Nanoparticle targeted therapy against childhood acute lymphoblastic leukemia

Abstract

The goal of our project is to develop a unique ligand-conjugated nanoparticle (NP) therapy against childhood acute lymphoblastic leukemia (ALL). LLP2A, discovered by Dr. Kit Lam, is a high-affinity and high-specificity peptidomimetic ligand against an activated α4β1 integrin. Our study using 11 fresh primary ALL samples (10 precursor B ALL and 1 T ALL) showed that childhood ALL cells expressed activated α4β1 integrin and bound to LLP2A. Normal hematopoietic cells such as activated lymphocytes and monocytes expressed activated α4β1 integrin; however, normal hematopoietic stem cells showed low expression of α4β1 integrin. Therefore, we believe that LLP2A can be used as a targeted therapy for childhood ALL. The Lam lab has developed novel telodendrimer-based nanoparticles (NPs) which can carry drugs efficiently. We have also developed a human leukemia mouse model using immunodeficient NOD/SCID/IL2Rγ null mice engrafted with primary childhood ALL cells from our patients. LLP2A-conjugated NPs will be evaluated both in vitro and in vivo using primary leukemia cells and this mouse model. NPs will be loaded first with DiD near infra-red dye, and then with the chemotherapeutic agents daunorubicin or vincristine. Both drugs are mainstays of current chemotherapy for childhood ALL. Targeting properties of LLP2A-conjugated NPs will be evaluated by fluorescent microscopy, flow cytometry, MTS assay, and mouse survival after treatment. We expect that LLP2A-conjugated NPs will be preferentially delivered and endocytosed to leukemia cells as an effective targeted therapy.

Nanotechnology-based diagnostics and therapeutics in acute lymphoblastic leukemia: a systematic review of preclinical studies

“…Therefore, the uptake of normal cells or off-target destruction diminishes. 6,12,15,16,121,124,125 All of the targeting tactics applied in the literature reviewed have been presented in Table 2. A higher chemotherapeutic drug concentration, longer exposure duration, and ultimately enhanced cytotoxicity arise from high absorption of the targeted particles by leukemia cells.…”

“… 126 Due to the upregulation of receptors on the surface of cancer cells, targeted nanoparticles can discriminate between cancer and normal cells. 95 In this review, we can point to some peptidomimetic ligands with high affinity and high specificity like LLP2A against activated α4β1 integrin, 125 a nonapeptide for CD21 (CR2), 135 and heptapeptide DT7, as a new target for the transferrin receptor (TFR or CD71 which is highly expressed in T-ALL cell lines). 136 …”

In vitro and in vivo Effects of Free and Chalcones-Loaded Nanoemulsions: Insights and Challenges in Targeted Cancer Chemotherapies

“…Many works have demonstrated the importance of lipoprotein and folate receptors in the uptake of nanoparticles loaded with different drugs [ 38 , 39 , 40 , 41 ]. Satake and collaborators developed a nanoparticle with a peptidomimetic ligand (LLP2A) targeted against an activated α4β1 integrin, which is highly expressed in childhood ALL [ 42 ]. CD22 is a receptor B-cell-specific and have been studied as a novel approach for targeting B-cell leukemias.…”