Modulation of intrabone distribution of anionic polypeptide nanocarriers through hydrophobic modification for the treatment of acute myeloid leukemia.
basic_science · Level V
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- Record sourced from PubMed, PMID 42025987.
- Also identified by DOI 10.1016/j.actbio.2026.04.031.
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Abstract
The treatment of acute myeloid leukemia (AML) with bone-targeting nanomedicine has shown great potential recently. Nevertheless, the fine-tuning of nanoparticle distribution in bone tissues, which is directly correlated with the therapeutic outcomes, remains challenging. Herein, we report the modulation of intrabone distribution of star-shaped, anionic polypeptides through hydrophobic modification, which mediated intracellular delivery of loaded drugs to bone-resident AML cells. The introduction of hydrophobic cores not only facilitated the loading of drugs, but also selectively improved the cellular uptake over mineral binding. After the size optimization, the gilteritinib-loaded, polypeptide-based unimolecular micelles showed enhanced therapeutic outcomes with significantly limited progression of AML in a systemic mouse xenograft model. We believe this work highlights the structural modulation of polymeric nanocarriers to regulate their sub-organ distributions, offering promising AML nanomedicine with enhanced efficacy and reduced toxicity. STATEMENT OF SIGNIFICANCE: Bone-targeting nanomedicine based on anionic nanocarriers has shown great potential to treat acute myeloid leukemia (AML), mainly due to their selective accumulation within bone tissues to eradicate the bone-resident leukemic cells. However, their high affinity to inorganic matrices limited the cellular internalization by AML cells. Herein we report the introduction of the hydrophobic core in the anionic polypeptide-based nanocarriers, which retains their circulation and bone-targeting ability but significantly alters their biodistribution within the bone tissues. The enhanced uptake by bone-resident, malignant leukemic cells facilitates the delivery of gilteritinib to treat AML. We believe our work highlights the structural modulation of polymeric nanocarriers to regulate their sub-organ distributions, offering promising AML nanomedicine design with enhanced efficacy and reduced toxicity.