Lymphocyte-mediated drug nanoparticle delivery to disseminated lymphoma tumors in vivo

Abstract

The dissemination of lymphoma into anatomical compartments that are poorly accessible from circulation, such as lymph nodes, necessitates high doses of systemic chemotherapy. However, the potencies of many chemotherapeutic drugs are hampered by off-target toxicity and poor pharmacokinetics. To deliver drugs into disseminated lymphoma tumors in vivo, we took advantage of the fact that lymphoma distribution is mirrored by the homeostatic trafficking of healthy lymphocytes. We hypothesized that we could use T cells as live vectors to transport drug-loaded nanoparticles into lymphoid organs where lymphoma cells are enriched. To test this concept, we synthesized a controlled-release liposome system to encapsulate the topoisomerase II poison doxorubicin, and a lipid-based nanoparticle system loaded with the topoisomerase I poison SN-38. We then generated in vitro-activated primary murine T cell carriers using optimized culture conditions that induced robust proliferation and high expression levels of CD62L for lymph node homing. The dox liposomes and SN-38 nanoparticles were surface functionalized with maleimide groups to allow covalent conjugation of the particles to the plasma membrane thiol groups on T cells. In the orthotopic syngeneic murine Emu-myc Arf-/- lymphoma model, drug nanoparticle-decorated T cells retained and delivered particles to multiple tumor sites in vivo as early as 15 h post-adoptive transfer. In vitro co-culture of Emumyc Arf-/- lymphoma cells and drug nanoparticle-functionalized T cells showed that lymphoma cells are much more sensitive to SN-38 nanoparticle-conjugated T cells than to dox liposome-conjugated T cells. Consistent with this, therapy studies in the Emu-myc Arfl~ model indicated that dox liposome-carrying T cells have limited therapeutic efficacy, while SN-38 nanoparticle-functionalized T cells rapidly reduce tumor burden in all major tumor sites. Finally, we examined the post-treatment biodistribution of Emu-myc Arf-/- lymphoma cells and discovered a therapeutic synergy between T cell-mediated drug particle delivery and blockade of lymphoma interactions with the bone marrow. These results suggest that autologous lymphocytes may be useful as chaperones for targeted delivery of chemotherapy-loaded nanoparticles to lymphoid tumors.