Targeting leukemic stem cells with multifunctional bioactive polypeptide nanoparticles.

Abstract

10.2217/FON.15.31 © 2015 Future Medicine Ltd RNA interference (RNAi) using synthetic small interfering RNA (siRNA) is being explored as a potential therapeutic strategy in oncology for silencing the expression of specific mRNA species that have been linked to chemotherapy resistance of cancer cells [1–9]. Systemically administered unformulated siRNA lack RNAi activity in vivo due to rapid enzymatic degradation in blood and very poor entry into target cells. As nanoparticles (NPs) can protect siRNA from degradation, facilitate their cellular uptake by endocytosis and enable an effective RNAi by allowing the endosomal escape of the endocytosed siRNA into the cytoplasm, they are generally considered the appropriate delivery platforms for siRNA as a new class of therapeutic agents against otherwise undruggable molecular targets. Several nanoscale formulation platforms have been developed for systemic delivery of siRNA [1–9]. However, a rapid development of nanoscale RNAi therapeutics has been hampered by the limited knowledge about the identity of the critical driver lesions in specific types of cancer, safety concerns about certain formulations and a very poor siRNA delivery efficiency into the target cancer cells. There is an urgent and unmet need to develop novel materials and delivery systems capable of safely and efficiently delivering siRNA to molecular targets in the most common cancer types. B-precursor acute lymphoblastic leukemia (ALL) is the most common cancer type and the most common cause of cancer-related deaths in children [10,11]. Leukemic clones in aggressive forms of pediatric B-precursor ALL are characterized by a genetic defect involving CD22, a negative regulator of signal transduction pathways controlling proliferation and survival [12–16]. Specifically, B-precursor ALL cells express an abnormal CD22 due to deletion of exon 12 (CD22ΔE12) [12,13]. Forced expression of the mutant CD22ΔE12 protein in transgenic (Tg) mice in early B-cell ontogeny causes fatal CD19CD24 CD45R/B220 CD127/ COMMENTARY