Intracellular delivery of anti-BCR/ABL antibody by PLGA nanoparticles suppresses the oncogenesis of chronic myeloid leukemia cells

Abstract

Background The pathogenesis of chronic myeloid leukemia (CML) is the formation of the BCR/ABL protein, which is encoded by the bcr/abl fusion gene, possessing abnormal tyrosine kinase activity. Despite the wide application of tyrosine kinase inhibitors (TKIs) in CML treatment, TKIs drug resistance or intolerance limits their further usage in a subset of patients. Furthermore, TKIs inhibit the tyrosine kinase activity of the BCR/ABL oncoprotein while failing to eliminate the pathologenic oncoprotein. To develop alternative strategies for CML treatment using therapeutic antibodies, and to address the issue that antibodies cannot pass through cell membranes, we have established a novel intracellular delivery of anti-BCR/ABL antibodies, which serves as a prerequisite for CML therapy. Methods Anti-BCR/ABL antibodies were encapsulated in poly(d, l-lactide-co-glycolide) nanoparticles (PLGA NPs) by a double emulsion method, and transferrin was labeled on the surface of the nanoparticles (Ab@Tf-Cou6-PLGA NPs). The characteristics of nanoparticles were measured by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Cellular uptake of nanoparticles was measured by flow cytometry (FCM). The effect of nanoparticles on the apoptosis and proliferation of CML cells was testified by FCM and CCK-8 assay. In addition, the anti-cancer impact of nanoparticles was evaluated in mouse models of CML. Results The results demonstrated that the Ab@Tf-Cou6-PLGA NPs functioned as an intracellular deliverer of antibodies, and exhibited an excellent effect on degrading BCR/ABL oncoprotein in CML cells via the Trim-Away pathway. Treatment with Ab@Tf-Cou6-PLGA NPs inhibited the proliferation and induced the apoptosis of CML cells in vitro as well as impaired the oncogenesis ability of CML cells in vivo. Conclusions In conclusion, our study indicated that this approach achieved safe and efficient intracellular delivery of antibodies and degraded BCR/ABL oncoprotein via the Trim-Away pathway, which provides a promising therapeutic strategy for CML patients, particularly those with TKI resistance.

Intracellular Delivery of Anti-Kirsten Rat Sarcoma Antibodies Mediated by Polymeric Micelles Exerts Strong In Vitro and In Vivo Anti-Tumorigenic Activity in Kirsten Rat Sarcoma-Mutated Cancers

“…Nevertheless, intravenous administration of antibodies could elicit the development of antidrug antibodies, which may interfere with its therapeutic response . In order to reduce the immunogenic response to intravenously administered antibodies, in the last few years, a number of nanoplatforms have been developed for the intracellular release of antibodies or fragments, involving mesoporous silica nanoparticles and poly­( d , l -lactide- co -glycolide), among others. We propose the Pluronic F127-based PMs as an antibody delivery system since these PMs present an easy and low-cost production, are biodegradable, biocompatible, and non-immunogenic .…”

KIAA1429 regulates the expression of RAB27B in a m6A YTHDF1 axis-dependent manner and promotes the progression of chronic myeloid leukemia, serving as a potential therapeutic target

“…Thus, both genetic and epigenetic factors could in uence the therapeutic e cacy of CML treatment. Notably, novel targets such as m 6 A modi cation may play an active role in inhibiting tumor progression and drug resistance [27,42,43] . Previously, several inhibitors of m 6 A regulatory factors have been developed as anti-cancer drugs with positive effects.…”

Trim-Away in adult animals through Nano-ERASER and its application in cancer therapy

“…Attributed to its merit in highly selective and rapidly degrading intracellular protein, A broad spectrum of proteins have been successfully down-regulated in various cells with Trim-Away. [1][2][3][4][5][6][7] Despite being broadly explored in vitro, the in vivo application of Trim-Away is limited in oocyte and zygote stages due to the lack of a practical approach to delivering antibodies in animal models, not to mention in humans for treating diseases. [2][3][4][5][6][8][9][10][11] By far, the intracellular delivery of antibodies in most Trim-Away applications was realized through micro-injection and electroporation, which are impractical for an in vivo setting.…”