title: Imatinib-loaded polyelectrolyte microcapsules for sustained targeting of BCR-ABL+ leukemia stem cells.
abstract: OBJECTIVE
  The lack of sensitivity of chronic myeloid leukemia (CML) stem cells to imatinib mesylate (IM) commonly leads to drug dose escalation or early disease relapses when therapy is stopped. Here, we report that packaging of IM into a biodegradable carrier based on polyelectrolyte microcapsules increases drug retention and antitumor activity in CML stem cells, also improving the ex vivo purging of malignant progenitors from patient autografts.
  
  
  METHODS
  Microparticles/capsules were obtained by layer-by-layer (LbL) self-assembly of oppositely charged polyelectrolyte multilayers on removable calcium carbonate (CaCO(3)) templates and loaded with or without IM. A leukemic cell line (KU812) and CD34(+) cells freshly isolated from healthy donors or CML patients were tested.
  
  
  CONCLUSIONS
  Polyelectrolyte microcapsules (PMCs) with an average diameter of 3 microm, fluorescently labelled multilayers sensitive to the action of intracellular proteases and 95-99% encapsulation efficiency of IM, were prepared. Cell uptake efficiency of such biodegradable carriers was quantified in KU812, leukemic and normal CD34(+) stem cells (range: 70-85%), and empty PMCs did not impact cell viability. IM-loaded PMCs selectively targeted CML cells, by promoting apoptosis at doses that exert only cytostatic effects by IM alone. More importantly, residual CML cells from patient leukapheresis products were reduced or eliminated more efficiently by using IM-loaded PMCs compared with freely soluble IM, with a purging efficiency of several logs. No adverse effects on normal CD34(+) stem-cell survival and their clonogenic potential was noticed in long-term cultures of hematopoietic progenitors in vitro.
  
  
  CONCLUSIONS
  This pilot study provides the proof-of-principle for the clinical application of biodegradable IM-loaded PMC as feasible, safe and effective ex vivo purging agents to target CML stem cells, in order to improve transplant outcome of resistant/relapsed patients or reduce IM dose escalation.
authors.affiliation: National Nanotechnology Laboratory of CNR-INFM, IIT Research Unit, Scuola Superiore ISUFI, University of Salento, Via Arnesano 73100 Lecce, Italy.
authors.forename: Ilaria E
authors.initials: IE
authors.lastname: Palamà
authors.forename: Stefano
authors.initials: S
authors.lastname: Leporatti
authors.forename: Emanuela
authors.initials: E
authors.lastname: de Luca
authors.forename: Nicola
authors.initials: N
authors.lastname: Di Renzo
authors.forename: Michele
authors.initials: M
authors.lastname: Maffia
authors.forename: Carlo
authors.initials: C
authors.lastname: Gambacorti-Passerini
authors.forename: Ross
authors.initials: R
authors.lastname: Rinaldi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Gigli
authors.forename: Roberto
authors.initials: R
authors.lastname: Cingolani
authors.forename: Addolorata M L
authors.initials: AM
authors.lastname: Coluccia
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D001854:Bone Marrow Cells / Q000166:cytology; D002214:Capsules / Q000737:chemistry; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003692:Delayed-Action Preparations / Q000737:chemistry*; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D010879:Piperazines / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D011743:Pyrimidines / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D002214:Capsules; D003692:Delayed-Action Preparations; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl