Evidence map›Paper›PMID 37543290›Full record

ArticleJournal of controlled release : official journal of the Controlled Release Society2023

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 and 11 more

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal of controlled release : official journal of the Controlled Release Society, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.

0numbers the graph read from it
0cells of the map it votes in
4citing papers in PubMed
1.4field-weighted citation impact, top 18% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

4 citing papers in PubMed, 5 citations in OpenAlex.

  1. Review
  2. Review
  3. Small Molecule Tyrosine Kinase Inhibitors (TKIs) for Glioblastoma Treatment.International journal of molecular sciences · 2024
    Review
  4. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

21 authors at 4 institutions in 1 country.

James M KelvinCoulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30322, USA.
Madison L ChimentiDepartment of Pediatrics, Emory School of Medicine, Atlanta, GA 30322, USA.
Dan Y ZhangWoodruff 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.
Evelyn K WilliamsCoulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30322, USA.
Samuel G MooreSystems Mass Spectrometry Core Facility, Georgia Institute of Technology, Atlanta, GA 30332, USA.
Gabrielle M HumberDepartment of Pediatrics, Emory School of Medicine, Atlanta, GA 30322, USA.
Travon A BaxterDepartment of Pediatrics, Emory School of Medicine, Atlanta, GA 30322, USA.
Lacey A BirnbaumCoulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30322, USA.
Min QuiDepartment of Pharmacology and Chemical Biology, Emory Chemical Biology Discovery Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
Henry ZeccaDepartment of Chemistry, Emory University, Atlanta, GA 30322, USA.
Aashis ThapaDepartment of Pediatrics, Emory School of Medicine, Atlanta, GA 30322, USA.
Juhi JainDepartment 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.
Nathan T JuiPetit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA; Department of Chemistry, Emory University, Atlanta, GA 30322, USA.
Xiaodong WangCenter 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.
Haian FuDepartment 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.
Yuhong DuDepartment 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.
Melissa L KempCoulter 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.
Wilbur A LamCoulter 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.
Douglas K GrahamDepartment 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.
Deborah DeRyckereDepartment 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.
Erik C DreadenCoulter 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.
Emory University · USGeorgia Institute of Technology · USEmory Healthcare · USUniversity of North Carolina at Chapel Hill · US

Funding

T32 Research Training Program in ImmunoEngineeringT32EB021962 · NIBIB · GEORGIA INSTITUTE OF TECHNOLOGY · PI JULIA E BABENSEE · 2017 to 2026
$1.9M
NIBIB NIH HHS T32 EB021962
6 · The paper itself

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.

Indexed as

Leukemia, T-CellPrecursor Cell Lymphoblastic Leukemia-LymphomaPrecursor T-Cell Lymphoblastic Leukemia-LymphomaAnimalsAntineoplastic Combined Chemotherapy ProtocolsCell CycleHumansMiceProtein Kinase InhibitorsVincristineProtein Kinase InhibitorsVincristineCombination therapyDrug deliveryDrug screeningLipid nanoparticleNanotechnologySynergy

Identifiers

PMID37543290
PMCPMC10544718
OpenAlexW4385616396

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.