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A multivalent Ara-C-prodrug nanoconjugate achieves selective ablation of leukemic cells in an acute myeloid leukemia
Victor Pallarès1, Ugutz Unzueta2, Aïda Falgàs1
1Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, 08041, Spain; Josep Carreras Leukaemia Research Institute, Barcelona, 08916, Spain; CIBER en Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Madrid, 28029, Spain.
Abstract:
Current therapy in acute myeloid leukemia (AML) is based on chemotherapeutic drugs administered at high doses, lacking targeting selectivity and displaying poor therapeutic index because of severe adverse effects. Here, we develop a novel nanoconjugate that combines a self-assembled, multivalent protein nanoparticle, targeting the CXCR4 receptor, with an Oligo-Ara-C prodrug, a pentameric form of Ara-C, to highly increase the delivered payload to target cells. This 13.4 nm T22-GFP-H6-Ara-C nanoconjugate selectively eliminates CXCR4+ AML cells, which are protected by its anchoring to the bone marrow (BM) niche, being involved in AML progression and chemotherapy resistance. This nanoconjugate shows CXCR4-dependent internalization and antineoplastic activity in CXCR4+ AML cells in vitro. Moreover, repeated T22-GFP-H6-Ara-C administration selectively eliminates CXCR4+ leukemic cells in BM, spleen and liver. The leukemic dissemination blockage induced by T22-GFP-H6-Ara-C is significantly more potent than buffer or Oligo-Ara-C-treated mice, showing no associated on-target or off-target toxicity and, therefore, reaching a highly therapeutic window. In conclusion, T22-GFP-H6-Ara-C exploits its 11 ligands-multivalency to enhance target selectivity, while the Oligo-Ara-C prodrug multimeric form increases 5-fold its payload. This feature combination offers an alternative nanomedicine with higher activity and greater tolerability than current intensive or non-intensive chemotherapy for AML patients.
Insights
A novel nanoconjugate selectively targets CXCR4-positive acute myeloid leukemia (AML) cells. This targeted approach enhances drug delivery and reduces toxicity, offering a more effective and tolerable treatment for AML patients.
Area of Science:
- Nanomedicine
- Oncology
- Drug Delivery
Background:
- Current acute myeloid leukemia (AML) treatments use high-dose chemotherapy with poor selectivity and severe side effects.
- Leukemic cells in the bone marrow niche are protected, contributing to treatment resistance.
Purpose of the Study:
- To develop a novel nanoconjugate for targeted delivery of chemotherapy to CXCR4-positive AML cells.
- To improve the therapeutic index of AML treatment by enhancing drug payload and reducing toxicity.
Main Methods:
- Development of a multivalent protein nanoparticle (T22-GFP-H6) targeting the CXCR4 receptor.
- Conjugation with an Oligo-Ara-C prodrug, a pentameric form of Ara-C, to create T22-GFP-H6-Ara-C nanoconjugate.
- In vitro and in vivo evaluation of nanoconjugate's selectivity, efficacy, and toxicity in CXCR4+ AML models.
Main Results:
- The T22-GFP-H6-Ara-C nanoconjugate selectively eliminated CXCR4+ AML cells in vitro and in vivo.
- Demonstrated CXCR4-dependent internalization and antineoplastic activity.
- Showed significantly enhanced leukemic cell elimination in bone marrow, spleen, and liver compared to controls.
- Exhibited no significant on-target or off-target toxicity, indicating a wide therapeutic window.
Conclusions:
- The T22-GFP-H6-Ara-C nanoconjugate offers enhanced target selectivity through multivalency and increased payload delivery via the Oligo-Ara-C prodrug.
- This nanomedicine presents a promising alternative to current AML chemotherapy, with higher activity and improved tolerability.
