In a new study, researchers have demonstrated that targeting of acute myeloid leukemia (AML) stem cells (LSCs) can be improved by using functionalized and antigen directed mesoporous silica nanoparticles (MSNs) as carriers for anti-leukemic drugs.
There is urgent need to develop innovative therapeutic concepts for patients with AML as still the majority of patients die of this disease despite intensive polychemotherapy and allogeneic transplantation.
Experiments in murine models as well as in xenograft models using primary human AML samples have convincingly proven that AML is propagated by leukemic stem cells (LSCs).
Acute leukemia is initiated and maintained by leukemia stem cells (LSCs) and therefore there is great interest to develop innovative therapeutic approaches which target LSCs.
The team have shown that LSCs share many characteristics with normal hematopoietic stem cells (HSCs) with regard to their antigen profile, but also with regard to their transcriptional profile.
Differences in the antigen profile between LSCs and HSCs would open the door to the antibody-based preferential targeting of LSCs, sparing normal HSCs. Previously it was showed that AML can be propagated by LSCs with lymphoid characteristics in a CALM-AF10 positive AML model.
These LSCs showed incomplete immunoglobulin DJ rearrangement, but also importantly expressed the lymphoid-associated antigen B220 in contrast to normal HSCs.
The research team provided evidence that a multifunctional particle system based on zwitterionic mesoporous silica nanoparticles (MSNs) functionalized with succinic anhydride, tagged with an anti-B220 antibody.
The MSNs loaded with the anti-leukemic drug anthracycline daunorubicin are efficiently incorporated into murine B220-positive AML LSCs and preferentially kill these cells in comparison to B220-negative AML LSCs in vitro.
Furthermore, short-term treatment of the AML LSCs with these MSNs before transplant significantly delayed leukemia development in recipient mice. These data demonstrate that targeting of AML LSCs can be improved by using functionalized and antigen directed MSNs as carriers for anti-leukemic drugs.
In our approach, the team confirmed the specificity of drug delivery by performing B220 blocking experiments and by using nanoparticles linked to an anti-CD9 antibody as the control.
Furthermore, the team demonstrated a significantly higher toxicity of anti-B220 MSN-DN on B220+ AML LSCs compared to B220– AML LSCs, by this approach comparing cells with highly similar morphology, metabolic state and nature, but discriminated by B220 antigen expression.
In conclusion, the data indicate that functionalized antibody-tagged MSNs are able to target LSCs in vitro and efficiently kill AML LSCs at Daunorubicin (DN) concentration levels well below those needed by free DN. These proof-of-principle experiments demonstrate that it is feasible to tag MSNs with antibodies and to use these nanoparticles in a targeted approach in a leukemia model.