

Methods: Studies were performed using Ramos and SUP-B8 human Burkitt’s lymphoma cell lines, as well as cell lines representative of other hematologic malignancies. Commercially available nanoparticles (Qdots; Invitrogen) as well as nanoparticles generated using PRINT (particle replication in non-wetting templates) technology, were used with idiotype and control peptides.

Results: A biotinylated peptide recognized by the SUP-B8 idiotype was bound to streptavidin-containing Qdots, as well as to 200 nm polymeric PRINT particles. Both of these nanoparticle types bound specifically to SUP-B8 Burkitt’s lymphoma cells, as determined by the induction of a fluourescence shift by flow cytometry. These same particles showed no detectable binding to Ramos Burkitt’s lymphoma cells, whose idiotype recognizes a distinct set of peptide sequences, nor to other malignant cell lines, such as RPMI 8226 and ANBL-6 multiple myeloma cells. Moreover, when these nanoparticles were coated with control biotinylated peptides, no binding was seen to any of these cell types, demonstrating the specificity of this approach. Studies utilizing a number of techniques, including fluorescence and electron microscopy, revealed that, after binding, these idiotype-specific particles were internalized by SUP-B8 cells, but not by control cells, or when control peptides were used. Studies in vivo are underway to determine if these targeted nanoparticles can be used for imaging, as well as for delivery of lethal cargoes such as doxorubicin.

Conclusion: Nanoparticles can be targeted to specific neoplastic B-cell clones through the use of peptides recognized by the surface idiotype, possibly thereby sparing toxic effects to other B-cell clones, as well as to non-lymphoid cells. The ability to generate nanoparticles of various chemistries, sizes, and porosity, as well as nanoparticles containing a wide array of cargoes, will allow these to be used as platforms for the future personalization of therapy of B-cell malignancies.