Rationale & aim: Imatinib mesylate (IM), a selective tyrosine kinase inhibitor of the oncoprotein BCR-ABL, is the 'gold standard' for patients with chronic myeloid leukemia (CML) but the drug does not eliminate CML stem cells, leading to disease relapse on drug discontinuation. At present, much effort is focused on delivery carriers that can increase the intracellular retention and antileukemic impact of IM. We previously validated IM-loaded polyelectrolyte microcapsules as effective purging agents to eradicate BCR-ABL(+) cells from CML patient autografts. The aim is to develop controlled release carriers that can increase the intracellular retention and functionality of IM in leukemia cells. Materials & methods: Herein, novel polyelectrolyte complexes were used as model carriers for IM in a CML cell line (KU812) and CD34(+) cells freshly isolated from patients. Results & discussion: Polyelectrolyte complexes promoted a long-acting BCR-ABL kinase inactivation that was necessary to promote apoptosis at approximately twofold lower intracellular IM dose compared with the microscale formulation polyelectrolyte microcapsules. Conclusion: IM-loaded polyelectrolyte complexes can be used as more efficient delivery devices for overcoming drug resistance of BCR-ABL(+) leukemic cells. Original submitted 26 September 2012; Revised submitted 17 July 2013.
Uptake of imatinib-loaded polyelectrolyte complexes by BCR-ABL+ cells: a long-acting drug-delivery strategy for targeting oncoprotein activity
GIGLI, Giuseppe
2013-01-01
Abstract
Rationale & aim: Imatinib mesylate (IM), a selective tyrosine kinase inhibitor of the oncoprotein BCR-ABL, is the 'gold standard' for patients with chronic myeloid leukemia (CML) but the drug does not eliminate CML stem cells, leading to disease relapse on drug discontinuation. At present, much effort is focused on delivery carriers that can increase the intracellular retention and antileukemic impact of IM. We previously validated IM-loaded polyelectrolyte microcapsules as effective purging agents to eradicate BCR-ABL(+) cells from CML patient autografts. The aim is to develop controlled release carriers that can increase the intracellular retention and functionality of IM in leukemia cells. Materials & methods: Herein, novel polyelectrolyte complexes were used as model carriers for IM in a CML cell line (KU812) and CD34(+) cells freshly isolated from patients. Results & discussion: Polyelectrolyte complexes promoted a long-acting BCR-ABL kinase inactivation that was necessary to promote apoptosis at approximately twofold lower intracellular IM dose compared with the microscale formulation polyelectrolyte microcapsules. Conclusion: IM-loaded polyelectrolyte complexes can be used as more efficient delivery devices for overcoming drug resistance of BCR-ABL(+) leukemic cells. Original submitted 26 September 2012; Revised submitted 17 July 2013.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
