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Antineoplastic effect of a diphtheria toxin-based nanoparticle targeting acute myeloid leukemia cells overexpressing
Victor Pallarès1, Yáiza Núñez1, Laura Sánchez-García2
1Biomedical Research Institute Sant Pau (IIB-Sant Pau), Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; Josep Carreras Research Institute, Barcelona, Spain; CIBER en Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Barcelona, Spain.
Abstract:
Nanomedicine has opened an opportunity to improve current clinical practice by enhancing the selectivity in the delivery of antitumor drugs to specific cancer cells. These new strategies are able to bypass toxicity on normal cells increasing the effectiveness of current anticancer treatments. In acute myeloid leukemia (AML) current chemotherapy treatments generate a relevant toxic impact in normal cells and severe side effects or even patient death. In this study, we have designed a self-assembling protein nanoparticle, T22-DITOX-H6, which incorporates a ligand (T22) targeting CXCR4-overexpressing (CXCR4+) cells, and a potent cytotoxic diphtheria toxin domain. CXCR4 is overexpressed in AML leukemic cells and associates with poor prognosis, being, therefore, a relevant clinical target. We demonstrate here that T22-DITOX-H6 induces apoptosis in CXCR4+ leukemic cells through CXCR4-dependent internalization. In addition, repeated T22-DITOX-H6 treatment (10 μg/dose per 10 doses, intravenously injected) in a disseminated AML mouse model (NSG mice intravenously injected with THP-1-Luci cells, n = 10 per group) potently blocks the dissemination of AML cells in bone marrow, spleen and liver of treated mice, without inducing toxicity in healthy tissues. In conclusion, our strategy of selectively ablating CXCR4 positive leukemic cells by administering the T22-DITOX-H6 nanoparticle could be a promising treatment, especially in patients undergoing AML relapse after chemotherapy, in which leukemic cells overexpress CXCR4.
Insights
A novel nanomedicine, T22-DITOX-H6, targets and eliminates CXCR4-positive acute myeloid leukemia (AML) cells. This targeted approach shows promise for treating AML relapse without harming healthy tissues.
Area of Science:
- Nanomedicine
- Oncology
- Molecular Biology
Background:
- Current acute myeloid leukemia (AML) chemotherapy causes significant toxicity to normal cells.
- Overexpression of CXCR4 in AML cells is linked to poor prognosis, making it a key therapeutic target.
Purpose of the Study:
- To design and evaluate a novel self-assembling protein nanoparticle, T22-DITOX-H6, for targeted delivery of a cytotoxic agent to CXCR4-positive AML cells.
- To assess the efficacy and safety of T22-DITOX-H6 in preclinical models of AML.
Main Methods:
- Engineered a protein nanoparticle (T22-DITOX-H6) incorporating a T22 ligand for CXCR4 targeting and a diphtheria toxin domain for cytotoxicity.
- Demonstrated T22-DITOX-H6-induced apoptosis in CXCR4-positive leukemic cells via receptor-dependent internalization.
- Administered repeated intravenous doses of T22-DITOX-H6 to a disseminated AML mouse model.
Main Results:
- T22-DITOX-H6 effectively induced apoptosis in CXCR4-positive leukemic cells.
- Repeated T22-DITOX-H6 treatment in a mouse model significantly inhibited AML cell dissemination in bone marrow, spleen, and liver.
- The nanoparticle treatment did not cause observable toxicity in healthy tissues.
Conclusions:
- The T22-DITOX-H6 nanoparticle selectively eliminates CXCR4-positive leukemic cells.
- This targeted nanomedicine represents a promising therapeutic strategy for AML, particularly in relapsed cases with high CXCR4 expression.
