Development of constitutively synergistic nanoformulations to enhance chemosensitivity in T-cell leukemia

James M Kelvin; Madison L Chimenti; Dan Y Zhang; Evelyn K Williams; Samuel G Moore; Gabrielle M Humber; Travon A Baxter; Lacey A Birnbaum; Min Qui; Henry Zecca; Aashis Thapa; Juhi Jain; Nathan T Jui; Xiaodong Wang; Haian Fu; Yuhong Du; Melissa L Kemp; Wilbur A Lam; Douglas K Graham; Deborah DeRyckere; Erik C Dreaden

doi:10.1016/j.jconrel.2023.07.045

Development of constitutively synergistic nanoformulations to enhance chemosensitivity in T-cell leukemia

J Control Release. 2023 Sep:361:470-482. doi: 10.1016/j.jconrel.2023.07.045. Epub 2023 Aug 14.

Authors

James M Kelvin¹, Madison L Chimenti², Dan Y Zhang³, Evelyn K Williams¹, Samuel G Moore⁴, Gabrielle M Humber², Travon A Baxter², Lacey A Birnbaum¹, Min Qui⁵, Henry Zecca⁶, Aashis Thapa², Juhi Jain⁷, Nathan T Jui⁸, Xiaodong Wang⁹, Haian Fu¹⁰, Yuhong Du¹⁰, Melissa L Kemp¹¹, Wilbur A Lam¹², Douglas K Graham⁷, Deborah DeRyckere¹³, Erik C Dreaden¹⁴

Affiliations

¹ Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30322, USA.
² Department of Pediatrics, Emory School of Medicine, Atlanta, GA 30322, USA.
³ Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA; Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA.
⁴ Systems Mass Spectrometry Core Facility, Georgia Institute of Technology, Atlanta, GA 30332, USA.
⁵ Department of Pharmacology and Chemical Biology, Emory Chemical Biology Discovery Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
⁶ Department of Chemistry, Emory University, Atlanta, GA 30322, USA.
⁷ Department of Pediatrics, Emory School of Medicine, Atlanta, GA 30322, USA; Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, GA 30322, USA.
⁸ Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA; Department of Chemistry, Emory University, Atlanta, GA 30322, USA.
⁹ Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
¹⁰ Department of Pharmacology and Chemical Biology, Emory Chemical Biology Discovery Center, Emory University School of Medicine, Atlanta, GA 30322, USA; Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA.
¹¹ Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30322, USA; Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA; Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA.
¹² Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30322, USA; Department of Pediatrics, Emory School of Medicine, Atlanta, GA 30322, USA; Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA; Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, GA 30322, USA; Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA.
¹³ Department of Pediatrics, Emory School of Medicine, Atlanta, GA 30322, USA; Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, GA 30322, USA. Electronic address: deborah.deryckere@emory.edu.
¹⁴ Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30322, USA; Department of Pediatrics, Emory School of Medicine, Atlanta, GA 30322, USA; Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA; Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, GA 30322, USA; Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA. Electronic address: e.dreaden@emory.edu.

Abstract

Advances in multiagent chemotherapy have led to recent improvements in survival for patients with acute lymphoblastic leukemia (ALL); however, a significant fraction do not respond to frontline chemotherapy or later relapse with recurrent disease, after which long-term survival rates remain low. To develop new, effective treatment options for these patients, we conducted a series of high-throughput combination drug screens to identify chemotherapies that synergize in a lineage-specific manner with MRX-2843, a small molecule dual MERTK and FLT3 kinase inhibitor currently in clinical testing for treatment of relapsed/refractory leukemias and solid tumors. Using experimental and computational approaches, we found that MRX-2843 synergized strongly-and in a ratio-dependent manner-with vincristine to inhibit both B-ALL and T-ALL cell line expansion. Based on these findings, we developed multiagent lipid nanoparticle formulations of these drugs that not only delivered defined drug ratios intracellularly in T-ALL, but also improved anti-leukemia activity following drug encapsulation. Synergistic and additive interactions were recapitulated in primary T-ALL patient samples treated with MRX-2843 and vincristine nanoparticle formulations, suggesting their clinical relevance. Moreover, the nanoparticle formulations reduced disease burden and prolonged survival in an orthotopic murine xenograft model of early thymic precursor T-ALL (ETP-ALL), with both agents contributing to therapeutic activity in a dose-dependent manner. In contrast, nanoparticles containing MRX-2843 alone were ineffective in this model. Thus, MRX-2843 increased the sensitivity of ETP-ALL cells to vincristine in vivo. In this context, the additive particles, containing a higher dose of MRX-2843, provided more effective disease control than the synergistic particles. In contrast, particles containing an even higher, antagonistic ratio of MRX-2843 and vincristine were less effective. Thus, both the drug dose and the ratio-dependent interaction between MRX-2843 and vincristine significantly impacted therapeutic activity in vivo. Together, these findings present a systematic approach to high-throughput combination drug screening and multiagent drug delivery that maximizes the therapeutic potential of combined MRX-2843 and vincristine in T-ALL and describe a novel translational agent that could be used to enhance therapeutic responses to vincristine in patients with T-ALL. This broadly generalizable approach could also be applied to develop other constitutively synergistic combination products for the treatment of cancer and other diseases.

Keywords: Combination therapy; Drug delivery; Drug screening; Lipid nanoparticle; Nanotechnology; Synergy.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Antineoplastic Combined Chemotherapy Protocols / therapeutic use
Cell Cycle
Humans
Leukemia, T-Cell* / drug therapy
Mice
Precursor Cell Lymphoblastic Leukemia-Lymphoma* / drug therapy
Precursor Cell Lymphoblastic Leukemia-Lymphoma* / pathology
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma* / drug therapy
Protein Kinase Inhibitors / pharmacology
Vincristine / therapeutic use

Substances

Vincristine
Protein Kinase Inhibitors

Grants and funding

T32 EB021962/EB/NIBIB NIH HHS/United States