Cooperation of IRAK1/4 inhibitor and ABT-737 in nanoparticles for synergistic therapy of T cell acute lymphoblastic leukemia

Wu, Xiaoyan; Wang, Lin; Qiu, Yining; Zhang, Bingyu; Hu, Zhenhua; Jin, Runming

doi:10.2147/ijn.s146875

Cited by 12 publications

(25 citation statements)

References 35 publications

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“…To generate the human cell line xenograft in ALL mouse model, we injected Jurkat cells (1 × 10 6 cells) into the tail veins of the female NPG mice. 28 After 7 days, we randomly placed the mice in three groups. Over the course of 2 weeks, 6-MPNs and 6-MPCs were administered at 20 mg/kg once daily by oral gavage (n = 6), and PBS was administered as the control.…”

Section: Methodsmentioning

confidence: 99%

Preparation, Characterization, Pharmacokinetic, and Therapeutic Potential of Novel 6-Mercaptopurine-Loaded Oral Nanomedicines for Acute Lymphoblastic Leukemia

Zou¹,

Mei²,

Yuan³

et al. 2021

IJN

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Background Acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy in children. It requires a long and rigorous course of chemotherapy treatments. 6-Mercaptopurine (6-MP) is one of the primary drugs used in chemotherapy. Unfortunately, its efficacy has been limited due to its insolubility, poor bioavailability and serious adverse effects. To overcome these drawbacks, we constructed 6-mercaptopurine (6-MP)-loaded nanomedicines (6-MPNs) with biodegradable poly(lactide-co-glycolide) (PLGA) to enhance the anticancer efficacy of 6-MP. Methods We prepared the 6-MPNs using a double-emulsion solvent evaporation method, characterizing them for the physicochemical properties. We then investigated the plasma, intestinal region and other organs in Sprague Dawley (SD) rats for pharmacokinetics. Additionally, we evaluated its anticancer efficacy in vitro on the human T leukemia cell line Jurkat and in vivo on the ALL model mice. Results The 6-MPNs were spherical in shape with uniform particle size and high encapsulation efficiency. The in vitro release profile showed that 6-MPNs exhibited a burst release that a sustained release phase then followed. The apoptosis assay demonstrated that 6-MPNs could improve the in vitro cytotoxicity in Jurkat cells. Pharmacokinetics profiles revealed that 6-MPNs had improved oral bioavailability. Tissue distribution experiments indicated that 6-MPNs increased the duodenum absorption of 6-MP, at the same time having a low accumulation of the toxic metabolites of 6-MP. The in vivo pharmacodynamics study revealed that 6-MPNs could prolong the survival time of the ALL model mice. The prepared 6-MPNs, therefore, have superior properties in terms of anticancer efficacy against ALL with reduced systemic toxicity. Conclusion Our nanomedicines provide a promising delivery strategy for 6-MP; they offer a simple preparation method and high significance for clinical translation.

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Section: Methodsmentioning

confidence: 99%

Preparation, Characterization, Pharmacokinetic, and Therapeutic Potential of Novel 6-Mercaptopurine-Loaded Oral Nanomedicines for Acute Lymphoblastic Leukemia

Zou¹,

Mei²,

Yuan³

et al. 2021

IJN

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“…Most reports focus on drug delivery to the T cell surface, thus not requiring nanoparticle internalization. 14,[167][168][169]171 Although this is a valuable approach for drugs that can be delivered to the cell surface, in this review, we focus on strategies for nanoparticle-mediated intracellular drug delivery to T cells, noting that most reported studies originate from the field of oncology 19,26,140,144,[172][173][174][175][176][177] and HIV. [178][179][180][181][182][183] For a detailed listing of the studies described in this section, see Table 2.…”

Section: Nanoparticle-mediated Drug Delivery To T Cells: Successes To...mentioning

confidence: 99%

“…Despite the importance of T cells in various diseases, there are relatively few studies exploring direct T cell-targeted drug delivery using nanoparticles. Most reports focus on drug delivery to the T cell surface, thus not requiring nanoparticle internalization. ,− , Although this is a valuable approach for drugs that can be delivered to the cell surface, in this review, we focus on strategies for nanoparticle-mediated intracellular drug delivery to T cells, noting that most reported studies originate from the field of oncology ,,,,− and HIV. − For a detailed listing of the studies described in this section, see Table .…”

Section: Nanoparticle-mediated Drug Delivery To T Cells: Successes To...mentioning

confidence: 99%

“…Only a selection of these studies discuss the mechanism of drug release from the nanomaterial. Most of the studies report a sustained drug release over time, ,,,, which in one study is shown to be further triggered after nanoparticle internalization . Drug release from gold nanoparticles has been described to be pH-dependent , or triggered by endosomal cleavage of the nanoparticle shell …”

Section: Nanoparticle-mediated Drug Delivery To T Cells: Successes To...mentioning

confidence: 99%

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In Vivo T Cell-Targeting Nanoparticle Drug Delivery Systems: Considerations for Rational Design

et al. 2021

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T cells play an important role in immunity and repair and are implicated in diseases, including blood cancers, viral infections, and inflammation, making them attractive targets for the treatment and prevention of diseases. Over recent years, the advent of nanomedicine has shown an increase in studies that use nanoparticles as carriers to deliver therapeutic cargo to T cells for ex vivo and in vivo applications. Nanoparticle-based delivery has several advantages, including the ability to load and protect a variety of drugs, control drug release, improve drug pharmacokinetics and biodistribution, and site-or cell-specific targeting. However, the delivery of nanoparticles to T cells remains a major technological challenge, which is primarily due to the nonphagocytic nature of T cells. In this review, we discuss the physiological barriers to effective T cell targeting and describe the different approaches used to deliver cargo-loaded nanoparticles to T cells for the treatment of disease such as T cell lymphoma and human immunodeficiency virus (HIV). In particular, engineering strategies aiming to improve nanoparticle internalization by T cells, including ligand-based targeting, will be highlighted. These nanoparticle engineering approaches are expected to inspire the development of effective nanomaterials that can target or manipulate the function of T cells for the treatment of T cell-related diseases.

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“…To improve the solubility and bioavailability of ABT-737, two different research teams have encapsulated the drug in nanoparticles (NPs). , Schmid et al . showed that encapsulating ABT-737 in PEGylated polymeric NPs could reduce the thrombocytopenia associated with delivery of the free drug .…”

mentioning

confidence: 99%

Nanoparticle-Mediated Co-Delivery of Notch-1 Antibodies and ABT-737 as a Potent Treatment Strategy for Triple-Negative Breast Cancer

et al. 2020

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Triple-negative breast cancer (TNBC) accounts for nearly one-quarter of all breast cancer cases, but effective targeted therapies for this disease remain elusive because TNBC cells lack expression of the three most common receptors seen on other subtypes of breast cancer. Here, we exploit TNBC cells’ overexpression of Notch-1 receptors and Bcl-2 anti-apoptotic proteins to provide an effective targeted therapy. Prior studies have shown that the small molecule drug ABT-737, which inhibits Bcl-2 to reinstate apoptotic signaling, is a promising candidate for TNBC therapy. However, ABT-737 is poorly soluble in aqueous conditions, and its orally bioavailable derivative causes severe thrombocytopenia. To enable targeted delivery of ABT-737 to TNBC and enhance its therapeutic efficacy, we encapsulated the drug in poly(lactic-co-glycolic acid) nanoparticles (NPs) that were functionalized with Notch-1 antibodies to produce N1-ABT-NPs. The antibodies in this NP platform enable both TNBC cell-specific binding and suppression of Notch signaling within TNBC cells by locking the Notch-1 receptors in a ligand unresponsive state. This Notch inhibition potentiates the effect of ABT-737 by up-regulating Noxa, resulting in effective killing of TNBC cells. We present the results of in vitro studies that demonstrate N1-ABT-NPs can preferentially bind TNBC cells versus noncancerous breast epithelial cells to effectively regulate Bcl-2 and Notch signaling to induce cell death. Further, we show that N1-ABT-NPs can accumulate in subcutaneous TNBC xenograft tumors in mice following systemic administration to reduce tumor burden and extend animal survival. Together, these findings demonstrate that NP-mediated co-delivery of Notch-1 antibodies and ABT-737 is a potent treatment strategy for TNBC that may improve patient outcomes with further development and implementation.

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Cooperation of IRAK1/4 inhibitor and ABT-737 in nanoparticles for synergistic therapy of T cell acute lymphoblastic leukemia

Cited by 12 publications

References 35 publications

Preparation, Characterization, Pharmacokinetic, and Therapeutic Potential of Novel 6-Mercaptopurine-Loaded Oral Nanomedicines for Acute Lymphoblastic Leukemia

Preparation, Characterization, Pharmacokinetic, and Therapeutic Potential of Novel 6-Mercaptopurine-Loaded Oral Nanomedicines for Acute Lymphoblastic Leukemia

In Vivo T Cell-Targeting Nanoparticle Drug Delivery Systems: Considerations for Rational Design

Nanoparticle-Mediated Co-Delivery of Notch-1 Antibodies and ABT-737 as a Potent Treatment Strategy for Triple-Negative Breast Cancer

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