CD19-targeting liposomes containing imatinib efficiently kill Philadelphia chromosome-positive acute lymphoblastic leukemia cells

Abstract

Patients with Philadelphia chromosomepositive acute lymphoblastic leukemia (Ph ؉ ALL) have poor prognosis despite intensive therapeutic intervention. Recently, imatinib, a BCR-ABL tyrosine kinase inhibitor, has been proven to be an effective treatment for Ph ؉ ALL, but nearly all patients rapidly acquire resistance. High-dose imatinib administration might overcome this resistance; however, systemic toxicities would likely limit this approach. Therefore, a new delivery system allowing for the specific targeting of imatinib is urgently needed. Because almost all Ph ؉ ALL cells express CD19 on their surface, we have developed an immunoliposome carrying anti-CD19 antibody (CD19-liposomes). The internalization efficiency of the CD19-liposomes approached 100% in all Ph ؉ ALL cells but was very low in CD19 ؊ cells. The cytocidal effect of imatinib-encapsulated CD19-liposomes (imatinib-CD19-liposomes) on Ph ؉ ALL cell lines and primary leukemia cells from patients with Ph ؉ ALL was much greater than that of imatinib with or without control liposomes. Importantly, the imatinib-CD19-liposomes did not affect the colony formation of CD34 ؉ hematopoietic cells, even at inhibitory concentration of free imatinib. Taken together, these data clearly demonstrate that the imatinib-CD19-liposomes induced specific and efficient death of Ph ؉ ALL cells. This new therapeutic approach might be a useful treatment for Ph ؉ ALL with fewer side effects than free imatinib. IntroductionDespite the successes of high-dose chemotherapy followed by hematopoietic stem cell transplantation for the treatment of leukemia, Philadelphia chromosome-positive (Ph ϩ ) acute lymphoblastic leukemia (ALL) remains refractory to most therapeutic modalities currently available. The Philadelphia chromosome includes one of several forms of fusion genes between bcr and c-abl, and these fusions play a substantial role in the pathogenesis of chronic myelogenous leukemia (CML) and ALL. 1 The p190 bcr-abl fusion gene is detected in 20% to 35% of patients with ALL, and the prognosis of these patients is particularly poor. [2][3][4] Allogenic stem cell transplantation is the only curative therapeutic option today. Long-term survival rates are between 35% and 65% in cases of first complete remissions, but survival rates quickly decline in cases of second and third remissions. [4][5][6][7][8][9] Additionally, the relapse rate for Ph ϩ ALL remains quite high even with transplantation. [4][5][6][7][8][9] Recently, targeted molecular therapy has been introduced to treat such refractory cases, and a BCR-ABL tyrosine kinase inhibitor, imatinib (Glivec, STI571), proved to be a useful agent for Ph ϩ ALL as well as CML. 10 However, in contrast to patients with CML, most of the patients with Ph ϩ ALL quickly become resistant to imatinib. 10,11 In a phase 2 clinical trial examining cases of relapsed or refractory Ph ϩ ALL, only 6% of patients maintained a complete response for more than 4 weeks, in contrast to an overall response rate of 29%. 12 Moreover, the median estimated time...

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Combination of ultrasound and bubble liposome enhance the effect of doxorubicin and inhibit murine osteosarcoma growth

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